IL25931A

IL25931A - New 4-or 5-nitro imidazole and 5,6-dihydroimidazo(1,2-a)pyrrol-7-yl-carbamates and pseudo thioureido imidazoles and their preparation

Info

Publication number: IL25931A
Application number: IL25931A
Authority: IL
Original assignee: Merck & Co Inc
Priority date: 1965-07-07
Filing date: 1966-06-08
Publication date: 1972-01-27
Also published as: FI46961C; GB1154290A; CY565A; GB1155530A; NL6609552A; BR6681050D0; FR5890M; MY7100055A; JPS5138718B1; BE683796A; DE1620018B2; AT284114B; AT291989B; ES329085A1; DK141287B; GB1155529A; AT291990B; NO122186B; AT294487B; SE343578B

Description

25931/2 New 4 or 5-nitro imidazole and 5»6-dihydro-i^dazo[l>2^]pyrrol-7»yl-carDainates and pseudo thioureido imidazoles and their preparation . & co, inc., C:24720 - 2 - 25931/2 This invention relates to imidazole carbamates and acid addition salts thereof* to methods for their production and to antiparasitic compositions containing them.

The compounds according to the invention are l-substituted-5(4)-nitroimidassol-2-ylalkyl carbamates, 2(3)-nitro-5»6«dihydroimldazo[l,2:a]-pyrrol-7-yl carbamates and ^-substituted carbamates, thloureldo imidazoles and acid addition salts of these compounds.

The novel compounds of this invention may be represented by the following structural formulae: W W X wherein R^* is or hydroxyalkyl and is alkyl, suitably loweralkyl, such as, methyl, ethyl, propyl, butyl or pentyl; phenyl, or p-nltropheny ; or alkyl substituted by;oxo; alk enyl; halo; phenylalkanoyloxy, suitably loweralkanoyl-oxy, for example, acetoxy, propionoxy, butyryloxy, or valeryloxy; aralkanoyloxy, suitably phenylalkanoyloxy, such as, phenylacetox j benzoyloxy; alkoxy, suitably loweralkoxy, such as methoxy, propoxy, or butoxy; phenyl-loweralkoxy, suitably, benzyloxy; carboalkoxy, such as, carboloweralkoxy, preferably, carbomethoxy, carboethoxy and carbopropoxy» carbamoyl and N-mono- or db-substituted carbamoyl, wherein the substituent is alkyl, suitably loweralkyl, such as, methyl, propyl, butyl and pentyl; phenyl, phenylloweralkyl, such as benzyl^ carbamoyloxy ; - 3 - 25931/2 cyano; thio-, sulfinyl- or sulfonyl, substituted by alk l, suitably lower alk l, such as ethyl, propyl and butyl, phenylloweralkyl, such as benzyl, or phenyl*, and mono- or dialkylamino or an optionally alkyl substituted saturated 5- or 6- membered heterocyclic amino group^ which may contain a further N,G or S heteroatom; represents nltro, cyano, phenyl, chlorophenyl or hydrogen and P represents hydrogen or nitro, provided that one of the groups and P is Q is alk lene, such as, loweralkylene suitably methylene* propylene, butylene and ethylene; alk lidene such as loweralkylidene suitably ethylidene, propylldene and butylidene; alkenylene such as loweralkenylene suitably propenylene and aralkylidene suitably phenylloweralkylid-ene, for example, phenylmethylene.

T is carbamo lox , carbamo lthio, thion^arbamoyl-oxy, thiocarbamoylthio, pseudo-ureido, pseudo-thioureido, and the N-substituted and N»N-disubstituted derivatives thereof. The group T may be represented by the structure where M is oxygen, sulfur,imino or alkylimino.

A is oxygen or sulfur, and and include the following! hydrogen; alkyl, suitably loweralkyl, such as, methyl, ethyl, propyl or butyl, or substituted alkyl, wherein the substituenta of the alkyl group may be trihalo halo, pol-ybal-o, hydroxy; - 4 - 259312 (trihojo, hydroxy) alkoxy (halo, hydroxy)/or(polykale, hydroxy^T" such as (trichloro, hydroxy), (trifluoro, hydroxy) and (tribromo, hydroxy); alkoxy, suitably loweralkoxy, such as methoxy, propoxy, or butoxy; oxo; (aryl, oxo), such as (phenyl, oxo); carboxy, carboalkoxy, suitably carboloweralkoxy such as, carbomethoxy, carboethoxy and carbopropoxy; alkanoyloxy such as, loweralkanoyloxy, suitably acetoxy, propionoxy or haloloweralkanoyloxy such as triOuoroacetoxy or butyroxy/; aralkano lox , for example, phen lloweralkanoy1-oxy, such as, benzoyloxy; carbamoyl, or sulfamoyl and the N-mono or N,Jti-disubstituted derivatives thereof wherein the N-substituents may be: alkyl, such as, methyl, propyl, pentyl, aryl, such as phenyl or aralkyl such as phenylloweralkyl i.e. benzyl; mercapto and substituted mercapto wherein the substituents may bet alkyl, sue/, as, loweralkyl, for example, methyl, ethyl, and propyl and aralkyl, suitably phenyl-loweralkyl, such as benzyl; thionocarbamoyl; N-mono or Ν,Ν-disubstituted thionocarbamoyl, wherein the substituents may be: N,N-dialkyl, such as Ν,Ν-dimethyl, N,N-diethyl, Ε,Μ-dipropyl, Μ,Κ-diaralkyl, such as fi,N-di(phenylloweralkyl) , suitably N,K-dibenzyl; amino; or substituted amino, wherein the substituents may be: alkyl, suitably diloweralkyl, such as dimethyl, dibutyl, dipentyl or dlaralkyl, such as di(phenyl-loweralkyl), suitably dibenzyl; or a saturated 5 or 6 aiembered heterocyclicamino group, for example, morpholino, thiamorpholino, piperidino, piperazino, 4-methyl-piperazino, - 5 - 25 31/ Imldazolidlno, and pyrrolldino; phenyl, and halo, nitro or alkyl substituted phenyl such as nitrophenyl, chlorophenyl, luorophenyl or alkyl-phenyl; alk lene; phenylalkylene ; alk lidene, substituted by alkoxy, preferably loweralkoxy, such as, methoxy, butoxy and pentoxy; aralkoxy, suitably phenylloweralkoxy such as, benzoxy and aroxy, for example, phenoxy, substituted amino, wherein the sub-stituents may be dialkyl, such as diloweralkyl, such as, dimethyl, dipropyl or dipentyl; diaralkyl, for example di(phenylloweralkyl) , suitably dibenzyl; alkenylene substituted by (carboalkoxy.,. alkyl), such as (carbolo¾eralkoxy¾ loweralkyl), suitably (carbo-racthoxy^methyl) ; ,Η-dlalkyl ormiminium halide wherein the alkyl groups may be loweralkyl, such as, methyl, ethyl or propyl; acyl, for example, alkanoyl, suitably loweralkanoyl, or haloalkanoyl such as chloroacetyl such as, formyl, acetyl, propionyl, butyryl, or valeryli aralkanoyl, suitably phenylloweralkanoyl, sucli as phenyl-acetyl; cyanoalkanoyl, suitably cyanoloweralkanoyl, such as cyanoacetyl or cyanopropionyl; alkenoyl, suitably loweralkenoyl, such as acryloyl or crotonyl; and aroyl, such as benzoyl; hydroxy optionally substituted by: acyl, such as alkanoyl, suitably lower alkanoyl, such as, formyl, acetyl, propionyl, butyryl, or valeryl, aralkanoyl, suitably phenylloweralkanoyl, such as, phenylacetyl; and aroyl, such as benzoyl; alkyl, suitably loweralkyl, for example, methyl, ^ loweralkyl, suitably benzyl and aryl, for example, phenyl; carbamoyl, thlocarbamoyl and substituted carbamoyl or thlocarbamoyl wherein the substituents may be alk l, suitably loweralkyl, for example, methyl, ethyl, butyl and pentyl; aralkyl, such as phenylloweralkyl, suitably benzyl and aryl, for example, phenyl; heterocycloalkyl-carbonyl, wherein the heterocycloalkyl ring contains at least one nitrogen atom bonded to the carbonyl group, suitably a 6- or 5-membered saturated heterocycloalkyl, for example, morpholino, thiamorpholino, piperidino, piper-azino, 4-meth. lpiperazlno and pyrrolidine; nitro; amino and N-mono or ,JN-di( lkyl-, phenyl- or benzyl) substituted amino; -alkanoyl-N-alkanoyloxy , suitably N-loweralkanoyl-N-loweralkanoyloxy, such as, W-acetyl-N-acetoxy, Jtt-prop-ionyl-N-propionox , ft-valeryl-N-valeroxy; -phenyllower-a kanoyl-iv-phenyllowe; alkanoyloxy, such as K-phen lacetyl- K-phenylacetox , N-phenylpropionyl-N-phenylpropionox ; arvlsulfonyl, sulfamoyl,/ alk leulfamoyl, dlalkylsulfamoyl, phenylalk l-sulf moyl; alkylsulfonyl, alk larylsul on 1; bis(alkylamino)phosphor 1, bis(dialkylamino) phosphoryl, bis(phenylamino) hosphory1 and bis(benzylamino) phosphoryl; or R¾ and together with the nitrogen atom to which they are attached form an optionally alkyl-substituted saturated 5- or 6-membered heterocyclic ring wnich may contain a further oxygen, sulfur, imino or alkylimino group, for - 7 - 25931/2 example, a morpholino, thiomorpholino, piperidino, 4-methylpiperazino or pyrrolino group. Furthermore, within the scope of the present invention are thos compounds wherein T has the substructure II for compounds of formula I, wherein A is oxygen or sulfur* and -000Μ-2 for compounds of formula II.

Also within the purview of the invention are acid addition salts of these imidazole carbamates. The salts may be of an inorganic acid such as the hydrochloride, hydrobromide, phosphate, nitrate or sulfate, or of an organic acid, examples of which are the citrate, tartrate, adipate, methanesulfonate, p-toluenesulfonate and the like. Non-toxic acid addition salts, i.e., those tolerated by the host at the dose levels employed, are employed when the carbamates are to be used in their salt form as antiparasitic agents.

The invention also consists in processes for making compounds of formulae I or II froal-substituted-5-nitroimidazoles having at the 2- position of the imidazole ring, a hydroxyalkyl, mercaptoalkyl, alk laulfonyloxyalkyl, alkarylsulfonyloxyalkyl, haloalkyl, halocarbonyloxyalkyl, or halothiocarbonyloxyalkyl radical.

The invention also provides compositions useful against parasitic diseases, for example, trichomoniasis, enterohepatitis and as antihelminthic compositions against accarids and schistosomes containing the compounds of formulae I or II above. Certain of them are also effective 8 - 25931 ϋ against amoebiasis and trypanosomiasis as well s chronic respiratory diseases in fowl caused by PPLO organisms.

Certain of the compositions of the present invention also show antibacterial activity.

The preferred compounds of this invention are the l-substituted-5-nitroimidazol-2-ylalkyl carbamates and substituted carbamates. More speci ically, the preferred compounds are the imldazolylalkyl carbamates of foriaila I wherein is hydrogen, P is nitro, Q is lo eralkylene suitably methylene or ethylene, or loweralkylidene suitably 1-e hylidene, R^ is alkyl or hydroxyalk 1 such as methyl, ethyl or 2-hydroxyethyl and T is the group wherein A is oxygen or sulfur, is oxygen or R 4 sulfur and R^ and R^ are each hydrogen, loweralkyl, hydroxy or loweralkanoyl, or R^, ^ and taken together are heterocycloalkyl. These preferred embodiments will be discussed at more length than others in the description of the invention. The following explanations of processes apply to most substances embraced by the generic formulae I and II. however, it should be understood that these processes do not constitute the preferred processes for certain ^-substitut d carbamates. The preferred processes for this latter class of N-substituted carbamates will be discussed below following the discussion of the principal processes. - 9 - 25931/2 THE Oj-a BAL PROCESSES 1. The, Ieocyanate and Sgolft-kpc a ftlfe Procedy.re One method for making the carbamates is by the reaction of an appropriate ieocyanate or isothiocyanate with a l-subatituted-2-hydroxyalkyl-5-nitroiinidazole or substituted-2-mercaptoalkyl-5-nitroimidazole: 6 7 wherein W , P, Q, A, M, ^ ^ and R^ are aa above. 8 In the preferred modif cation of this process, 9 the significance of the substituents is as follows: W is hydrogen; 11 P is nitro; 12 Q is loweralkylene suitably methylene or ethylene; or 13 lower alkylidene suitably ethylidene; I R^ is lowerallyl suitably methyl, ethyl or propyl or acyloxyalkyl, suitably loweralkanoyloxyalkyl, such as acetoxy- 16 propyl or valeroxyethyl, or aroyloxyalkyl such as benzoyloxy- 17 ethyl or benzoyloxypropyl, R-^is Rx or hydroxyalkyl such as 18 hydroxyethyl or hydroxypropylj 19 A and each represent oxygen or sulfur; R^ represents hydrogen, alkyl, suitably loweralkyl, such 21 as methyl, ethyl or propyl; aryl, such as phenyl aralkyl, 22 suitably arylloweralkyl , such as benzyl; alkoxyalkyl, suit- 23 ably loweralkoxyloweralkyl , such as ethoxyethyl or ethoxy-¾ propyl; haloalkyl suitably haloloweralkyl , such as chloro- 25 ethyl, bromoethyl, o trifluoropropyl; substituted sulfonyl, 26 for example h>lc awl-Tony! , ¾vtcY> aa c lawaiiLf·ηγ ov ¾*ar«o 27 oulffeny- or loweralkyl or arylsulfonyl, such as methane- 28 sulfonyl or p-toluenesulfonyl; 29 di loi epheepTa sgyl; and acyl suitably loweralkanoyl, such as . 1 When it is desired to prepare the 1-hydroxyalkyl 2 imidazolylalkyl carbamates according to this and the other 3 processes described herein, it is necessary to "block" this Ij. 1-substituent during the reaction involving the 2-hydroxy- 5 alkyl or 2-mercaptoalkyl radical of the imidazole, or else 6 the free hydroxy group will react with the isocyanate or 7 isothiocyanate. This "blocking" is conveniently accomplished 8 by esterifying, i.e., by employing a 1-acyloxyalkyl imidazole 9 as starting material, an ester of a loweralkanoic acid or benzoic acid, for example, an ester of acetic acid, propionic 11 acid or benzoic acid, is conveniently employed, for example, 12 the starting material may be l-(2-acetoxyethyl)-2-hydroxy- 13 methyl- -nitroiraidazole, l-(2-propionoxypropyl)-2-mercapto-U{. methyl-5-nitroimidazole or l-(2-benzoyloxyethyl)-2- 1 (1 -hydroxyethyl )-5-nitroimidazole . 16 This esterified radical normally survives the iso- 17 cyanate reaction unchanged under the preferred process 18 conditions, and the resulting l-acyloxyalkylimidazole car- 19 bamate may then be hydrolyzed with base to the corresponding 1-hydrox alkyl carbamate. 21 Where is halosulfonyl or dihalophosphoryl, the 22 carbamate produced in accordance with this process may be 23 readily converted to the corresponding N-sulfaraoyl carbamate 21). or N-diaminophosphoryl carbamate by reaction with ammonia 2 suitably liquid ammonia. If desired, the corresponding 26 -(Ν· -substituted sulfamoyl ) carbamates or N-(N* -substituted 27 diaminophosphoryl)carbamates may be obtained by utilizing 28 a suitable substituted amine in place of ammonia. 29 The isocyanate reaction of the above flow diagram is conveniently brought about by contacting the Imidazole 1 and substituted isocyanate (or isothiocyanate) reactants, 2 preferably in equimolar amounts or with a slight molar 3 excess of isocyanate (or isothiocyanate), in an inert · Ij. solvent medium at a temperature of between about 20-120°C.

Aromatic hydrocarbons such as benzene and toluene, or halo- 6 genated aliphatic hydrocarbons, e.g., dichloro- or tetra- 7 chloroethane are examples of suitable solvents. It is 8 desirable to have present a minor amount of base such as a 9 tertiary amine, e.g., pyridine or triethylamine, or even stronger bases such as alkali metal alkoxides, such as 11 sodium methoxide or potassium ethoxide, since the reaction 12 is base catalyzed. 13 Examples of imidazolylalkyl carbamates which may lij. be obtained in this manner from the appropriate nitro-l£ imidazole are 1-methyl -5-nitroimidazol-2-ylmethyl benzoyl- 16 carbamate, l-methyl-5-nitroimidazol-2-ylmethyl acetyl- 17 carbamate, l- (2 ! -acetoxyethyl) -5-m roimidazol - -ylmethyl 18 ethylcarbamate, 1 -(1 '-ethyl-£' -iiitroimidazol-2 '-yljethyl 19 methylcarbamate, 1-propyl -5-nitroimidazol-2-ylmethyl armate . l-morpholinecarbe9¾¾*fee-, 1-methyl -5-nitroimidazol-2-ylmethyi o 21 methylthiolfearbamate and l-( 2 ' -acetoxypropyl) -5-nitroimid-32 azol-a-ylxaothrl phenylthio&arbsmate. 23 The method may also be used for making carbamates 2I4. where is hydrogen and M is oxygen, in which case the cyanic acid reactant is preferably generated in situ from 26 an alkali metal cyanate, as by addition of acetic or ri- 27 fluoroacetic acid to the reaction mixture. It might be 28 mentioned, however, that other methods described herein 29 &**e generally more satisfactory for making the unaubs ituted carbamates, and further that this particular process is not 1 suitable for preparing the unsubstituted thloncarbamates 2 where R^ in the formula is hydrogen and M is sulfur. 3 ile Alkali Metal Cyanate or Thiocyanate/Acid Procedure Certain of the 1-substituted imIdazol-2-ylalkyl carbamates and thiocarbamates of this invention may be 6 obtained by another process which comprises the reaction 7 of the corresponding l-substituted-2-halomethyl (or 2-alkyl 8 or arylsulfonyloxymethyl ) imidazolyl with an alkali metal 9 cyanate or thiooyanate to produce a l-substItuted-2-cyanato- 10 methyl or 2-thiocyanatomethylimidazo e and treatment of said 11 compound with a mineral acid, preferably sulfuric acid. It 12 is preferred, however, to use this method for the preparation 13 of thiocarbamates rather than carbamates due to the possibil- 1 lty of rearrangement of the cyanato intermediate to an iso-V~> cyanato derivative. This problem is not of practical impor- 16 tance where the thiocyanato intermediate Is concerned. The 17 reaction may be schematically represented as follows: 27 28 wherein W, P, R^, R^»and Q are as above; and X is halo or 29 substituted sulfonyloxy. 1 In the preferred modification of this process, 2 the significance of the substituents is as follows: 3 W is hydrogen i+ P is nitro; > Q is loweralkylene suitably methylene or ethylene; 6 or 1owerallcylidene suitably ethylidene; 7 Ηη is loweralkyl suitably methyl, ethyl or propyl 8 or acyloxyalkyl, suitably loweralkanoyloxyalkyl, such as 9 acetoxypropyl or valeroxyethyl, or aroyloxyalkyl such as 0 benzoyloxyethyl or benzoyloxypropyl , R^'is or hydroxy-1 alk l such as hydroxyeth l or hydroxypropyl; 2 A and M each represent oxygen or sulfur; and 3 X is chloro, mesyl or tosyl, or bromo. 2; It is preferred to affect the reaction with thiocyanate in a solvent medium such as loweralkanol, for 6 example, methanol or ethanol, dimethylformamide, a lower-7 alkanoylnitrile, such as acetonitrile and the like, at a 8 temperature of between about l5°C and about 100°C. The 9 immediate product is a l-substituted-2-thiocyano-5-nitro-0 imidazole, for example, a 1-alkyl or 1-acylox lowe alkyl-1 2-thiocyano-5>-nitroimidazole, such as, a l-methyl, 1-ethyl, 2 or l-acetoxyethyl-2-thiocyano-5-nitroimidazole. A similar 3 product is obtained when there is employed, as starting 2>. material, a 2-alkylsulfonyloxymethyl or 2-arylsul onyloxy-$ methyl imidazole, such as, 2-methylsulfonyloxymethyl or 6 2-p-toluenesulfonyloxymethyl- -nitroimidazole instead of 7 the 2-halomethyl imidazole, such as the corresponding 8 2-chloro or 2-bromomethyl-i?-nitroimidazole« 9 Conversion of the l-substituted-2-thiocyanoalkyl 1 carbamate is conveniently accomplished by contacting it 2 with an excess of strong acid, preferably concentrated 3 sulfuric acid in the cold, for example, at between 0° and Ij. 15°C» The reaction is then quenched in water to precipitate the thiolcarbamate · In those cases where the 1-substituent 6 is acyloxyalkyl, this ester is hydrolyzed to the correspond- 7 ing 1-hydroxyalkyl radical during the sulfuric acid reaction. 8 Examples of compounds prepared in accordance with this 9 procedure include: 1-methyl-5-nitroimidazol-2-ylmethyl thiolcarbamate, l-ethyl-5-nitroimldazol-2-ylmethyl thiol- 11 carbamate and 1-methyl-5-nitroimidazol-2-yleth 1 thiol- 12 carbamate . 13 iii. The Imidazole Halocarbonate Process llj. Still another process for making the carbamates of this invention consists in reaction of the halocarbonate 16 or halothioncarbonate ester of l-substituted-2-hydroxyalkyl 17 (or 2-mercaptoalkyl)-5-nitroimidazole with a primary or 18 secondary amine. The reaction may be schematically repre- 19 sented as follows : $ 26 wherein W, P, Q, A, M, R^, R^' , R^ and R^ are as above, and 27 X is halo. 28 In the preferred modification of this process, the 29 significance of the substituents is as follows: W is hydrogen; 1 P is nitro; 2 Q is loweralkylene suitably methylene or ethylene; 3 or loweralkylidene suitably ethylidene; k- ¾. s loweral¾rl suitably methyl, ethyl or propyl or acyloxyalkyl, suitably loweralkanoyloxyalkyl, such as 6 acetoxypropyl or valeroxyethyl, or aroyloxyalkyl such as 7 benzoyloxyethyl or benzoyloxypropyl , R^f is R^ or hydrox - 8 alkyl such as hydroxyethyl or hydroxypropyl; 9 A and M each represent oxygen or sulfur; X is chloro; 11 and R^ individually represent hydrogen; alkyl, 12 suitably loweralkyl, such as methyl, ethyl or propyl; ap l, 13 ouoh as phenyl; aralkyl , suitably arylloworallcyl , such as llj. benzyl, hydroxyalkyl , suitably hydroxyloweralkyl , such as hydroxypropyl, and hydroxyethyl; alkox lkyl, such as 16 ethoxyethyl or ethoxypropyl; hydroxy; amino; or R, and R} 17 together represent the group 18 is oxygen, sulfur, or N-R^, and is hydrogen or 19 loweralkyl, for example together with the N atom to which R^ and R^ are attached, they represent morpholino, thio- 21 morpholino, piperidino, piperazino, -.-methylpiperazlno or 22 pyrrolidino . 23 The two reactants are contacted in a suitable 2¾. inert solvent Medium such as dioxane, tetrahydrofu n or an 2f? aromatic hydrocarbon, such as, benzene, at a temperature in 26 the range of about 0-75°c » An excess of amine react&nt is 27 generally employed and good results are obtained with from 28 about 2.0-5*0 moles of amine per mole of halocarbonate 29 ester, such as chlorocarbonate ester, at reaction temper- ° 1 be noted that the ester reactants are frequently referred 2 to by those In this art as the haloformate (or halothion- 3 formate) esters of the l-substituted-2-hydroxyalkyl (or.

I4. mercaptoalkyl) -5-nIta*oimidazole. > The molar excess of amine Is desired since It is 6 convenient and customary to use 1 mole of the amine (in 7 addition to the mole needed for the reaction Itself) as an 8 acid binding agent to neutralize the acid formed in the 9 reaction. The haloformate ester starting material may be 0 charged to the reaction in the form of an acid addition 1 salt, and it is then necessary to have another mole of amine 2 to neutralize this salt. As previously indicated, the amine 3 present in the reaction medium may hydrolyze a 1-acyloxy-i+ alkyl imidazole substituent to the corresponding 1-hydroxy-5 alkyl substituent. 6 Amines which are suitable for use in this reaction 7 include ammonia, methylamine, dimethylamine , aniline, benzyl-8 amine, ethanolamine, propanolamine , ethoxyethylamine, ethoxy-9 propylamine, hydroxylamine , hydrazine and morpholine, thia-0 morpholine, piperidine, piperazine, --methylpiperazine and 1 pyrrolidine· 2 When ammonia Is used as the amine reactant to 3 form carbamates where and are both hydrogen, a very ij. large excess is generally used, and frequently liquid ammonia is employed as reaction solvent. When the process 6 Is carried out with ammonia, the reaction temperature may 7 be from about -35°C. (refluxing liquid ammonia) to about 8 room temperature. At the higher temperatures, it is, of 9 course, necessary to use a pressure vessel, or to dissolve 0 the ammonia in an organic solvent such as chloroform or a 1 loweralkanol such as ethanol or methanol. 2 Examples of carbamates which may be prepared in 3 this way from the corresponding chloroformate or chlorothion- I. formate ester are 1-methyl-5-nitroimidazol-2-ylmethyl car- 5? bamate, l-ethyl-5-nitroimidazol-2-ylmethyl carbamate, 6 l-methyl-5-nitroimidazol-2-ylmethyl p-fluorophenylcarbamate, 7 l-methyl-5-nitroimidazol-2-ylmethyl p-chlorophenylcarbamate, 8 1-propyl-5-nitroimidazol-2-ylmethyl p-nitrophenylcarbamate, 9 l-methyl-5-nitroimidazol-2-ylmethyl thio]¾arbamate, 1-methyl- 10 5-nitroimidazol-2-ylmethyl methylcarbamate , l-(2-hydroxy- 11 ethyl)-5-ni roimldazol-2-ylmethyl ethylcarbamate, 12 l-(2-hydroxyethyl)-5--itroimidazol-2-ylmethyl carbamate, 13 l-methyl- -nitroimidazol-2-ylmethyl methylethylcarbamate, ¾. l-(l-ethyl-£-nitroimidazol-2-yl) -ethyl ethylcarbamate, 1-methyl-5-nitroimidazol-2-ylmethyl methox ethylcarbam e 16 and l-(l-methyl-5-nitroimidazol-2-yl)ethyl methylthion 17 carbamate. 18 iv. Preparation of Imidazole Halocarbonate 19 The imidazole chlorocarbonate or chlorothion* carbonate ester used in the above process is obtained by 21 reacting phosgene or thiophosgene at a temperature of 22 between about -10°C. and room temperature with an imidazole 23 of the structure 27 . Ηχ 28 29 where W, P, Q, A and are as above. Generally the lower 1 with thiophosgene · The process is conducted in an inert 2 organic solvent medium. Satisfactory solvents are dioxane, 3 tetrahydrofuran and toluene, or mixtures thereof, as well as I . ketones and esters such as ethyl acetate. It is desirable to employ a solvent in which the imidazole reactant is 6 essentially completely soluble. For best results, the 7 process is conducted in the presence of an acid binding 8 agent, normally a tertiary amine such as trialkylamine or 9 dimethylaniline, although solvents such as tetrahydrofuran 0 and dioxane may themselves be used as said binding agents 1 in this reaction. The chloroformate or chlorothionformate 2 ester may be isolated, if desired, but this is unnecessary, 3 and it is a preferred embodiment of the invention to prepare the ester in solution and to react it without isolation with 5 the amine. 6 v. The Carbamyl Halide/Loweralkyl Carbamate Processes 7 An additional method for preparing the imidazolyl- 8 alkyl carbamates of this invention comprises reacting a 9 l-substituted-2-hydroxyalkyl (or 2-mercaptoalkyl) -5-nitro- 0 imidazole with the appropriate carbamyl halide or loweralley 1 1 carbamate. This process may be schematically represented 2 as follows: 8 9 wherein W, P, R^, R^ a, M, R^ and R^ are as above, and a we a ko . 1 In the preferred modification of this process, the 2 significance of the substituents is as follows: 3 W is hydrogen; I4. P is nitro; Q is loweralkylene suitably methylene or ethylene; 6 or loweralkylidene suitably ethylidene; 7 Ri is loweralkyl suitably methyl, ethyl or propyl 8 or acyloxyalkyl, suitably loweralkanoyloxyalkyl, such as benzoyl 9 acetoxypropyl or valeroxyethyl, or -aaM>yloxyalkyl such as benzoyloxyethyl or benzoyloxypropyl, ¾' is ¾. or hydrox - 11 alkyl such as hydroxyethyl or hydroxypropyl; 12 B is chloro or methoxy or ethoxy; 13 R3 and Rj^ individually represent hydrogen; alkyl, 11). suitably loweralkyl, such as methyl, ethyl or propyl; aryl, l suoh as phenyl; aralkyl, ouitably orylloworallcyl, such as 16 benzyl, hydroxyalkyl, suitably hydro yloweralkyl, such as 17 hydroxymethyl, and hydroxyethyl; alkoxyalkyl, such as 18 ethoxyethyl or ethoxypropyl; or R3 and together 19 represent the group -(CE2) R$"(^2^2"» where R£ is oxygen, sulfur, -CK2- or N-R&, and R is hydrogen or loweralkyl, 21 for example, together with the N-atom to which R3 and R^ 22 are attached, they represent morpholino, thiamorpholino, 23 piperidino, piperazino, lj/-methylpiperazino or pyrrolidino. 2I . As will be understood by those in the art, when B is chloro, a carbamyl chloride is reacted with the 2-substituted 26 imidazole, · and when E is loweralkoxy, the reactant is an 27 alkyl carbamate. 28 In order to prepare the imidazolylalkyl thion> 29 carbamates, i.e., where M in the above structural formula is sulfur, a thiocarbam l chloride is emplo ed. 1 In the carbamyl chloride method, the two reactants 2 are brought together in a suitably inert solvent medium, 3 such as benzene, toluene, tetrahydrofuran or dioxane · It -4. is preferred to use a slight molar excess (e.g. 1-1$%) of £ carbamyl halide, and to have an acid binding agent present 6 in the medium since acid is produced during the reaction. 7 When this process is employed to make unsubstituted carbamates 8 or thion^arbamates (where and are both hydrogen) , the 9 carbamyl chloride reactant is generated into the reaction medium since it is a highly unstable compound. The disub- 11 stituted carbamyl chlorides are stable and are added directly 12 to the reaction mixture. 13 When the imidazole is treated with a loweralkyl 3J+. carbamate, e.g., ethyl or methyl carbamate, the two reactants > are brought together in essentially equimolar amounts in the 16 presence of a strong base, preferably an alkali metal alkoxide 17 such as sodium ethoxlde, sodium methoxide, potassium iso- 18 propoxide and the like in an inert solvent such as 1 ,2-di- 19 me hoxyethane. Because of the base present, an acyloxylower- 20 alkyl radical at the 1-posit on of the imidazole ring will 21 be saponified to the corresponding hydro loweralkyl sub- 22 stituent. Care should be taken not to prolong the reaction 23 time unduly since the imidazole compound is sensitive to ¾ strong base. 2£ Among the products which may be prepared by this 26 process are 1-me hyl-^-nitroimidazol -2-ylmethyl carbamate, 27 l-ethyl- -nitrolmidazol-2-ylmethyl carbamate, and 28 l-( 2,-ethoxyethyl) -5-nitroimida'sol-2-ylmethyl carbamate. 1 vi. The Phenyl Kalocarbonate Method 2 Still another process, which is very useful for 3 preparing the novel imidazolylalkyl carbamates described i+ herein comprises the conversion of a l-substituted-2- 5 hydroxyalkyl (or mercaptoalk l) imidazole to a phenyl 6 carbonate or phenyl thioncarbonate derivative, and sub- 7 sequent treatment of said carbonate or thioncarbonate with 8 an amine, as illustrated below: 1 wherein W, P, Q, R R 1 , R R t A and M are as above 2 and X is halo. 3 This process for making imidazolylalkyl carbamates, i+ which process is itself not a part of this invention, but is 5 rather an invention of our colleague George Gal, is highly 6 satisfactory for obtaining carbamates of the above 7 Structure III. 8 In the preferred modification of this process, 9 the significance of the substituents is as follows: 1 P is nitro; 2 Q is loweralkylene suitably methylene or ethylene; 3 or loweralkylidene suitably 1-ethylidene; i+ R^ is loweralkyl suitably methyl, ethyl or propyl f? or acyloxyalkyl , suitably lower lkanoyloxyalkyl, such as 6 acetoxypropyl or valeroxyethyl , or aroyloxyalkyl such as 7 benzoyloxyethyl or benzoyloxypropyl, R^'is R^ or hydroxy- 8 alkyl such as hydroxyethyl or hydroxypropyl; 9 A and M each represent oxygen or sulfur; 0 R^ individually represent hydrogen; alkyl, 1 suitably loweralkyl, such as methyl, ethyl or propyl; aryl, 2 such as phenyl; aralkyl, suitably arylloweralkyl, such as 3 benzyl; hydroxyalkyl , suitably hydroxyloweralkyl, such as hydroxyethyl; alkoxyalkyl, such as ethoxyethyl or ethcxy-5 propyl; hydroxy; amino; or ^ and R^ together represent 6 the group -(CH ) R -(CK ) -, where R is oxygen, sulfur, 2 2 5 2 2 5 7 ~G^2~ ΟΓ ^"^ * and ¾ S kydro8en OI* loweralkyl, for 8 example when taken together with the ϊΓ-atom to which they 9 are attached, they represent orpholino, th omorpholino, 0 piperidino, piperazino, _+-methylpiperazino or pyrrolicJ.no· nt 1 In carrying out this last-me$Rioned process, a 2 1-loweralkyl -2-hydroxyalkyl (or mercaptoalkyl) -5-nitro-3 imidazole such as l-acyloxyalkyl-2-hydroxyalkyl (or mercapto-i+ alkyl) -5-nitroimid zole such as is first reacted for example 5 with phenoxy carbonyl chloride (phenyl chloro ormate ) or 6 phenoxythiocarbonyl chloride (phenyl thionciloroformate) . 7 This reaction is conveniently brought about in an organic 8 solvent^ such as pyridine, one of the picollnes, or lutidine. 9 These bases, in addition to serving as the liquid solvent 1 reaction. Alternatively, a non-basic solvent for the 2 reactants such as dioxane or chloroform may be employed, 3 and sufficient tertiary amine or alkali metal hydroxide' added to bind the liberated hydrogen chloride. It is preferred to employ a slight molar excess of phenyl chloro- 6 formate reactant and to carry out the process at temper- 7 atures of from about -5°C. to about JJ5°C. Preferably, the 8 reactants are mixed at about 0°C. and the reaction then 9 continued at about room temperature for the desired time. 0 When a phenyl carbonate of a 2-hydroxymethyl or 2-mercapto-1 methyl is being prepared, reaction times of from about 1-5 2 hours are satisfactory for good results. However, longer 3 times of up to about 30 hours may be necessary for complete i+ reaction in the case of 2-(a-hydroxyethyl) and 2-(a-¾»ierc pto-5 ethyl )imidazoles . The resulting imidazole phenyl carbonate, 6 such as for instance l-methyl-5-n troimidazol-2-ylmethyl 7 phenyl carbonate or l-methyl-5-nitroimidazol-2-ylmethyl 8 phenyl thion¾arbonate is conveniently recovered by quenching 9 the reaction mixture in ice water, thus precipitating the 0 desired product. These substances may be used without further 1 purification in the next step of the process, and this is 2 preferred in the case of the phenyl thioncarbonates which 3 are less stable than the phenyl carbonates* -. The imidazolylalkyl carbamate is then obtained by intimately contacting the imidazole phenyl carbonate or 6 phenyl thioncarbonate with an amine in an inert organic 7 solvent medium. For this purpose, chloroform or ethers such 8 as dioxane, tetrahydrofuran or ethylene glycol dimethyl ether 9 are satisfactory. It will, of course, be understood that the 0 particular carbamate produced will depend upon the amine 1 substantially complete in about 1-5 hours. The imidazole 2 phenyl carbonate and the amine may be reacted in essentially 3 equimolar amounts although it is preferred to employ a I. excess of the amine. Good results are obtained by using from l.O-ij. moles of amine per mole of phenyl carbonate. 6 When the unsubstituted carbamate itself is being prepared, 7 it is convenient and preferred to use a very large excess 8 of liquid ammonia since the excess serves as reaction 9 solvent and the resulting carbamate moiety is stable and 0 not destroyed under such conditions. In preparing the 1 unsubstituted thion¾arbamate, however, it is preferable to 2 employ about 2 moles of ammonia per mole of thion¾arbonate 3 and to carry out the reaction at about room temperature in a solvent such as chloroform or an ether. Where in Structure III is hydroxyalkyl, it is preferred to carry out 6 the reaction on a 1-acyloxyalkylimidazole, for example, a 7 l-acetoxyalkylimidazole or a 1-benzoyloxyalkylimidazole, 8 such as l-(2'-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazole, 9 and followed by removal of the acyl group by base hydrolysis 0 after completion of the reaction. It should be noted, however, 1 that in the second stage of the process, that is to say, the 2 reaction with the amine, the basicity of the amine is often 3 sufficient to bring about this hydrolysis · (. Representative examples of imidazolylalkyl carba- mates which may be prepared by this method are: 1-methyl-6 5-nitroimidazol-2-ylmethyl carbamate; l-ethyl-5-nitrcimidazol-7 2-ylmethyl p-fluorophenylcarbamate; l-(2-hydrox ethyl )-8 5-nitroimidazol-2-ylmethyl N-(2-methoxyethyl) carbamate; 9 l-(l-methyl-5-nitroimidazol-2-yl)ethylcarbamate; 1-methyl-0 5-nitroimidazol-2-ylmethyl thion¾arbamate; 1-propyl- 1 £-nitroimidazol-2-ylmethyl thiolcarbaraate ; 1-methyl- 2 5-nitroimidazol-2-ylmethyl hydroxycarbamate and 3 l- (2-hydroxypropyl ) -5-nitroiinidazol-2-ylmethyl me hyl- ' Zj. carbamate . vii . Preparation of Pseudo-thioureido Imidazoles 6 The compounds of Formula I above , wherein N is 7 imino or substituted imino are obtained by reacting a 8 l-substituted-2-halome hyl or sulfonyloxyme hyl imidazole 9 with a thiourea or substituted thiourea as shown by the 0 following reaction scheme : 6 wherein W, P , R^ , R^ , Q, S , R^ and R^ are as above and M 7 is imino or substituted imino , and X is halo or substituted 8 sulfonyloxy. 9 In the preferred modification of this process , 0 the significance of the substituents is as follows : 1 W is hydrogen; 2 P is nitro; 3 Q is loweralkylene suitably methylene or ethylene ; -4- or lower allcylidene suitably l-ethylidene ; $ R, is loweralkyl suitably methyl, ethyl or propyl or 1 6 acyloxyalkyl , suitably lower lkanoyloxyalkyl , such as 7 acetoxypropyl or valeroxyethyl , or aroyloxyalkyl such as 8 benzoylox ethyl or benzoyloxypropyl; R^ « is or hydrox - 9 alkyl such as hydroxyethyl or hydr oxypropyl ; A io sulfur 1 15 is imino; or alkylimino, such as methyl, propyl or 2 pentylimino; 3 M1 is amino or alkylamino, such as methyl, propyl or pentylamino; !? ^ and R^ individually represent hydrogen; alkyl, 6 suitably loweralkyl, euch as methyl, ethyl or propyl; aa?y¾ra 7 ouch ao phenyl; aralkyl, suitably arylloweralkyl, such as 8 benzyl; hydroxyalkyl, oui ably hydroxyloworalkyl, such as 9 hydroxymethyl, and hydroxyethyl; alkoxyalkyl, such as ethoxyethyl or ethoxypropyl; or R^ and ^ together represent 11 the group -(CH2)2R^-(CH2)2-, where is oxygen, sulfur, 12 -CH2- or and R^ is hydrogen or loweralkyl, for example 13 taken together with the N-atom to which ^ and ^ are IJ4. attached, they represent morpholino, thiamorpholino, l£ piperidino, i^-methylpiperazlno or pyrrolidine; and 16 X is chloro, methylsulfonyl or p-toluenesul onyl . 17 The reaction is carried out in an organic solvent 1,8 medium, preferably a loweralkanol , suitably ethanol or 19 methanol. It is preferred to use essentially equimolar quantities of the two reactants, or a slight molar excess 21 of the 2-haloalkyl or 2-sulfonyloxyalkyl imidazole reac an s . 22 Acid is formed in the reaction, and the products are normally 23 recovered as the hydrochloride or sulfonate acid addition 22}. salts. Included among the compounds prepared in accordance with this process are: S-(l-methyl-5-nitroimidazol-2-yl- 26 methyl)-pseudo-thiourea; S-l-(l,-methyl-51 -nltroimidazol- 27 2!-yl)ethyl-pseudo-thlourea; S-(l-acetoxyethyl-S>-nitro- 28 imidazol-2-ylmethyl)-pseudo-thiourea; and S-(l-methyl-5- 29 nitroimidazol-2-ylmethyl) -pseudo-dimethylthiourea.

II· The Specific Processes The following processes are directed to the preparation of carbamates having particular substituents attached to the nitrogen of the carbamate group. Although these processes are directed to the formation of the compounds having these particular substituents, it should be unders ood that they are not specifically limited thereto. i. 5-Nitroimidazol-2-ylalky.l allophanates -Nitroimidazol-2-ylalky1 allophanates may be produced by reaction of a 5-nitroimidazol-2-yl alkanpl or thioaikanol with excess cyanic acid. In the preferred procedure, the 5-nitroimidazole, suitably a l-R^-5-nitro-imidazol-2-yl methanol, wherein has the value shown on page 2 above but having a significance other than hydroxy-alkyl, suitably l-methyl-5~nitroimidazol-2-yl methanol, is dissolved in an oxygenated organic solvent, suitably an ether, for example 1,2-dimethoxy ethane, cooled to dry ice temperature, that is to between -75°c and -50°C and 2-moles of cyanic acid added thereto. It is a critical feature of this process that there be at least 2 moles of cyanic acid per mole of nitroimidazole . The reaction vessel is tightly sealed, allowed to warm to from about -f>°C. to about 0°C« and allowed to stand from about 36 to about 60 hours. The product is then isolated. In the preferred procedure, the reaction mixture is filtered and the solid residue extracted with water,, suitably hot water, having a temperature of from about 8 °C. to 100°C. The hot extract is immediately filtered and the desired product obtained as a crystalline precipitate from the aqueous filtrate.

Included among the compounds which may be produced 1 in accordance with this procedure are l-raethyl-5-nitro- 2 imidazol-2-ylmethyl allophanat'e, 1- (1 » -ethyl- 1 -nitroimidazol- 3 2,-yl)sthyl allophanate, 1- Γ» -(acetoxyethyl ) -5' -nitroimidazol- I . 2'-yl7ethyl allophanate and 1- (acetoxyethyl ) -5-nitro- . imidazol-2-ylmethyl thioallophanate. 6 Where it is desired to produce the 1- (hydroxyalkyl). 7 5>-nitroimidazol-2-ylalkyl allophanates, the corresponding 8 1-acyloxy allophanate is produced in accordance with the 9 above procedure and subsequently subjected to base hydrolysis in the usual manner. 11 ii. 5-Ni¾roimida_zol-2-ylalkyl N- ( 2 ' , 2' , 2' -trlhalo- 12 1 ' -hydrox ethoxy ^carbamates 13 . 5-liitroimidazol-2-ylalkyl N- ( 2« , 2' , 2» -trihalo-II . I1 -hydroxyethoxy ) carbamates may be obtained by reacting the corresponding 5-nitroimidazol-2-ylalkyl N-hydroxycarbamate 16 with a trihalo substituted acetaldehyde. In the preferred 17 procedure, the 5-nitroimidazole, suitably a l-Ri-5-nitro- 18 imidazol-2-ylmethyl N-hydroxycarbamate, wherein ¾_ is as 19 shown on page 2 above, but having a significance other than hydroxyalkyl, for example, l-methyl-5-nitroiraidazol-2-yl- 21 methyl N-hydroxycarbamate is mixed with the haloacetaldehyde, 22 for example, chlo alhyd ate or bromalhydrate in approximately 23 equimolar proportions and heated under reflux in the presence 2I . of a drying agent, for example, anhydrous magnesium sulfate 2$ for from about 6 to about 12 hours. In the preferred method 26 of isolation, the reaction mixture is filtered, and the 27 - product recovered from the filtrate. . Among the compounds 28 which may be produced in accordance with this procedure are: 29 l-methyl-5-nitroimidazol-2-ylmethyl N- ( 2« , 2' ,2' -trichloro- 30 1 » -hydroxyethoxy ) carbamate; 1-ethyl -5-nitroimidazol-2-yl- 1 methyl N-(2',2' ,2'-trlchloro-l,-hydroxyethoxy)carbaiate; 2 l-acetoxyethyl-5-nitroimidazol72-ylmethyl N-(2* ,2» ,2*- · 3 trichloro-lV-hydroxyethoxy)carbamate; and 1-methyl-5-ij. nitroimidazol-2-ylmethyl N-(2* ,2» ,2' -trIfluoro-l» -hydroxy- 5 ethoxy)carbamate. 6 Where it is desired to obtain a compound of this 7 class having a 1-hydroxyalkyl stibstituent, the reaction is 8 carried out using the corresponding 1-acyloxy hydroxycarbamate 9 and subjecting the thus produced N-(2t ,2' ,2 ' -trlhalo-l 1 -0 hydroxyethoxy)carbamate to base hydrolysis* 1 iii. 5-Nltroimidazol-2-ylalkyl N-hydroxymethylcarbamate 2 £-Nitroimidazol-2-ylalkyl N-hydroxymethylcarbamates 3 may be obtained by reacting the corresponding 5-nItroimidazol--4. 2-ylalkyl carbamate with formaldehyde. In the preferred modification of the process, the 5~nitroimidazole carbamate-,-6 suitably a l-R^-5-nitroimidazol-2~ylmethylcarbamate, wherein is as shown on page 2 above but having a significance other 8 than hydroxyalkyl or carboxyalkyl, is dissolved in an inert 9 solvent, dimethyl sulfoxide being particularly suitable, and 0 heated in a sealed vessel with an excess of paraformaldehyde, 1 2 moles excess being preferred, at from 70-l50°C. for from 2 l8 to 30 hours. In one method of isolation, the solvent is 3 evaporated from the reaction mixture, the residue dissolved -. in a suitable water miscible solvent, such as, dimethyl- formamide and water added. The product separates as a 6 crystalline precipitate and may be isolated by filtration. 7 Included among the compounds which may be produced 8 in accordance with this procedure are: 1-methyl-£-nItro-n (ro.p* 137-138 G) 9 imidazol-2-ylmethyl N-hydroxymethylcarbamate/; 1-(11 -methyl-0 1 -nltroimidazol-2J.ylethyl) N-hydroxymethylcarbamate; 1 a-il'-me hyl-S'-nitroimldazol-a'-ylJethyl N-hydroxymethyl- 2 carbamate; and l-e hyl-5-nitroimidazol-2-ylmetnyl N-hydroxy- 3 methylcarbamate. · ; ■ k iv. troimidazol -2- 1alky 1 IT-alkoxyalkylcarbamates $ 5-NitroImidazol-2-ylalkyl N-alkoxyalkylcarbamates 6 may be produced by reacting the corresponding 5-nltroimidazol- 7 2-ylalkyl N-hydroxyalkyl carbamate with an alkanol in the 8 presence of an acid. In the preferred procedure, the 9 N-hydroxymethylcarbamate, suitably a l-R^-5-nitroimidazol- 10 2-yl e hy 1- -hydroxycarbamate, wherein is as shown on 11 page 2 above, but having a significance other than hydroxy- 12 alkyl or carboxyalkyl, for example, 1-methyl -5-nitroimidazol- 13 2-ylmethyl N-hydroxymethylcarbamate, is mixed with the I/4. alkanol, for example, ethanol or methanol, in the presence > of a catalytic amount of strong acid, hydrochloric acid or 16 p-toluene sulfonic acid being preferred, and allowed to stir 17 for 12 to ¾ hours, at between 15°C and 30°C. The product 18 may be isolated by extraction of the reaction mixture with 19 a suitable solvent such as, chloroform and working up in the usual manner. 21 Included among the products which may be obtained 22 by means of this procedure are: 1-methyl -5-nitroimidazol- 23 2-ylmethyl N-ethoxymethylcarbamatej 1-methyl-£-nitroimidazol-2ij. 2-ylmethyl N-propoxymethylcarbamate; l-(l'-methyl-5'-nitro-2f? imidazol-2 ' -yl )ethyl N-methoxymethylcarbamatej and 1-ethyl- 26 3>-nitroimidazol -2-ylmethyl N-ethoxymethylcarbamate · 27 v. 5-N^troimidazol-2-ylalkyl N-alkoxycarbamates 28 5-Nitroimidazol-2-ylalkyl N-alkoxycarbama ea may 29 be prepared by reacting the corresponding 5-nitroimidazole N-hydroxycarbamate with a diazo hydrocarbon. In the preferred 1 procedure, the 5-nitroimidazole N-hydroxycarbamate , 2 suitably a l-R^-^-nitroimid^zol^-ylmethyl-N-hydroxy- . 3 carbamate, wherein is as shown on page 2 above but ' i\. having a significance other than hydrox alkyl or carboxy- 5 allyl, for example, l-methyl-5-nitroimidazol~2-ylmethyl 6 N-hydroxycarbamate is dissolved in an alkanol, for example, 7 methanol or ethanol and treated with an excess of diazo 8 hydrocarbon, suitably in solution, for example, an ethereal 9 solution of diazomethane, diazoethane or diazophenylme hane . 0 The product may be isolated in the form of an acid salt. 1 In one suitable method of isolation, the reaction mixture is 2 filtered, the residue chromatographed on silica gel and the 3 residue, after evaporation of the eluate, treated with one 1 equivalent of a solution of acid, suitably -toluenesulfonic 5 acid in methylethylketone · 6 Included among the products which may be obtained 7 by this procedure are: 1-methyl -5-nitroimidazol -2-ylmethyl-8 N-methoxycarbamate; l-methyl-5-nitroimidazol-2-ylme h l 9 N-methyl-N-methoxycarbamate; l-ethyl-5-nitroimidazol-2-yl-0 methyl N-ethox carbamate; and l-(21 -acetoxyethyl) -5-nitro-1 imidazol -2-ylmethyl N-phenylmethoxycarbamate · 2 vi . Acylation of -nitroimidazol-2-ylalkyl carbamates, 3 N-hydroxycarbamates and N-alkylhydroxycarbamates . .. 5-Nitroimidazol-2-ylalkyl carbamates, -hydroxy-5 carbamates and N-alkylhydroxycarbamates may be acylated in 6 the usual manner. In 'the preferred procedure, the compound 7 to be acylated, for example a 1-^- -nitroimidazol-2-ylmethyl 8 carbamate wherein is as shown on page 2 above, provided 9 however that has a value other than hydroxyalkyl or 0 carbamoylalkyl, is reacted with an acylating agent such as 1 an alkanoyl anhydride, suitably a loweralkanoyl anhydride, 2 such as acetic anhydride, propionic anhydride or valeric 3 anhydride; an alkanoyl halide, such as acetyl chloride ·.or ft. propionyl chloride; an aroyl halide, such as benzoyl halide; an alkenoyl halide suitably a loweralkenoyl halide, such as 6 acryloyl chloride or crotonyl chloride or a cyano alkanoic 7 acid in the presence of a dehydrating agent, for example, 8 cyano acetic acid in the presence of acetic anhydride* 9 The product of the acy!atlon reac ion may be isolated by any of the usual procedures. 11 vii * 5~Nitroimidazol-2-ylalkyl and ft.' ,ft.T -substituted 12 allophanates 13 5-Mtroiraidazol-2-ylalkyl and ft' ,ft.» -substituted lft. allophanates may be prepared by reacting a £-nitroimidazole carbamate with a carbamyl chloride, In the preferred 16 procedure, a l-R^-^-nitroimidazol^-ylalkyl carbamate, 17 wherein is as shown on page 2 above, but wherein R^ 18 has a value other than hydroxy or carbamoyl and further 19 including compounds such as l-R^-5-nitroiBildazol-2-ylalkyl carbamates, suitably 1-me thyl-5-nltroimidazol-2-ylmethyl 21 carbamate; l-R^-^-nitroimidazol^-ylalkyl N-alkylcarbamates , 22 such as l-d'-methyl-^'-nitroimidazol^^yDethyl N-methyl 23 carbamate; 1-(11 -acetoxyethyl-^' -nitroiraidazol-2' -yl) ethyl 2ft. N-methylcarbamate; or 2-(l,-ethyl-5t-nitroimidazol-2'-yl) ethyl N-propylcarbamate is dissolved in a base, suitably 26 an organic base . such as pyridine,-' lutidine or collidine, 27 and the mixture cooled to a range of between -5°C. and 28 +$°C, and the carbamyl chloride introduced. This 29 introduction may be achieved by passing the carbamyl chloride into the reaction mixture in gaseous form, for example where 1 carbamyl chloride itself is used; or by dropwise addition 2 of a substituted carbamyl chloride, for example dimethyl 3 carbamyl chloride in the liquid form. The reaction proceeds J+ at a temperature of between $°C. and 30°C. in from 2 to ¾ hours. The product may then be isolated; suitably, the 6 isolation is carried out by concentration with the reaction 7 mixture under reduced pressure followed by extraction with 8 a suitable solvent, for example, a water immiscible solvent 9 such as ethyl acetate and work up in the usual manner.

Included among the products which may be obtained 11 by this method are: 1-(1 ! -methyl~5V-nitroimidazol- ' -yl ) 12 ethyl 1^' -methylallophanate, l-d'-acetoxyethyl-S'-nitro- 13 imidazol-2'-yl)ethyl I4. ' -methylallophanate and 1-(1 · -ethyl-llj. 5 ' -nitroimidazol-21 -yl) ethyl Ij-'-propylallophanate. Where the carbamyl chloride is a substituent carbamyl chloride, 16 for example dimethyl carbamyl chloride, there are obtained 17 compounds such as 1- (1 ' -methyl- ' -nitroimidazol-2 ' -yl)ethyl- 18 1 » '-trimethylallophanate, and l-(l'-ethyl-5'-nit o- 19 lmidazol-2'-yl)ethyl I'-me hyl- ,-4.,-dimethylallophariate.

Where the desired compound has a hydroxyalkyl 21 substituent at the 1-position, the reaction Is carried out 22 with the corresponding 1-acyloxyalkyl compound which Is 23 subsequently subjected to base hydrolysis in the usual ¾ manner. 2 viii. 5-Nitroimidazol-2-ylalkyl 3 * -thioallophanates 26 and I4. ' 3l '-substituted 3 ' -thioallophanates 27 5-Nitroimidazol-2-ylalkyl 3-thloallophanates and 28 J.1 -substituted V -thioallophanates are produced by 29 reaction of a 5>-nitroimidazol-2-ylalkyl haloformate with anhydrous alkali metal thiocyanate followed by treatment 1 with an amine. In a preferred modification of the process, 2 a 5-nitroimidazol-2-ylalkyl chloroformate, for example a 3 . l-Ri- -nitroimidazol-2-ylmethyl chloroformate, wherei ;Ri is as shown on page 2 above, provided that ¾ has a value . other than hydroxyalkyl, suitably l-methyl-5-nitroimidazol- 6 2-ylmethyl-chloroformate, and the alkali metal thiocyanate 7 is taken up in a reaction inert organic solvent such as 8 benzene and stirred at moderately elevated temperatures 9 preferably from about 20* C. to about $$°C. for a period of about 3 "to about 6 days. This mixture is then treated with 11 an excess of the desired amine, for example, anhydrous gaseous 12 ammonia to yield the unsubstituted 3 ' -thionallophanate, or a 13 substituted amine, such as an alkylamine, such as ethylamine, 1/ to yield the corresponding i' -alkyl -3 ' -thionallophanate or 1 a disubstituted amine, for example, dibenzylamine to yield 16 the corresponding kT ,Ι^' -disubstituted-3 f -thionallophanate, 17 such as l-methyl-5-nitroimidazol-2-yl-methyl Ij.' -dibenzyl- 18 3 ' -thionallophanate. 19 Included among the compounds which may be produced by this method are: l-methyl-5-nitroimidazol-2-ylmethyl 21 3 ' -thionallophanate, and l-ethyl-5-nitroimidazol-2-ylmethyl 22 1+' -butyl -3 ' -thionallophanate. 23 Where it is desired to obtain a compound of this ¾ group having a 1-hyd oxyalkyl substituent, the reaction is 2 suitably carried out on the corresponding 1-acyloxyalkyl 26 chloroformate, which is then subjected to base hydrolysis 27 in the usual manner to yield the desired 1-hydroxyalkyl 28 compound. It should be borne in mind, however, that the 29 basicity of the ammonia or the amine added in the course of the present reaction may be sufficient to affect this 1 ix. 5-Stttroiaildagol-l-ylalfcirl N- (N1 -substituted 2 dithiocarbamoylmethyl )carbamates 3 5-Nitroimidazol-l-ylalkyl N-(N» -substituted Ij. dithiocarbamoylmethyl)carbamates may be produced by the reaction of a 5-nitroimidazol-2-ylalkyl carbamate with 6 a substituted amine, formaldehyde and carbon disulfide. 7 In the preferred modification of the procedure, a substituted 8 amine, for example dime hylamine and formaldehyde, both in 9 aqueous solution, suitably in solutions containing betwee 30 and $0% of each of the reagents, are added to a solution 11 of the 5-nitroimidazol-2-ylalkyl carbamate, such as a 12 l-R^-5-nitroimidazol-2-ylmethyl carbamate wherein R is as 13 shown on page 2 above, provided that has a value other li+ than hydroxyalkyl, carbamoylbxyalkyl, carbamoylalkyl or 1$ oxoalkyl, suitably 1-methyl-£-nitroimidazol-2-ylmethyl 16 carbamate In a water miscible organic solvent, suitably 17 dimethylformamide . To this mixture is added an excess of 18 carbon disulfide and the reaction mixture agitated, suit- 19 ably for from 18 to 30 hours at a temperature of between about 10 and 30°C. The product is then isolated, suitably 21 by the addition of an excess of water and separation of the 22 product as a precipitate. Among the products which may be 23 obtained by this procedure are: l-methyl-5-nitroimidazol-¾ 2-ylmethyl N-(dimethyldithiocarbamoylmethyl)carbamate, l-ethyl-5-nitroimidazol-2-ylmethyl N-(diethyldithiocarbamoyl- 26- methyl)carbamate and l-(l!-acet0xyethyl- T-nitroimidazol- 27 2» -yl)ethyl N-( dibenzyldithiocarbamoylmethyl)carbamate. 28 x. - g-Nitroimidazol-2-ylalkyl N-(disubs ituted 29 aminomethyl )carbamates -Nitroimidazol-2-ylalkyl N-(disubstituted amino- 31 methyl)carbamates may be produced by the reaction of a 1 carbamate with a dlsubstltuted 2 amine together with formaldehyde. In the preferred 3 modification of the procedure, the l-R^-5-nitroimidazol- J+ 2-ylalkyl carbamates, for example, l-methyl-5-nitroimidazol- 5 2-ylmethyl carbamate together with a dlsubstltuted amine ±c radicals 6 including nitrogene«e heterocyclic a-lliartoo-, for example, a 7 di alkyl amine , such as dime hyl amine , dipropylamine , or 8 dipentylamlne and al kylaryl amine for example N-methyl- 9 aniline, a diarylamine such as diphenyl mine or a di- 10 aralkyl amine , such as dibenzylamlne or a secondary cyclic 11 amine, for example, morpholine, thiamorpholine, pyrrolidine, 12 or N-methylplperazine and paraformaldehyde, suitably in 13 equimolar amounts, are taken up in a water miscible iner ll organic solvent, suitably dimethylformaraide and heated in a sealed vessel at a temperature of from about 80° to about 16 150 °C. for a period of from about 12 to abou 30 hours. In 17 a suitable method of isolation, " the reaction solvent is 18 removed, preferably under reduced pressure, and the residue 19 dissolved in a polar solvent, suitably a ke onic solvent, such as methyl ethyl ketone and an acid in the same solvent, 21 suitably p-toluene sulfonic acid is added thereto and the 22 product isolated as the acid salt. 23 Included among the compounds which may be prepared 21. in accordance with this procedure are: l-methyl-5-nitroimid- 25 azol -2-ylmethyl N-(N† jN'-dimethylaminome thyl) carbamate 26 l-ethyl-5-nitrolmidazol -2-ylmethyl N-(N» ,N ' -dipropylamino 27 methyl) carbamate, l-acetoxyethyl-5-nitroimidazol -2-ylmethyl 28 N-iN^methyl-N'-phenylaminomethyDcarbamate, 1- (1» -methyl -5'- 29 nitroimldazol-2'-yl) ethyl N-(N» ,Ν' -diphenylaminomethyl)carba- 30 mate, 2-(lt-metbyl-5,-nitrolmidazol-2'-yl)ethyl N- (morpholln- 1 2j.-ylmethyl ) carbamate, l-propyl-5-nltroimldazol-2-ylmethyl 2 N-(lj.-methylpiperazin-l-ylmethyl)oarbamate, and 3 l-il^hydroxyethyl-^'-nitroimidazol^'-ylJethyl N-pyr- ; i+ rolldin-l-ylme thyl ) carbamate · i> xi · 5-^itroimidazol-2-ylalkyl N-( carboalkoxyalkyl- 6 i dene ) c arb ama e s 7 5-Nitroimidazol-2-ylalkyl N-(carboalkoxyalkyl- 8 idene) carbamates may be prepared by reacting a £-nitro- 9 imidazol-2-ylalkyl carbamate with a β-keto ester in the presence of an acid. In the preferred procedure, a £-ni troll imidazol-2-ylalkyl carbamate, for example, a l-R^-5-nitro- 12 imidazol-2-ylalkyl carbamate, wherein is as shown on 13 page 2 above provided that is other than carbamoylalkyl, lij. such as, 1 -methyl -$ -nitroimidazol-2-ylme thyl carbamate, is lf> heated with a β-keto ester, such as ethylacetoacetate or 16 ethyl 3-oxopentanoate in the presence of a catalytic amount 17 of an anhydrous acid suitably an organic acid, such as, 18 p-toluene sulfonic acid, at a temperature of from about 19 60°C. to about 100°C. for a period of from about 3 hours to about 2/Lj. hours. The product may be isolated by any suitable 21 method, for example, the solvent may be removed by evapora- 22 tion under reduced pressure, the residue washed thoroughly 23 with ether, filtered and the ether removed under reduced -. pressure to yield a residue which may then be recryst alii zed, suitably from ether to yield the' desired product, included . 26 among the compounds which may be 'produced in accordance with 27 this procedure are l-methyl-^-nitroimidazol-2-ylmethyl 28 N-[l,-carboethoxy-(prop-2t-ylidene)]oarbamate, l-ethyl-5- 29 nitroimidazol-2-ylmethyl N- [11 -carboethoxy- (pent-2 » -ylidene ) 3 carbamate, and l-(l»-ethyl-5,-riitrolmidazol-2'-yl)ethyl 1 xii. 5- itroimidazol-2-ylalkyl N-alkoxymethylene 2 carbamates 3 5-Nitroimidazol-2-yialkyl N-alkoxyme hylene _+ ' carbamates may be' produced by reacting a 5-∑*itroimidazol- 5 2-ylalkyl carbamate with a trisubstituted orthoformate in 6 the presence of a Lewis acid. In the preferred procedure, 7 a 5-nitroimidazol-2-ylalkyl carbamate, such as a l-R^- 8 5-nitroimidazol-2-ylmethyl-N-hydroxycarbamate, wherein 9 is as shown on page 2 above, but having a significance other 0 than hydroxy alkyl or carboxy alkyl, suitably 1-methyl-1 5-nitroimidazol-2-ylmethyl carbamate, a Lewis acid, prefer-2 ably boron trifluoride etherate, and a trisubstituted ortho-3 formate, for example a trialkyl orthoformate , such as triethyl orthoformate , are heated together at a temperature 5 of from about 60° to about 100°G. for from about 12 to 6 about l8 hours. The product is then isolated. In a suitable 7 method of isolation, the excess trisubstituted ortho ormate 8 is removed under reduced pressure, the residue taken up in im 9 a suitable water/m scible organic solvent, for example chloro-0; form, and washed with a mild base, suitably aqueous sodium 1 bicarbonate; the product is then isolated from the chloroform 2 solution. Included among the compounds which may be produced 3 in accordance with the above procedure are: 1-methyl -5-nitro-1}. imidazol-2-ylmethyl N-ethoxymethylene carbamate, 1-eth.yl-5 5-nitroimidazol-2-yimethyl N-propyloxymethylene carbamate, and 6 1-Cl « -(2 -hydroxyethyl) -51 -ni roimidazol-2 ' -ylethyl ] 7 N-benzyloxymethylene carbamate. 1 oimid zol-2-y1alkyl N-alkoxyme.thy1ene 2 carbamates 3 5-Nitroimidazol- -ylalkyl N-alkoxymethylene l\. carbamates may be' produced by reacting a 5-∑iitroimidazol- £ 2-ylalkyl carbamate with a trisubstituted orthoformate in 6 the presence of a Lewis acid. In the preferred procedure, 7 & 5-nitroimidazol-2-ylalkyl carbamate, such as a l-R^- 8 5-nitroimidazol-2-ylmethyl-N-hydroxycarbamate, wherein 9 is as shown on page 2 above, but having a significance other 10. than hydroxy alkyl or carboxy alkyl, suitably 1-methyl- 11 5-nitroimidazol-2-ylmethyl carbamate, a Lewis acid, prefer- 12 ably boron trifluoride etherate, and a trisubstituted ortho- 13 formate, for example a trialkyl orthoformate, such as II. triethyl ortho ormate, are heated together at a temperature of from about 60° to about 100°C. for from about 12 to 16 about l8 hours. The product is then isolated. In a suitable 17 method of isolation, the excess trisubstituted orthoformate 18 is removed under reduced pressure, the residue taken up in 19 a suitable water miscible organic solvent, for example chloro- 20. form, and washed with a mild base, suitably aqueous sodium 21. bicarbonate; the product is then isolated from the chloroform 22 solution. Included among the compounds which may be produced 23 in accordance with the above procedure are: l-me hyl-5-ni rp-2l imidazol-2-ylmethyl N-ethoxymethylene carbamate, 1-ethy - 25 5-nitroimidazol-2-yimethyl N-propyloxymethylene carbamate, and 26 1-[1 « -(2 -hydroxyethyl ) - ' -nitroimidazol-2 » -ylethyl ] 27 N-benzyloxymethylene carbamate. 1 xiii . 5- itrolmidazol-2-ylalkyl N-amino and sub¬ 2 stituted aminonethylene carbamates 3 5-Nitroimidazol-2-ylalkyl ΕΓ-amino and substituted k aminomethylene carbamates may be produced by reacting a 5-nitroimidazol-2-ylalkyl alkoxyme hylene carbamate with an 6 amine. In the preferred procedure, a 5-nitroimidazol- 7 2-ylalkyl N-alkoxymethylene carbamate, such as is produced 8 in accordance with the previous subsection, is heated 9 together with an amine, suitably a substituted amine, such as ethylamine, diethylamine, or dibenzylainine , in a moderate- 11 ly high boiling reaction inert organic solvent, suitably an 12 ether such as 1 ,2-dimethoxy ethane, at a temperature of 13 between 0° and l50°C. fo from about 1 hour to about lij. 3 hours. In a suitable method of isolation, the product is l£ isolated as the acid salt by the addition of a suitable 16 anhydrous acid, for example, p-toluene sulfonic acid, to the 17 cooled reaction mixture, 18 Included among the compounds which may be produced 19 in accordance with this procedure are: 1-methyl -5-nitro- 20 imidazol-2-ylmethyl N-(dimethylaminomethylene)carbamate, 21 l-ethyl-5-nitroimidazol-2-ylmethyl N-(dibutylaminometh lene ) 22 carbamate, and 1-( 1 '-propyl-S'-nitroimidazol^'-yl)ethyl 23 N-(dibenzylaminomethylene)carbamate. 1+ xiv. N ' - (5-^itroimidazol-2-ylalkoxycarbonyl) 2 N^N^-diallylformamidinium salts 26 Nt - (5-Nitroimidazol-2-ylalkoxycarbonyl) N2,N2-di- 27 alkylformamidiniura halides may be prepared by reacting a 28 5-nitroimidazol -2-ylalkyl carbamate with a dialkylformamide 29 in the presence of a thionyl halide. In the preferred procedure, a fj-nitroimidazol -2-ylalkyl carbamate, suitably 1 a l-R^-5-nitroimidazol-2-ylmeth l carbamate, wherein 2 is as shown on page 2 above provided that is other than 3 hydroxyalkyl, carboxyalkyl , or carbamoylalkyl, is dissolved in an excess of dialkylformamide , suitably dimethylformamide and a small excess of a thionyl halide,such as thionyl 6 chloride is added thereto. The mixture is allowed to stand 7 at a temperature of from about 15°C. to about 30°C. for from 8 about 12 to about 21+ hours. In the preferred method of 9 isolation, the product is obtained as a crystalline precip-0 itate and is separated from the reaction mixture for filtration. 2 Among the compounds which may be produced in accord-3 ance with this procedure are N'-(l-methyl-5-nitroimidazol-+ 2-ylmethoxycarbonyl) N2,N2-dime hylformamidinium chloride hydrochloride, TS t -(l-methyl-5-nitroimidazol-2-ylmethoxy- carbonyl) N2,N2-dimethylformamidinium bromide hydrobromide , N'-d-ethyl-S-nitroimidazol^-ylmethoxycarbonyl) N2,N2-di- methylformamidinium chloride hydrochloride, and ' - (1-acetoxy- ethyl-5-nitroimidazol-2-ylmethoxycarbonyl) N2,N2-dimethyl- formamidinium chloride hydrochloride. 2 5-Nitroimidazol-2-ylalkyl N-formylcarbamates may 3 be produced by reacting an N» -5-nitroimidazol-2-ylalkoxy-+ carbonyl) N ,N -dialkylformamidinium halide hydrohalide in a mild alkaline hydrolyzlng agent., In the preferred modifica- tion of the procedure, an N' -(l-R^-5-nitroimldazbl-2-yl-7 methoxycarbonyl) N ,N -dialkylformamidinium halide hydrohalide, 8 as produced in accordance with the aforementioned procedure, 9 is dissolved in a mild aqueous base, a solution of sodium 0 bicarbonate in water bein preferred and the solution 1 allowed to stand at a temperature of 15° to 30°C for from. 2 about 12 to about 2Lj. hours. .The product may be isolated as 3 the residue by filtration* i+ It should be noted that 1-hydroxyalkyl or 1-carboxy- 5 alkyl compounds of this class cannot be prepared by this 6 method, although the corresponding acyloxy derivatives, that 7 is to say, i-acylbxyalkyl and 1-carboxyacyl analogs may bo 8 obtained. It should be noted that an attempted hydrolysis 9 of the acyl groups would simultaneously remove the formyl substituent on the carbamyl group. 11 xvi. 5- itroimidazol-2-ylalkyl N-nitrocarbamates 12 5>-Nitroimidazol-2-ylalkyl N-nitrocarbamates may be 13 produced by reaction of a S>-nitroimidazol-2-ylalkyl carbamate lij. with nitric acid. In the preferred modification of the procedure, the 5>-nitroimidazol-2-ylalkyl carbamate, suitably 16 a l-R1-5-nitroimidazol~2-ylmethyl carbamate, wherein is 17 as shown on page 2 above, suitably 1-methyl -5-n troimidazolio" 2-ylmethyl carbamate, is dissolved in an alkanoic anhydride, 19 such as acetic anhydride and treated with an equimolar amount of 95% nitric acid. After standing at a temperature of from 21 about 1 ° to about 30°C. for a period of from about If? minutes 22 to 2 hours, the reaction is quenched, suitably by pouring the 23 reaction mixture into an aqueous solution. The product may 2I. then be isolated, suitably by extraction of the aqueous mix- 25 ture with a suitable, water immiscible organic solvent and 26 work up in the usual manner. 27 . A suitable form in which the product may be obtained 28 is as the ammonium salts. This may be obtained by saturating 29 the previously dried extract of the reaction mixture in the 0 aforementioned or anic solvent with ammonia gas and separat- 1 Among the compounds which may be obtained by this 2 procedure are: l-methyl-$-nitroimidazol-2-ylmethyl N-nitro- .5 carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-methyl- 1+ N-nitrocarbamate , and l-ethyl-5-nitroimidazol-2-ylmethyl N-nitroc rbamate. 6 xvii. -Mi oimidazo 1 -2-ylalkyl N2-alkyliden - 7 carbazates 8 5-Nitroimidazol-2-ylalkyl N2-alkylidenecarbazates 9 may be produced by reacting a 5-nitroimidazol-2-ylaliyl carbazate with a carbonyl compound. In the preferred 11 modification of the procedure, a l-R^-^-nitroimidazol-2-yl- 12 methyl carbazate wherein is as shown on page 2 above, 13 such as l-methyl-5-nitroimidazol-2-ylmethyl carbazate, is llj. allowed to react (with or without a solvent) with an excess of carbonyl compound suitably an aldehyde or ketone, for 16 example benzaldehyde , acetone, methylethylketone or aceto- 17 phenone, and heated under reflux, for example, at a emper- 18 ature of between ij.0°C. and 120°C. for a period of from 5 to 19 30 minutes. The product is then isolated, suitably the solvent is removed under reduced pressure and the product 21 recrystallized from the residue. It should be noted that 22 compounds wherein TL is oxoalkyl cannot be produced by this 23 method, ?)|. Included among the compounds which may be produced 5 in accordance with this procedure are: l-methyl-5-ni roimid- 26- azol-2-ylmethyl N2-butylidenecarbazate , l-othyl-5-ni roimid- 27 azol-2-ylmethyl N2-benzylidenec8rbazate , and l-(l'-(2'!-hy- 28 droxyethyl) -51 -ni roimidazol-2 ' -yl )ethyl N2-isopropylidene- 29 carbazate . 1 xviii . 5-Nitroimldazol-2-ylalkyl y-acyl-N-acyloxy- 2 carbamates 3 5-Nitroim dazol-2-ylalkyl N-acyl-N-acyloxycarba- i mates may be produced by reacting a 5-nitroimidazol-2~yl- 5> alk l N-hydroxycarbamate with an excess of an acyl anhydride 6 in the presence of a base catalyst. In a further modifica- 7 tion of the process, a l-R^-5-nitroimidazol-2-ylalkyl 8 N-hydroxycarbama.te, wherein is as shewn on page 2 above, 9 but having a value other than hydroxyalkyl or carboxyalkyl , such as l-methyl-5-nitrolmidazol-2-ylmethyl N-hydroxycarba- 11 mate is heated together with a weak base, suitably potassium 12 acetate or sodium carbonate, and respectively an alkanoic 13 anhydride or aralkanoic anhydride, for example, acetic II. anhydride, propionic anhydride or benzoic anhydride, at a temperature of from about 70°C. to about 100°C. for a 16 period of from about 1 to about hou s. The product may 1 then be isolated. Suitably, the isolation is carried out 18 by removing the volatile components from the reaction mix- 19 ture at reduced pressure and extracting the residue with a mixture of water and a water immiscible organic solvent, 21 suitably chloroform. The product is then isolated and the 22 chloroform extracted in the usual manner. 23 Included among the compounds which may be produced ?i\ by .the above procedure are: l-methyl-5-nitroimidazol-2-yi-2$ methyl N-acetyl-N-acetoxycarbamate , l-ethyl-5-nitroimidazol- 26 2-ylmethyl N-butyryl-N-butyroxyearbamate , l-(lf-ethyl- 27 '-nitroimidazol-2-yl) ethyl N-benzoyl-N-benzoyloxycarbamate , 28 and 2-U1 -ethyl- ' -nitroimidazol-2 T-yl) ethyl N-phenylacetyl- 29 N-phenylacetoxycarbamate . 1 xix. l-Me hyl-5-nitroimidazol-2-ylmethyl 2 N-diaminophosphoryl and N-aminosulfonyl 3 ' carbamates l-Methyl-5-nltroimldazol-2-ylmethyl N-diamino- phosphoryl and N-aminosulfonyl carbamates may be prepared 6 by reacting a 2-hydroxymethyl or 2-mercaptomethyl-£-nitro- 7 imidazole with a dihalophosphoryl or halosulfonylisocyanate 8 followed by reaction with a suitable amine. In the preferred 9 procedure, a l-R1-2-hydroxymethyl-5-nitroimidazole wherein is as shown on page 2 above, provided that is other 11 than hydroxyalkyl, for example, l-methyl-2-hydroxymethyl- 12 5-nitroimidazole , is taken up in a reaction inert organic 13 solvent, for example a hydrocarbon solvent such as benzene Uj. or an ether such as tetrahydrofuran or 1 ,2-dimethox ethane, If? suitably, but not critically, in the presence of a trace of 16 an organic base, such as pyridine and heated with dichloro- 17 phosphorylisocyanate or chlorosulfonylisocyanate under 18 reflux for from about 30 minutes to about 2 hours. The 19 solvent is then removed under reduced pressure and the product taken up in a suitable solvent, for example tetra- 21 hydrofuran, and treated with the desired amine, for example 22 gaseous ammonia, an alkylamine such as methylamine or butyl- 23 amine, an aryl mine such as aniline or an aralkylamine such i as benzylamlne or a secondary amine such as morpholine . The mixture is allowed to stand for from 1 to i+ hours at from 26 10°C. to 30°C, filtered, and the solvent removed from the 27 filtrate under reduced pressure. The product is then iso- 28 lated. In a suitable procedure, the residue from the filtra- 29 tion is dissolved in water and any insoluble material is combined with the residue from the - -nation of the solvent 31 and the combined fractions recrys :: ·ά suitably from a 1 xx. 3-Nitro-5,6-dihydroimidazo-[l(2-c.3pyrrol-2 7-yl carbamates 3 3-Nitro- ,6-dihydroimidazo-[l,2-a]pyrrol-7-yl carbamates may be" prepared in the following manner: 3-nitro-7-oxo-5,6-dihydroimidazo-[l,2-a]pyrrole is 6 reduced to the corresponding 7-hydroxy compound and then 7 converted into the corresponding 7-yl carbamate by means 8 of any of the general procedures for the formation 9 carbamates disclosed in the present application, preferably 0 method ν·, wherein the hydroxy compound is reacted with a 1 phenylhaloformate and subsequently treated with an amine, 2 In the preferred modification of this procedure, 3-nitro-3 7-oxo-5,6-dihydroimidazo-[l,2-a]pyrrole is taken up in lower alkanol such as ethanol, and treated with a reducing 5 agent, suitably an organo metallic reducing agent, sodium 6 borohydride being especially suitable, and the reaction 7 mixture is allowed to stand at a temperature of from about 8 10°C. to about 25°G. for a period of from about i+ to about 9 8 hours. The product is then isolated. In the preferred 0 method, a small amount of a volatile acid suitably an organic 1 acid, such as a lower alkanoic acid, suitably acetic acid, 2 is added to decompose the excess borohydride. The reaction 3) mixture is concentrated to small volume under reduced pressure I . and an excess of water added slowly. The 3-nltro-7-oxo- 5#6-dihydroimidazo-[l,2-a]pyrrole separates as a precipitate 6 and is Isolated by filtration. , 7 * The dried 3-nitro-7-hydroxy-5,6-dihydroImidazo-8 [l,2-a]pyrrole is taken up in an organic base, suitably 9 pyridine, lutidine or collidine and treated with a phenyl-0 haloformate, suitably phenylchloroformate , and the reaction ί allowed to proceed and the product isolated as set forth in 2 Section I - v . above . The product , 3-ni tro-5,6-dihydro- 3 imidazo-[l ,2-a]pyrrol-7-yl phenyl carbonate is then taken up in a suitable inert organi c solvent , a halo hydrocarbon 5> such as chloroform being e specially suitable . Where i t is 6 desired to produce the corresponding carbamate itself , the 7 solution is added to an approximately equal ' volume of liquid 8 ammonia , maintained at a temperature of from about ~35PC . to 9 about -75°C . The reaction mixture is then worked up in the 0 usual manner and the product isolated . 1 Where it is d esired to obtain an N-substituted 2 carbamate , the solution of the 3-ni tro -5, -dihydroimidazo-3 [l ,2-a]pyrrol-7-yl"phenyl carbonate in chloroform, is reacted i with a substituted amine a s set forth in the various pro- ' · cedures for the preparation of these compounds hereinabove . 6 Among the products which may be produced in 7 accordance with this procedure are 3-nitro-5,6-dihydroimidazo-8 [l ,2-a]pyrrol-7-yl carbamate and the N-substituted derivati ves 9 thereof . 0 The l-substituted-2-imidazolylalkyl carbamates 1 of Formulas I and II above have antiprotozoal activity , 2 and are particularly active against the causative organisms 3 of the protozoal parasitic diseases trichomoniasis and 1L enterohepatitis . Certain of them are also effective against ^ amoebiasis and trypanosomiasis as well as agains t the PPLO 6 organisms and schistosomes . It will , of cours e , be under-7 stood that the compounds differ in their degree of efficacy 8 e ^ninst these various organisms . 9 Trichomoniasis is a protozoan disease caus ed 1 invention are effective against the particularly troublesome 2 form of trichomoniasis known as.T. vaginalis vaginitis, 3 caused by infestation of the vagina with T. vaginalis. ' In Zj. treating this disease, the imid&zolylalkyl carbamates may be administered either orally or topically. For oral 6 adminis ration unit dosage, forms such as tablets or capsules ; 7 are normally employed which may contain from about 50 to 8 about 00 mg. of active Ingredient. These are prepared by 9 techniques known in the art, and contain the usual diluents, granulating agents, extenders and/or lubricating agents known 11 to be satisfactory for the compounding of tablets and capsules. 12 It is preferred to administer the compounds of the invention 13 orally at a dose level of from about 2 - 1 ,000 mg./day, in I.Jj either single or divided doses with divided doses being used more frequently than a single daily dose. An example of a 16 suitable compressed tablet is the following: 17 Component Mg. per Tablet 18 l-Me hyl-5-nitrolmidazol-2- 19 ylmethyl carbamate 250 Dicalci m phosphate 100 21 Lactose 75 22 Starch 0 23 Guar gum 12 2i Magnesium stearate 2-3 If desired, tablets may be sugar coated or enteric 26 coated by standard techniques. Alternatively, the an i- 27 trichomona! agent may be formulated in capsule form using 28 fillers vsuch as lactose, starch or kaolin. A typical capsule 29 would contain 50 mg. of, for instance, 1-methyl -5-nitro-30 - imidazol- -ylmethyl methylcarbamate, 2-3 g» of magnesium 1 stearate and about 75 mg« of lactose in a No. 0 size capsule » 2 Tablets and capsules containin smaller quantities of active 3 ingredient may be made by reducing proportionately the amounts of excipients and diluents illustrated above* Alterna i ely, the carbamates may be administered orally in liquid pharma- 6 ceutical vehicles such as solutions, emulsions, syrups or 7 suspensions containing the diluents, flavoring agents and 8 preservatives customarily employed in the pharmaceutical art* 9 For topical application, vaginal creams or suppositories containin the active ingredient may be used. 11 To illustrate, a cream is prepared by mixing sufficient 12 quantities of hydrophilic ointment and water, containing 13 from s.bout $-10% by weight of carbamate, in sufficient llj. quantities to produce a cream having the desired consistency. 1 Representative examples of carbamates of this 16 invention that are highly active and thus particualrly use- 17 f l for treating tr chomonias s are: l-methyl-5-nitroimidazol- 18 2-ylmethyl carbamate, 1-methyl-5-nitroimidazol -2-ylmeth l 19 methylcarbamate , l-methyl-5-nitroimidazol-2-ylmethyl -.-morpholinecarboxylate , 1-methyl- -nitroimidazol-2-ylmethyl 0 21 thiolcarbamate, l-methyl-5-nitroimidazol -2-ylmethyl methyl- o 22 thioicarbamate, 1-methyl- -nitroimidazol-2-ylmethyl thio∑»- 23 carbamate, 1 -( 1 ' -methyl-5' -nitroimidazol-2 ' -yl )ethyl carbamate, 2I . l-(l,-methyl- ,-nitroi idazol-2,-yl)ethyl hydroxycarbamate, l-methyl-5-n:ltroinidazol-2-ylrcethyl hydroxyc rbamate, l-ethyl- 26 5-∑iitroimidazol-2-ylmethyl carbamate, and l-othyl-5-rxitro- 27 imidazol -2-ylmethyl hydroxycarbamate. These represent 28 preferred anti-trichomonal agents of the invention, although 2 -ol e other imidazolylalkyl carbamates of the invention are of value against this disease. 1 Enterohepatltis is a disease occurring primarily 2 in turkeys and is caused by the. protozoan parasite 3 Histomonas meleagridis. It is also known as turkey blackhead I4. disease. The imi azolylalkyl carbamates of this invention are useful in the prevention and treatment of this disease 6 and for this purpose are administered to turkeys mixed with 7 an element of turkey sustenance., i.e. in the feed or drink- 8 ing water. Although the optimum dose level will depend on 9 the particular compound employed and the severity of the infection, good control of enterohepatltis is obtained by 11 orally administering to the turkeys a feed containing from 12 about 0.003/2 to about 0.1 by weight of carbamate. When the 13 material is administered via the drinking water, somewha lij. higher levels may be employed, especially for therapeutic use. For instance, the drinking water may contain up to 16 about 0. by weight of the active ingredient with good 17 results. Those substances previously mentioned as preferred 18 an i-trichomonal agents are also among those preferred in 19 combating turkey blackhead, As previously stated, the imidazolylalkyl carbamates 21 described herei may also be employed against trypanosomiasis 22 and amoeblasis. In addition, certain of them, and particular- 23 ly l-methyl- -nitroimidazol-2-ylmeth l carbamate, 1-methyl-2I. 5-nitroimidazol-2-ylmethyl ydroxycarbamate and 1-ethyl- 2$ 5-nitroimidazol-2-ylmethyl carbamate, possess activity 26 against the pieuro-pneumonia like organisms whic have come 27 to be known as PPL0 organisms . 28 Certain of the substituted imidazoles which are 29 employed as intermediates in making these new imidazolylalkyl carbamates also possess useful anti-parasitic activity. Of 1 particular interest in this regard are the l-loweralkyl- 2 thiocyanoalkyl-5-nitroimidazoles , and especially 1-methyl- 3 2-thiocya_nomethyl-5-nitroiiriidazole · These compounds have ij. an i-trichomonal activit and may be employed against $ trichomoniasis in the same manner and within the same dose 6 levels as described previously for the imidazolylalkyl 7 carbamates · 8 The following examples are given for the purpose 9 of illustration and not by way of limitation.

EXAMPLE 1 l-Methyl-5-NitroimidazoI-2-yl-niethyl Chloroformate 3· 12 G. l-methyl-2-hydroxymethyl-5-nitrolmidazole is dissolved in a mixture of 4.3 ml. of dimethylaniline and 20 ml. of dioxane. This solution is then added dropwise . to 30 ml. of phosgene. The resulting suspension is stirred for two hours at 0-5°C, and then for two hours at room temperature. The solvent is then removed by blowing dry nitrogen through the suspension for two hours. The oil re-maining at the end of this time consists predominantly of l-methyl-5-nitroimidazol-2-ylmethyl chloroformate .

In accordance with the above procedure, but start-ing with l-methyl-2-mercap omethyl-5-nitroimidazole, i place of l-methyl-2-hydroxymethyl-5-nitroimidazole, there is obtained l-methyl-5-nitrolmidazol-2-yl-methyl chlorothio-formate.

In accordance with the above procedure and start-ing with either of the aforementioned nitroimidazoles but using thiophosgene in place of phosgene, there is obtained l-methyl-5-nitroimidazol-2-yl-methyl chlorothioformate and l-methyl-5-nitroimidazol-2-yl-methyl chlorodithioformate .

EXAMPLE 2 l-Methyl-5-Nitroimidazol-2-ylmethyl Carbamate 0.05 G. of l-methyl-5-nitroimidazol-2-ylmetnyl phenyl carbonate is dissolved slowly in 50 ml. of- liquid ammonia. After solution is complete, the ammonia is per-mitted to evaporate and the residue washed with ethanol and recry stallized from methanol to yield l-methyl-5-nitro-imidazol-2- lmeth l carbamate m. . 166-170°C.

In accordance with the above procedure, but start-ing with l-( l-methyl-5-nitroimidazol-2-yl) -ethyl phenyl carbonate, 2-(l-me-thyl-5-nitroimidazol-2-yl) -ethyl phenyl carbonate and 3-( l-methyl-5-nitroimidazol-2-yl) -prop-2-en-l-yl phenyl carbonate in place of l-methyl-5-nitroimidazol-2-yl-methyl phenyl carbonate there is obtained the correspond-ing l-( l-methyl-5-nitroimidazol-2-yl) ethyl carbamate, (m.p. 164-166°G) 2-(l-methyl-5-nitroimidazol-2-yl) ethyl carbamate/^ and 3-( l-methyl-5-nitroimidazol-2-yl)prop-2-enyl carbamate.

EXAMPLE 3 l-Methyl-5-Nitroimidazoi-2-ylmethyl Carbamate 3.12 G. of l-methyl-2-hydroxymethyl-5-nitroimida-zole is dissolved in 100 ml. of methylene dichloride and cooled to 0°C. 2.64 G. of sodium cyanate and 4.5 g. of trifluoroacetic acid are added. The flask is stoppered. tightly and the mixture stirred for 24 hours at 0°C. 200 Mi. of methylene chloride is then added and the mixture washed with saturated aqueous potassium bicarbonate solution. The methylene chloride solution is concentrated to dryness in vacuo to give a residue of i-methyl-5-nitro-2-imidazolyl-methyl carbamate. This solid is recrystallized from a minimum volume of ethyl acetate to give substantially pure l-methyl-5-nitroimidazol-2-ylmethyl carbamate; m.p. 166-170°C.

EXAMPLE 4 l-Methyl-5-Nitroimldazol-2-ylmethyl ThiolScarbamate 1.35 G. of l-methyl-2-chloromethyl-5-nitroimidazole is dissolved in 25 ml. of dr ethanol at room tem erature and 1.11 g. of potassium thiocyanate Is added, to this solu- . tlon. The resulting mixture is refluxed for two hours and then allowed to stand at room temperature for about 12 hours . It is warmed to about 75°C. on a steam bath and the solid material removed by filtration. The filtrate is diluted with an equal volume of water and the resulting solution chilled and scratched to induce crystallization. The solid which forms is removed by filtration, washed with ice-water and dried. It is l-methyl-2-thiocyanomethyl-5-nitroimida- zole; m.p. 87-88°C. This product is crystallized from a ■ minimum volume of benzene containing a trace of hexane to give yellow crystals of l-methyl-2-thiocyanomethyl-5- nitroimidazole; m.p. 87.5-38°C.

G. of l-methyl~2-thiocyanomethyl-5-nitroimidazole is added portionwise over a period of 15 minutes to 25 ml. of cold concentrated sulfuric acid. The resulting solution is held at 0°C. for about 14 hours and then poured onto an excess of crushed ice. The solution is adjusted to pH 6 with saturated potassium bicarbonate solution. The solid material is removed by filtration and washed with ice-water. The solid is extracted with about 10 ml. of ethyl acetate and the ethyl acetate solution dried over sodium sulfate and then concentrated essentially to dryness. A small volume of hexane is added to the residue and the solid l-methyl-5- nitro-2-imidazolylmet'hyl thiol¾arbamate removed by filtra- tion. There are obtained in this way 4.34 g. of 1-methyl- 5-nitroimidazol-2-ylmethyl thi Carbamate; m.p. 138-l40°C.

EXAMPLE l-Methyl-5-Nitroimldazol-2-ylm¾triyl Carbamate l-Methyl-5-nitroimidazol-2-ylmethyl chloroformate as obtained in accordance with Example 1 is cooled to 0°C. and 25 ml. of liquid ammonia added thereto. The resulting mixture is stirred for 10 minutes in the cold and then an additional 25 ml. of liquid ammonia is added. The mixture is then allowed to warm to room temperature and stirred until the excess ammonia evaporates. The residue thus obtained is dissolved in 100 ml. of water and the aqueous solution extracted with three 100 ml. portions of ethyl acetate. The ethyl acetate extracts are combined, bacic-washed with 25 ml. of water and then dried over sodium sulfate. The ethyl acetate is then concentrated to dryness in vacuo to give a residue consisting of l-methyl-5-nitro-imidazol-2-ylmethyl carbamate. The product is recrystallized. from ethyl acetate and then from water to give substantially pure material; m.p. 172-173°C.

In accordance with the above procedure but start-ing with l-methyl-5-nitroimidazol-2-ylmethyl chlorothiol>-formate, l-methyl-5-nitroimidazol-2-ylmethyl chlorothione-formate, l-methyl-5-nitroimidazol-2-ylmethyl chlorodithio-formate in place of l-methyl-5-nitroimidazol-2-ylmethyl chloroformate , there is obtained the corresponding 1-methyl- o -nitroimidazol-2-ylmethyi thiol/carbamate , l-methyl-5- o nitroimidazoi-2-ylmethyl thiorcarhamate , and l-methyl-5-nitroim.idazol-2-yimethyl dithiocarbamate .

EXAMPLE 6 l-Methyl-5-Nltroimidazol-2-ylmethyl Carbamate 3-1 G., .(0.02 mole) of ( l-methyl-2-hydroxymethyl) -5-nitroimidazole is dissolved in 100 ml* of benzene and ml. of pyridine. 1.9 G., (0.022 mole) of gaseous carbamyl chloride is introduced into the stirred, solution. The solution is allowed to stand at 15°C. for 8 hours and then concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed with ice-water, and the ethyl acetate extract dried over sodium sulfate. On evapora-tion of the solvent under reduced pressure, the residue is recrystallized from acetone or ethyl acetate to yield 1-methyl-5-nitroimidazol-2-ylmethyl carbamate; m.p. 166-170°C.

In accordance with the above procedure but using dimethylcarba yl chloride or diethylcarbamyl chloride and adding these reagents in liquid rather than gaseous form to the reaction mixture in place of using carbamyl chloride, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N,N-dimethyicarbamat.e and l-methyl-5-nitroimida-zol-2-ylmethyl N ,N-diethyicarbamate .

In accordance with the above procedure but using thiocarbamoyl chloride, dimethylthiocarbamoyl chloride, and diethylcarbamoyl chloride, in place of carbamoyl methyl Ν,Ν-^dimethylthior/carbamate, and l-methyl-5-nitro- o imldazol-2-ylmethyl N, -diethylthior6arbamate .

EXAMPLE 7 l-Methyl-5-Nitroimidazol-2-ylmethyl Thioffcarb mate 3*5 G., (.02 mole) of l-methyl-2-mercapto methyl-5-nitroimidazole is dissolved in 100 ml.- of benzene and ml. of pyridine under nitrogen. 1.9 G. , (0.022 mole) of gaseous carbamoyl chloride is introduced into the. stirred solution. The solution is allowed to stand at 15°C . for 8 hours and then concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed with ice-water and the ethyl acetate extract dried over sodium sulfate.

On evaporation of the solvent under reduced pressure, the residue is recrystallized from acetone or ethyl acetate to o yield l-methyl-5-nitroimidazol-2-ylmethyl thio3carbamate; m.p. 138-1 0°C.

In accordance with the above procedure but using dimethylcarbamoyl chloride or diethylcarbamoyl chloride and adding these reagents in liquid rather than gaseous form to the reaction mixture in place of carbamoyl chloride, there is obtained the corresponding l-methyl-5-nitroimidazol- o 2-ylmethyl Ν,Ν-dimethylthio-lcarbamate and l-methyl-5-nitro-imidazol-2-ylmethyl N, -diethylthio]/carbamate.

In accordance with the above procedure but using thiocarbamoyl chloride and dimethylthiocarbamoyl chloride and diethylcarbamoyl chloride, in place of carbamoyl chloride, there is obtained l-met.hyl-5-nitroimidazol-2-yl-methyl dithiocarbamate, l-methyl-5-nitroimidazol-2-ylmethyl Ν,Ν-dimethyldithiocarbamate, and l-methyl-5-nltroimidazol-2-ylmethyl N,N-diethyldithiocarbamate.

» EXAMPLE 8 ' l-Methyl-5-Nitroimidazoi-2-ylme'thyI Carbamate 1.57 G. ,- (0.01 mole) of l-methyl-2-hydroxymethyl- 5-nitroimidazole, 0.1 g. sodium ethoxlde, 10 g. of ethyl carbamate, and 20 ml. of benzene are heated under reflu for 2 hours. The solvent is removed under reduced pressure and the residue stirred with 10 ml. of water. . The mixture is extracted with ethyl acetate. The ethyl acetate fraction is dried over sodium sulfate and evaporated to give crude l-methyl-5-nltroimidazol-2-ylmethyl carbamate.

In accordance with the above procedure but start- ing with l-methyl-2-mercaptomethyl-5-nitroimidazolei in place of l-methyl-2-hydroxy methyl-5-nitroimidazole and using ethyl carbamate, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl thio¾arbamate .

EXAMPLE 9 ' l-Methyl-5-Nltroiraidazol-2-ylmethyl Methylcarbamate 6 G. of l-methyl-2-hydroxymethyl-5-nitroimidazoIe and 3.5 ml. of methyl isocyanate are added to 200 ml. of benzene containing 0.5 ml. of pyridine. The resulting mix- ture is refluxed until complete solution is obtained. The solvent is then removed b evaporation under reduced pressure. The partially crystalline material thus obtained is recrystallized from 12 ml. of water to give 1.14. g. of l-methyl-5-nitroimidazol-2-ylm'ethyl methylcarbama e; m.p. 99-101?C.

In accordance with the above procedure, but start- ing with l-methyl-2-mercaptomethyl-5-nitroimidazole, in - - - - - z ere is EXAMPLE 10 o l-Methyl-5-Nitroimidazol-2-ylmethyl Methylthioncarbamate 0.5 G. of l-methyl-2-hydroxymethyl-5-nitroimidazole and 0.28 g. of methyl isothiocyanate are added -to 20 ml. of benzene containing 0.54 ml. of triethylamine . The resulting mixture is refluxed for 23 hours. It is then concentrated almost to dryness in vacuo and the solid material removed by filtration. This product is l-methyl-5-nit^imidazoles 2-ylmethyl methylthioiycarbamate; m.p. 133.5-135°C. It is recrystallized from water to give substantially pure material; m.p. 135.5-136°C.

In accordance with the above procedure, but start-· ing with l-methyl-2-mercaptomethyl-5-nitroimidazole, in place of l-methyl-2-hydroxymethyl-5-nitroimidazole, there is obtained the corresponding l-methyl-5-nitroimidazol-2-yl- methyl dithiocarbamate .

EXAMPLE 11 2-(l-Methyl-5-Nitroimidazol-2-ylmethyl) Pseudourea Hydro- fluoroborate A mixture of 3.12* g., (0.02 mole) of l-methyl-2- hydro ymethyl-5-nitroimidazole, 2.6 ml. of boron trifluoride diethylether, 50 ml. of 1,2-dimethoxyethane, and 1.0 g. of cyanamide is allowed to stand at 0°C. for 3 days. Anhydrous hydrogen fluoride (0.02 mole) in about 10 ml. of benzene is added. After the addition of another 40 ml. of benzene, the product 2 (l-methyl-5-nitroimidazol-2-ylmethyl) .pseudourea hydrofluoroborate is obtained by filtration.

EXAMPLE 12 2-(l-Methyl-5-Nitroimidazol-2-ylmethyl)-l,3-Diethylpseudo- urea Hydrochloride hydroxymethyl-5-nitroimidazoIe, 2.0 g., (0.02 mole) of dlethylcarbodiimide and 100 ml; of 1,2-dimethoxyethane is allowed to stand at room temperature for 2 'days . The.. addition of gaseous hydrogen chloride (0.7 g.), followed by 50 ml. of hexane results in the crystallization of product. After filtration, and washing with diethyl ether,-2-(l-methyl-5-nitroimidazol-2-ylmethyl)-l,3-diethylpseudo- . urea hydrochloride is obtained.

EXAMPLE 13 S-(l-Methyl-5-Nitroimidazol-2-ylmethyl) Pseudothiourea Hydrochloride : - 0.25 G., (.0016 mole) of l-methyl-2-chloroir.ethyl-5-nitroimidazole and 0.106 g., (.0014 mole) of thiourea are added to 2 ml. of dry ethanol and the resulting mixture re-fluxed for 17 hours. At the end of this time, the mixture is cooled to about 15°C. and the solid material removed by filtration. The solid product is washed with a few ml. of alcohol and etherj and air-dried. Recrystallization is accomplished from a mixture of 4-5 ml. of ethanol and 2-3 ml. of methanol. The solution is filtered hot, then con-centrated to a volume of about 6 ml. and chilled. The S-( l-methyl-5-nitroimidazol-2-ylmethyl) isothiouronium chloride is filtered, washed with alcohol and then ether, and dried to give substantially pure material; m.p. 200°C.

In accordance with the above procedure but start-ing with l-methyl-2-chloromethyi-5-nitroimidazole, 1-methyl-2-(l,-chloroethyl) -5-nitroimidazole, l-acetoxyethyl-2-chloromethyl-5-nitroimidazole, in place of l-methyl-2-chloromethyl-5-nitrolmidazole, there is obtained the corres-ponding S-(l-methyl-5-nitroimidazol-2-ylmethyl)-pseudo- . pseudo-thiourea, and S-(l-acetoxyethyi-5-nitroimidazol-2-ylmethyl) -pseudo-thiourea.

Similarly, but using dimethylthiourea in place of thiourea, there is obtained the corresponding S-( l-methyl-5-nitroimidazol-2-ylmethyl)-pseudo-dimethylthiourea.

EXAMPLE 1 2-(l-Methyl-5-Nitroimidazol-2-ylmethyl-thio)-2-Imidazoline 0.175 G. (0.001 mole) of l-methyl-2-chloromethyl-5-nitroimidazole and 0.102 g. (0.001 mole) of imidazolidine-2-thione are dissolved in 5 mli of ethanol and heated under reflux for 30 minutes, after which time a crystalline precipitate is produced. The mixture is heated under re-flux for a further 2 hours, cooled and filtered to yield 2-(l-methyl-5-nitroimidazol-2-ylmethyl-thio)-2-imidazoline; m.p. 220-226°C. (dec).

EXAMPLE 15 l-n-Butyl-5-Nitroimidazol-2-ylmethyl Carbamate ' A mixture of 1β·9 - (0.1 mole) of l-n-butyl-5-nitroimidazole, 15 g. (0.5 mole) of paraformaldehyde and 150 ml. of dimethyisulfoxide is heated in a sealed tube overnight at 110-150°C. The dimethyisulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina*. Elution with ethyl acetate and evaporation of the solvent yields l-n-butyl-2-hydroxymethyl-5-ni'tro-imidazole.

A solution of 2.0 g. (0.01 mole) of l-n-butyl-2- is stirred at 0°C. and 1.85 g. (0.012 mole) of phenyl chloro ormate is slowly added; The reaction mixture is stirred for 3- hours at room temperature and is poured, into about 200 ml. of water. The mixture is cooled overnight and the precipitate of l-n-butyl-5-nitroimidazol-2-ylmethyl phenyl carbonate is separated by filtration.

A solution of 640 mg. (0.002 mole) of 1-n-butyl-5-nitroimidazol-2-ylmethyl phenyl carbonate in 10 ml. of chloroform, cooled in an ice-bath, is saturated with dry ammonia. The mixture is allowed to stand for 1 day at 5°C. l-n-Butyl-5-nitroimidazol-2-ylmethyl carbamate is obtained after evaporating the solvent and washing the residue with water.

In accordance with the above procedure, but start-ing with l-methyl-5-nitroimidazole, l-ethyl-5-nitroiraidazole and l-propyl-5-nitroimidazole, in place of l-n-butyl-5-nitroimidazole, there is obtained the corresponding 1-methyl-5-nitroimidazol-2-ylmethyl carbamate, l-ethyl-5-nitroimidazol-2-ylmethyl carbamate, and l-propyl-5-nitro-imidazol-2-ylmethyl carbamate.

EXAMPLE 16 l-Benzyl-5-Nitroimidazol-2-ylmethyl Carbamate A mixture of 20.3 g. (0.1 mole) of l-benzyl-5-nitroimidazole, 15 g. (0.5 mole) of paraformaldehyde and 150 ml. of dimethylsulfoxide is, heated in a sealed tube overnight 'at 110-150°C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-benzyl-2-hydroxymethyl-5-nitroimidazole .

A solution of 2.3 g. (0.01 mole) of l-benzyl-2-hydroxymethyl-5-nitroimidazole in 25 ml. of dry pyridine is stirred at 0°C. and 1.85 g. (0.012 mole) of phenyl chloro-formate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled overnight and the precipitate of l-benzyl-5-nitroimidazol-2-ylmethyl phenyl carbonate is separated by filtration.

A solution of 706 g. (0.002 mole) of 1-benzyl-5-nitroimidazol-2-ylmethyl phenyl carbonate in 10 ml. of chloroform, cooled in an ice-bath, is saturated with dry ammonia. The mixture is allowed to stand for 1 day at 5°C. l-Benzyl-5-nitroimidazol-2-ylmethyl carbamate is obtained crystalline after evaporating the solvent and washing the residue with water.

EXAMPLE 17 l-Allyl-5-Nitroimidazol-2-ylmethyl Carbamate A mixture of 15.3 g- (0.1 mole) of l-allyl-5-nitroimidazole, 15 g. (0.5 mole) of paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 110-150°C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields i-allyl-2-hydroxymethyl-5-nitroimidazole .

A solution of 1.83 g. (0.01 mole) of l-all i-2- hydroxymethyl-5-nitroimidazole in 25 ml. of dry pyridine is stirred at 0°C. and 1.85 g. (0.012 mole) of phenyl chloro- formate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled overnight and the precipitate of l-allyl-5-nitroimidazol-2-ylmethyl phenyl carbonate is separated by filtration.

A solution of βθβ mg. (0.002 mole) of i-aliyl-5- nitroimidazol-2-ylmethyl phenyl carbonate in 10 ml.' of chloroform, cooled in an ice-bath, is saturated with dry ammonia. The mixture is allowed to stand for 1 da at 5°C. l-Allyl-5-nitroimidazol-2-ylmethyl carbamate is obtained crystalline after evaporating the solvent and washing the residue with water. ΞΧAMPLE 18 l-Phenyl-5- itroiniidazol-2-ylmethyl Carbamate A mixture of 13.9 g. (0.1 mole) of l-phenyl-5-' nitroimidazole, 15 g. (0.5 mole) of paraformaldehyde and 150 mi. of dimethylsulfoxide is heated in" a sealed tube overnight at 110-150°C. The dimethylsulfoxide is removed completely at reduced pressure, t and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column alumina. Elution with ethyl acetate and evaporation of the solvent yields l-phenyl-2-hydroxymethyl-5-nitroimidazoie . 1 A solution of 2.19 g. (0.01 mole) of l-phenyl-2- 2 hydroxymethyl-5-nitroimidazole in 25 ml. of dry pyridine 3 is stirred at 0°C and 1.85 g. (0.012 mole) of phenyl 4 chloroformate is slowly added. The reaction, mixture is stirred for 3-4 hours at room temperature and is poured into C about 200 ml. of water. The mixture is cooled overnight 7 and the precipitate of i-phenyl-5-nitroimidazol-2-ylmethyl S phenyl carbonate is separated by filtration. 9 A solution of .678 mg. (0.002 mole) of i-phenyl-5-0 nitroimidazol-2-yimethyl phenyl carbonate in 10 ml. of 1 chloroform, cooled in an ice-bath, is saturated with dry 2 ammonia. The mixture is allowed to stand for 1 day at 5°C. 3 i-Phenyl-5-nitrolmidazol-2-ylmethyl carbamate is obtained' 4 crystalline after evaporating the solvent and washing the 5 residue with water. 6 EXAMPLE 19 7 l-p-Nitro Phenyl- -Nitroirnidazol-2-ylmethyl Carbamat o A mixture of 23.4 g. (0.1 mole) of 1-p-nitro 9 phenyl-5-nitroimida ole, 15 g. (0.5 mole) of paraformalde-0 hyde and 150 ml. of dimethylsulfoxide is heated in a sealed 1 tube overnight at 110-150°C. The dimethylsulfoxide is 2 removed completely at reduced pressure, and the residue is 3 dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue 5 is dissolved in ethyl acetate, and the solution is charged 6 on a column of alumina. Eiution with ethyl acetate and 7 evaporation of the solvent yields 1-p-nitro phenyl-2-8 hydroxymethyl-5-nitroimidazol . 9 A solution of 2.64 . (0.01 mole of 1- -nitro pyridine is stirred at 0°C. and 1.05 g. (0.012 mole) of phenyl chloroforraate is slowly" added. The reaction mixture · is stirred for 3-Vnours at room temperature and is poured into about 200 ml. of water. The mixture is cooled overnight and the' precipitate of 1-p-nitro phenyl-5-nitroimida-zol-2-ylmethyl phenyl carbonate is separated by filtration.

A solution of .763 mg. (0.002 mole) of 1-p-nitro phenyl-5-nitroimidazol-2-ylmethyl phenyl carbonate in ml. of chloroform, cooled in an ice-bath, is- saturated with dry ammonia. The mixture is allowed to stand for 1 day at 5°C. 1-p-Nitro phenyi-5-nitroimidazol-2-ylmethyl carbamate is obtained crystalline after evaporating the solvent and washing the residue with water. .

EXAMPLE 20 l-( 2 T -Acetoxyethyl) -5-Nitroimidazol-2-ylmethyl Carbamate and l-( t-Hydroxyethyi)-¾-Nitroimida ol-2-ylmethyl Carbamate A mixture of 24.25 g. of l-(2 ' -acetoxyethyl) -5-nitroimidazole , 15 g. (0.5 mole) of paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 110-150°C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-( ' -acetoxyethyl) -2-hydroxymethyl-5-nitroimidazole; m.p. 13o-l45°C.

A solution of 1 g. of l-(2'-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazoie in 25 ml. of dry pyridine is formate Is slowly added. The reaction mixture is stirred for 3- hours at room temperature and is poured into about 200 ml. of water. -The mixture is cooled overnight -and the precipitate of l-( 2 ' -acetoxyethyl) -5-nitroimidazol-2-ylmethyl phenyl carbonate, m.p. 93-95°C, is separated by filtration. ■1.5 G. of l-( 2' -acetoxyethyl) -5-nitroimIdazol-2-ylmethyl phenyl carbonate is dissolved slowly in 50. mi. ' of liquid ammonia. ' After solution s complete, the ammonia is permitted to evaporate and the residue washed with ethanol and recrystaiiized to yield l-( 2 '-acetoxyethyl) -5-nitroimidazol-2-ylmethyl carbamate; m.p..160-162°C. o G. of l-(2 ' -acetoxyethyl) -5-nitroimidazoi-2-ylmethyl carbamate is dissolved in 100 mi. of ethanol and the solution saturated with ammonia. The mixture is allowed to stand for 12 hours at 15°C. and the solvent re- . moved by evaporation under reduced pressure. The residue is washed with methanol to yield l-( 2 ' -hydroxyethyl) -5-nitroimIdazol-2-ylmethyi carbamate; m.p. 150-152°C.

EXAMPLE 21 l-( 2 ' -Hydroxypropyl)-5-Nitroimidazol-2-ylmethyl Carbamate A mixture of 21.3 g. (0.1 mole) of l-( 2 ' -acetoxy-propyl) -5-nitroimidazole j ±5 g. (0.5 mole) of paraformaldehyde and 150 ml. of dimeth lsuifoxide is heated In a sealed tube overnight at 110-150°C. The dimethylsui oxide is removed, completely at reduced pressure, and the residue is., dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue - evaporation of the solvent yield l-( 2 '-acetoxypropyl) -2-hydroxymethyl-5-nitroimidazole;- m.p. 150-155°C.

A solution of 2.43 g. (0.01 mole) of l-(2'-acetoxypropyl)-2-hydroxymethyl-5-nitroimidazole in 25 ml. of dry pyridine is stirred at 0°C. and I.85 g. (0.012 mole) of phenyl chloroforma e is slowly added. The reaction mixture is stirred for 3- hours at room temperature and is . poured into about 200 ml. of water. The mixture is cooled overnight and the precipitate of l-( ' -acetoxypropyl)-5-nitroimidazol-2-ylmethyl phenyl carbonate is separated by filtration.

A solution of 726 mg. (0.002 mole) of l-(2'-acetoxypropyl) -5-nitroimidazol-2-ylmethyl phenyl carbonate in 10 ml. of chloroform, cooled in an ice-bath, is saturated with dry ammonia. It is allowed to stand for days at 5°C. l-( 2' -acetoxypropyl) -5-nitroimidazol-2-yl-methyl carbamate is obtained crystalline, m.p. 106-108°C, after evaporating the solvent and washing the residue with water.

The l-( 2' -acetoxypropyl)-5-nitroimidazol-2-yl-methyl carbamate produced as above is redissolved in methanol and the solution saturated with anhydrous ammonia. The mixture is allowed to stand for 2 days at 15°C. and concentrated under reduced pressure. The residue is re-crystallized from ethyl acetate, ethyl alcohol or a mixture of the two,' to yields l-( 2 '-hydroxypr0pyl)-5-nitroimidazol-2-ylmethyl carbamate.

In accordance with the above procedure, but start-ing with l-(2'-acetoxybutyl)-5-nitroimidazole, l-(2 '-acetoxy- - - - '- - - - imidazole, l-( 3 '-acetoxypentyl)-5-nitroimidazole and l-(3'-acetoxypropyl)-5-nitroimidazole-> in place of l-(2 '-acetoxy-propyl) -5-nitroimidazole, there is obtained the correspond-ing l-(2'-hydroxybutyl)-5-nitroimidazol-2-ylmethyl carbamate, l-(2'-hydroxypentyl)-5-nitroimidazol-2-ylmethyl carbamate, l-( 3 '-hydroxybutyl)-5-nitroimidazol-2-ylmethyl carbamate, l-(3 · -hydroxypentyl)-5-nitroimidazol-2-ylmethyl carbamate and l-( 3 '-hydroxypropyl)-5-nitroimidazol-2-yl-methyl carbamate, and the corresponding l-(acetoxyalkyl)-5-nitroimidazol-2-ylmethyl carbamate analogs thereof.

In accordance with the above procedure, but using the proplonoxy, butyroxy or valeroxy analogs of any of the aforementioned l-hydroxyalkyl-5-nitroimidazoles as starting materials in place of the l-acetoxyalkyl-5-nitroimidazoles utilized above, there are obtained the corresponding l-alkanoyloxyalkyl-5-nitroimidazol-2-ylmethyl' carbamates and l-hydroxyalkyl-5-nitroimidazol-2-ylmethyl carbamates.

EXAMPLE 22 l-( 2 ' -Oxopropy1) -5-Nitroimldazo -2-ylmethyl Carbamate .5 G., (0.1 mole) of l-( 2-oxopropyl)-5-nitro-imidazole hydrochloride is dissolved in 100 ml. 1,2-ethylenedithiol and dry gaseous hydrogen chloride passed through the solution for 30 minutes. The excess dithio-glycol is removed by evaporation under high vacuum. The residue treated with aqueous sodium bicarbonate, taken up in ethyl acetate, dried over sodium sulfate and the solvent removed by evaporation under reduced pressure to yield l-( 2 '-methyl-1» , 3 ' -dithiolan-21 -ylmethy1) -5-nitroimidazole . The dithlolane is dissolved in 125 ml. of dimethyl sulfoxide 1 tube at 120°C. for 2k hours. Excess paraformaldehyde is 2 removed by centrlfugation and the dimethyl sulfoxide is 3 removed by high vacuum concentration. The residue is k dissolved in acetone and centrifuged to remove insoluble paraformaldehyde. After concentration, the residue is 6 dissolved in ethyl acetate, thoroughly washed with water, 7 dried and treated with dry hydrogen chloride to give a 8 precipitate of l-(2 '-methyl-l · ,3 f-dithiolan-2 '-ylmethyD- 9 5-nitroimidazol-2-ylmethanol hydrochloride which is separated 0 by filtration. The thus produced 5-nitroimidazol-2-yl-1 methanol derivative is dissolved in 100 ml. of dry pyridine 2 and treated with 12.5 g., (0.08 mole) of phenyl chloro-3 formate at ice-bath temperature. After k hoursat room 4 temperature, the mixture is concentrated to dryness, taken 5 up in water, neutralized with sodium bicarbonate and 6 extracted into ethyl acetate. After thorough washing with 7 water, the solution is dried and concentrated. The product 8 is triturated with ether and filtered to yield l-(2 '-methyl-9 1 ' , 3 ' -dithiolan-2 · -ylmethyl) -5-nitroimidazol-2-ylmethyl 0 phenyl carbonate. The product (5-0 g.) is treated with dry 1 liquid ammonia (25 ml.) at -33°C. for 2 hours. After re-2 moval of the liquid ammonia, the residue is warmed on a 3 steam-bath for one hour with 100 ml. 1 N aqueous hydrochloric k acid to hydrolyze the dithiolane. The mixture is concen-5 trated to dryness to yield the hydrochloride of l-(2*-6 oxopropyl)-5-nitrolmidazol-2-ylmethyl carbamate. The 7 product may be further purified by recrystallization from 8 acetone. 9 Treatment with aqueous sodium bicarbonate followed 0 b extraction with eth l acetate and removal of the solvent - _ 1 In accordance with the above procedure, but start- 2 ing with l-( 2' -oxobutyl)-5-nitroimidazole, l-(2'-oxopentyl)- 3 5-nitroimidazole, l-( 3 ' -oxobutyl-5-nitroimidazole, and 4 l-( 3 '-oxopentyl) -5-nitroimidazole, in place of l-(2.'-oxo- 5 propyl)-5-nitroimidazole, there is obtained the corresponding 6 l-(2f-oxobutyl)-5-nitroimidazol-2-ylmethyl carbamate, 7 l-(2,-oxopentyl)-5-nitroimidazol-2-ylmethyl carbamate, 8 l-( 3'-oxobutyl)-5-nitroimidazol-2-ylmethyl carbamate, and 9 l-(3,-oxopentyl)-5-nitroimidazol-2-ylmethyl carbamate..

EXAMPLE 23 11 l-( 2 '-Ethoxyethyl)-5-Nitroimidazol-2-ylmethyl Carbamate 12 A mixture of 9.2 g. (0.05 mole) of l-(2'-ethoxy- 13 ethyl) -5-nitroimidazole, 15 g. (0.5 mole) of paraformalde- 14 hyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 110-150°C. The dimethylsulfoxide is 16 removed completely at reduced pressure, and the residue is 17 dissolved in water and extracted with chloroform. The 18 chloroform extract is dried and concentrated. The residue 19 is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and 21 evaporation of the solvent yields l-( 2' -ethoxyethyl)-2- 22 hydroxymethyl-5-nitroimidazole. 23 A solution of 1.99 g. (0.01 mole) of l-(2'-ethoxy- 2 ethyl)-2-hydroxymethyl-5-nitroimidazole in 25 ml. of dry pyridine is 'stirred at 0°C. and 1.85 g. (0.012 mole) of 26 phenyl chloroformate is slowly added. The reaction mixture 27 is stirred for 3-4 hours at room temperature and is poured 28 into about 200 ml. of water. The mixture is cooled over- - ' - - - - imidazol-2-ylmethyl phenyl carbonate is separated by filtra-tion. 3.19 G. of l-(2,-ethoxyethyl)-5-nitroimidazol-2-ylmethyl phenyl carbonate is dissolved slowly in 50 ml. of liquid ammonia. After solution is complete, the ammonia is permitted to evaporate. The residue is washed with ethanol and recrystallized from methanol to yield l-(2'-ethoxyethyl-5-nitroimidazol-2-ylmethyl carbamate.

In accordance with the above procedure, bu start-ing with l-( 2' -methoxyethyl) -5-nitroimidazole, l-(2'-propoxyethyl)-5-nitroimidazole, l-(2'-butoxyethyl)-5-nitroimidazole, l-( 2 '-benzyloxyethyl)-5-nitroimidazole, l-(2'-ethoxypropyl)-5-nitroimidazole, l-( 2 '-ethoxybutyl)-5-nitroimidazole, and l-(2 '-ethoxypentyl)-5-nitroimidazole , in place of l-(2 '-ethoxyethyl)-5-nitroimidazole, there is obtained the corresponding l-( 2' -methoxyethyl) -5-nitro-imidazol-2-ylmethyl carbamate, l-(2'-propoxyethyl)-5-nitro-imidazol-2-ylmethyl carbamate, l-(2'-butoxyethyl)-5-nitro-imidazol-2-ylmethyl carbamate, l-(2'-benzyloxyethyl)-5-nitroimidazol-2-ylmethyl carbamate, l-(2'-ethoxypropyl)-5-nitroimidazol-2-ylmethyl carbamate, l-(2f-ethoxybutyl)-5-nitroimidazol-2-ylmethyl carbamate, and l-(2'-ethoxypentyl)-5-nitroimidazole-2-ylmethyl carbamate EXAMPLE 24 · · -.

Ethyl 2-Carbamoyloxymethyl-5-Nitroimidazol-l-ylacetate * A mixture of 0.1 mole of ethyl-5-nitroimldazol-l-ylacetate, 15 g. (0.5 mole) of paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at reduced pressure, and the residue is dissolved in water and extracted with chloroform. 'The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina.. Elution with ethyl acetate and evaporation of the solvent yields ethyl 2-hydroxymethyl-5-nitroimidazol-l-ylacetate .

A solution of 0.01 mole of ethyl 2-hydroxymethyl-5-nitroimidazol-l-ylacetate in 25 ml. of dry pyridine is stirred at 0°C. and 1.85 g. (0.012 mole) of phenyl chloro-formate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled overnight and' the precipitate of ethyl 2-phenoxycarbonyloxymethyl-5-nitroimida-zol-l-ylacetate, m.p. 106-108°C, is separated by filtra-tion. 2.0 G. of ethyl 2-phenoxycarbonyloxymethyl-5-nitroimidazol-l-ylacetate is dissolved slowly in 20 ml. of liquid ammonia. After solution is complete, the ammonia is permitted to evaporate and the residue washed with ethanol and recrystallized from methanol to yield ethyl 2-carbamoyioxymethyl-5-nitroimidazol-l-ylacetate .

In accordance with the above procedure but start-ing with methyl-5-nitroimidazol-l-yl acetate, propyl-5-nltroimidazol-l-yl acetate, butyl-5-nitroimidazol-l-yl acetate, ethyl-5-nitroimidazol-l-yl propionate, methyl-5-nitroimidazol-l-yl propionate, propyl-5-nitroimidazol-l-yl propionate, and butyl-5-nitroimidazol-l-yl propionate, in place of ethyl-5-nitroimidazol-l-yl acetate, there is obtained the corresponding methyl-2-carbamoylmethyl-5-nitroimidazol-l-yl acetate, propyl-2-carbamoylmethyl-5- 1 nitroimidazol-l-yl acetate, ethyl-2-carbamoylmethyl-5- " 2 nitroimidazol-l-yl propionate, methyl-2-carbamoylmeth l-5- , 3 nitroimidazol-l-yl propionate, propyl-2-carbamoylmethyl-5- nitroimidazol-l-yl propionate, and butyl-2-carbamoylmethyl- 5 5-nitroimidazol-l-yl propionate.

EXAMPLE 25 Ethyl 2-Carbamoyloxymethyl-5-Nitroimidazol-l-ylacetamide 8 Ethyl 2-carbamoyloxymethyl-5-nitroimidazol-l-yl- 9 acetate, as obtained from the procedure set forth in Example. 24, is dissolved in 10 ml. of methanol saturated with 11 gaseous ammonia at 0°C, sealed in a tube and heated at 12 60°C. for 2 hours. The reaction mixture is concentrated 13 under reduced pressure and the residue recrystalllzed from 14 ethyl acetate to yield 2-carbamoyloxymethyl-5-nitroimidazol- 15 1-ylacetamide; m.p. 221-223°C. 16 In accordance with the above procedure, but start- 17 lng with any of the alkyl 2-carbamoyloxymethyl-5-nitro- 18 imidazol-l-ylalkanoates produced in accordance with the 19 previous example, there are obtained the corresponding 2-carbamoyloxymethyl-5-nitroimidazol-l-ylacetamide or 21 2-carbamoyloxymeth 1-5-nitroimidazol-l-ylpropionamide. 22 EXAMPLE 26 23 l-(2 t-Carbamoyloxyethyl)-5-Nitroimidazol-2-ylmethyl Carbamate 24 A -mixture of 0.1 mole of l-(2 '-hydroxyethyl)-5- 25 nitroimidazole , 5 g. (0.015 mole) of paraformaldehyde and 26 .150 ml. of dlmethylsulfoxlde is heated in a sealed tube over- 27 night at 110-150°C. The dlmethylsulfoxlde is removed 28 completely at reduced pressure, and the residue is dissolved extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-( 2 ' -hydroxyethyl) -2-hydroxymeth l-5-nitroimidazole.

A solution of 1.3 g. of l-( 2' -hydroxyethyl) -2-hydroxymethyl-5-nitroimidazole in 25 ml. of dry pyridine is stirred at 0°C. and 2.2 g. of phenyl chloroformate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is extracted with ethyl acetate, the extract dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue l-(2'-hydroxyethyl) -5-nitrolmidazol-2-ylmethyl phenyl carbonate is dissolved in 10 ml. of chloroform and the solution added to 50 ml. of dry liquid ammonia. The ammonia is allowed to evaporate and the residue recrystalllzed from ethyl acetate to yield l-(2 '-carbamoyloxyethyl)-5-nitroimidazol-2-ylmethyl carbamate; m.p. 174-175°C.

EXAMPLE 27 Ν,Ν-Diethyl 2-Carbamoyloxymethyl-5-Nitroimidazol-l-yl-acetamlde ' A mixture of 22.6 g. (0.1 mole) of N,N-diethyl-5-nitroimidazol-l-ylacetamide, 15 g. (0.5 mole) of para-formaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube Overnight at 110-150°C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and, concentrated. The residue is dissolved in ethyl acetate, and the solution is charged evaporation of the solvent yields Ν,Ν-diethyl 2-hydroxy-methyl-5-nitroimidazol-l-ylacetamide.

A solution of 2.56 g. (0.01 mole) of N,N-diethyl 2-hydroxymethyl-5-nitroimidazol-l-yl-acetamide in 25 ml, of dry pyridine is stirred at 0°C. and 1.85 g. (0.012 mole) of phenyl chloroformate is slowly added. The reaction mixture is stirred for 3- hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled overnight and the precipitate of 1-(N' ,N'-diethyl-carbamoylmethyl)-5-nitroimidazol-2-ylmethyl phenyl carbonate is filtered. 2.0 G. of 1-(N» jN'-diethylcarbamoylmethyD-S-nitroimidazol-2-ylmethyl phenyl carbonate is dissolved in 50 ml. of liquid ammonia. After solution is complete, the ammonia is permitted to evaporate and the residue washed with ethanol and recrystallized from methanol to yield Ν,Ν-diethyl 2-carbamoylmethyl-5-nitroimidazol-l-ylacetamide.

In accordance with the above procedure, but start-ing with N,N-dlbenzyl-5-nitroimidazol-l-ylacetamide, N,N- -n-dimethyl-5-nitroimidazol-l-ylacetamide, or N,N-dipropyl-5-nitroimidazol-l-ylacetamide, there is obtained the corres-ponding Ν,Ν-dibenzyl 2-carbamoyloxymethyl-5-nitroimidazol-1-ylacetamide, Ν,Ν-dimethyl 2-carbamoyloxymethyl-5-nitro- -n-imidazol-l-ylacetamide, and ,N-d½ropyl 2-carbamoyloxymethyl-5-nitroimidazol-l-ylacetamide. · ,> ' EXAMPLE 28 2-Carbamoyloxymethyl-5-Nitroimidazol-l-ylacetonitrile A mixture of 15.2 g. (0.1 mole) of 5-nitroimidazol 1-ylacetonitrile, 15 g. (0.5 mole) of paraformaldehyde and 1 150 ml. of dlraethylsulfoxide is heated in a sealed tube over- 2 night at 110-150°C. The dimethylsulfoxide is removed com-" 3 pletely at reduced pressure, and the residue is dissolved 4 in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved 6 in ethyl acetate, and the solution is charged on a column 7 of alumina. Elution with ethyl acetate and evaporation of 8 the solvent yields 2-hydroxymethyl-5-nitroimidazol-l-yl- 9 acetonitrile.

A solution of 1.82 g. (0.01 mole) of 2-hydroxy- 11 methyl-5-nitroimidazol-l-ylacetonitrile in 25 ml. of dry 12 pyridine is stirred at 0°C. and 1.85 g. (0.012 mole) of 13 phenyl chloro ormate is slowly added. The reaction mixture 14 is stirred for 3-4 hours at room temperature and is poured 15 into about 200 ml. of water. The mixture is cooled over-16 night and the precipitate of l-cyanomethyl-5-nitroimidazol- 17 2-ylmethyl phenyl carbonate is separated by filtration. 18 . To 3.0 g. of l-cyanomethyl-5-nitroimidazol-2-yl- 19 methyl phenyl carbonate dissolved in 50 ml. of chloroform is added 50 cc. of chloroform containing 0.4 g. of anhydrous 21 ammonia. The solution is allowed to stand overnight at 22 room temperature and then evaporated to dryness. The residue 23 is washed with water and recrystallized from methanol to 2 yield 2-carbamoyloxymethyl-5-nitroimidazol-l-ylacetonitrile .

In accordance with the above procedure, but start- 26 ing with 3-l5f-nitroimidazol-lf-yl)propionitrile in place 27 of 5-nit-roimidazol-l-ylacetonitrile, there is obtained the 28 corresponding 3-(2'-carbamoyloxymethyl- '-nitrolmidazol-l'- 29 yDpropionitrile.

EXAMPLE 29 · l-( 2 ' -N-Morphollnoethyl) ~5~Nltr6imi,dazol-2~ylmethy1 Carbamate A mixture- of 21.4 g. (0.1 mole) of l-(2»-N- morpholinoethyl)-5-nitroimidazole, 15 g. (0.5 mole), of . paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 110-150°C. The dimethyl- sulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-(2 '-N-morpholino- ! ethyl)-5-nitroimidazol-2-ylmethanol.

A solution of 2.44 g. (0.01 mole) of l-(2'-N- morpholinoethyl)-5-nitroimidazol-2-ylmethanol in 25 ml. of dry pyridine is stirred at 0°C. and 1.85 δ· (0.012 mole) of phenyl chloroformate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled overnight and the precipitate of l-(2 '-N-morpholino- Jiate ethyl)-5-nitroimidazol-2-ylmethyl phenyl carbawfce is separated by filtration. 0.05 moles of l-( 2 ' -N-morpholinoethyl)-5-nitro- imidazol-2-ylmethyl phenyl carbonate is dissolved slowly in 50 ml. of liquid ammonia. After solution is complete, the ammonia 'is permitted to evaporate and the residue washed with ethanol and recrystallized from methanol to yield l-(2,-N-morpholinoethyl)-5-nitroimidazol-2-ylmethyl carbamate.

In accordance with the above procedure, but start-ing with l-(2'-N-pyrrolidinoethyl)-5-nitroimidazole> 1-(2T-N-piperidinoethyl)-"5-nitroimidazole, l-(2 ' -N,N-dimethyl-aminoethyl)-5-nitrolmidazole, l-(2'-N,N-diethylaminoethyl)-'. 5-nitroimidazole, in place of l-(2'-morpholinoethyl)-5-nltrolmidazole, there is obtained the corresponding 1-(2T-N-pyrrolldinoethyl)-5-nitroimidazol-2-ylmethyl carbamate, l-(2,-N,N-piperidinoethyl)-5-nitroimidazol-2-ylmethyl carbamate, l-(2,- ,N-dimethylaminoethyl)-5-nitro^midazol-2-ylmethyl carbamate, and l-(2'-N,N-diethylaminoethyl)-5-nitroimidazpl-2-ylmethyl carbamate.

EXAMPLE 30 l-(2'-Ethylthioethyl)-5-Nitroimidazol-2-ylmethyl N-methyl-carbamate " A mixture of 1.03 g. (0.005 mole) of l-(2»-ethylthioethyl)-5-nitroimidazole, 0.5 g. (0.015 mole) of paraformaldehyde and 5 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 120°C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is slurried in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-(2 '-ethylthioethyl)-2-hydroxymethyl-5-nitroimidazole .

A mixture of 246 mg. (0.001 mole) of l-(2'-ethyl-thioethyl-2-hydroxymethyl-5-nitroimidazole, 68 mg. (0.0012 mole) of methyl isocyanate, and 120 mg. (0.0012 mole), of trlethylamine in 20 ml. of 1,2-dimethoxyethane is refluxed overnight. The solvent is concentrated to a small volume, a little hexane added, and the solid that separates is removed by filtration. The l-(2 '-ethylthioethyl)-5-nitroimidazol-2-ylmethyl N-methylcarbamate is recrystallized from a mixture of alcohol and water.

In accordance with the above procedure, but starting with l-(3 '-ethylthiopropyD-S-nitroimidazoie, l-(4*- . ethylthiobutyl)-5-nitroimidazole, l-(2 '-methylthioethyl)-5-nitroimidazole, l-(2 '-propylthioethyl)-5-nitroimidazole, l-(2'-phenylthioethyl)-5-nitroimidazole, and l-(2,-benzyl-thioethyl)-5-nitroimidazole, in place of l-(2 '-ethylthio-ethyl)-5-nitroimidazole, there is. obtained the corresponding l-(3'-ethylthiopropyl)-5-nitroimidazol-2-ylmethyl N-methyl-carbamate, l-( -ethylthiobutyl)-5-nitroimidazol-2-yl-methyl N-methylcarbamate, l-(2'-methylthioethyl)-5-nitro-imidazol-2-ylmethyl N-methylcarbamate , 1-( 2 *-propylthioethyl ) -5-nitroimidazol-2-ylmethyl N-methylcarbamate, l-(2'-phenyl-thioethyl)-5-nitroimidazol-2-ylmethyl N-methylcarbamate, and l-( 2 ' -benzylthioeth l) -5-nit oimidazol-2-ylmethyl N-methylcarbamate.

EXAMPLE 31 l-(2,-Ethylsulfinylethyl)-5-Nitroimidazol-2-ylmethyl N-methylcarbamate : A mixture of 1.08 g. (0.005 mole) of l-(2'-ethyl-sulfinylethyl)-5-nitroimidazole, '.5 g. (0.015 mole) of paraformaldehyde and 5 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 120°C. The dlmethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged . on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-(2'-ethylsulfinylethyl)- 5-nitroimidazol-2-ylmethanol.

A mixture of 246 mg. (0.001 mole) of l-(2'-ethyl- sulfinylethyl)-5-nitroimidazol-2-ylmethanol, 68 mg. (0.0012 mole) of methyl isocyanate, and 120 mg. (0.0012 mole) of triethylamlne in 20 ml. of 1,2-dimethoxyethane is re- fluxed overnight. The solvent is concentrated to a small volume, a little hexane is added, and the material that separates is removed by filtration. The l-(2'-ethyl- sulfinylethy1)-5-nitroimidazol-2-yImethyl N-methylcarbamate is recrystallized from a mixture of alcohol and water.

In accordance with the above procedure, but start- ing with l-(3'-ethylsulfinylpropyl)-5-nitroimidazole, l-(4'-ethylsulfinylbutyl)-5-nitroimidazole, l-( 2 ' -methyl- sulfinylethy1)-5-nitroimidazole, l-( 2 ' -propylsulfinylethy1) - 5-nitroimidazole, l-( 2· -phenylsulfinyleth l)-5-nitroimida- zole, and l-(2 '-benzylsulfinylethyl)-5-nitroimidazole, in place of l-(2 '-ethylsulfinylethyD-S-nitroimidazole, there is obtained the corresponding l-(3 '-ethylsul inylpropyl)-5- nltroimidazol-2-yImethyl N-methylcarbamate, l-(4'-ethyl- sulfinylbutyl)-5-nitroimldazol-2-ylmethyl N-methylcarbamate, l-( 2»-methylsulfinylethyl)-5-nitroimidazol-2-yImethyl N- methylcarbamate, l-(2 ?-propylsulflnylethyl)-5-nitroimidazol- 2-yImethyl N-methylcarbamate, l-(2'-phenylsulflnylethyl)-5- nitrolmidazol-2-ylmethyl N-methylcarbamate, and l-(2'-: benzylsulfinylethyl)-5-nitroimidazol-2-yImethyl N-methyl- EXAMPLE 32 l-( 2 ' -Ethylsulfonylethyl) -5-Nitroimidazol-2-ylmethyl N-methylcarbamate A mixture of 1.08 g. (0.005 mole) of l-(2'-ethyl-suifonylethyl) -5-nitroimidazole, .5 g. (0.015 mole) of paraformaldehyde and 5 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 120°C. The dimethylsulfdxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. . The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-(2 '-ethylsul onylethyl) -5-nitroimidazol-2-ylmethanol .

A mixture of 246 mg. (0.001 mole) of l-(2'-ethyl-sulfonylethyl)-5-nitroimidazol-2-ylmethanol, 68 mg. (0.0012 mole) of methyl isocyanate, and 120 mg. (0.0012 mole) of triethylamlne in 20 ml. of 1,2-dlmethoxyethane is refluxed ■ overnight. The solvent is concentrated to a small volume, a little hexane added, and the material that separates is removed by filtration. The l-( 2 '-ethylsulfonylethyl) -5-nitroimidazol-2-ylmethyl N-methylcarbamate is recrystallized from a mixture of alcohol and water.

In accordance with the above procedure, but start-ing with l-( 3 '-ethylsulfonylpropyl) -5-nitroimidazole, l-( ' -ethylsulfonylbutyl) -5-nitroimidazole, l-( 2 ' -methy1-sulfonylethyl)-5-nitroimidazole, l-( 2' -propylsulfonylethyl) -5-nitroimidazole, l-(2 ' -phenylsulfonylethyl )-5-nitro-imidazole, and l-(2,-benzylsulfonylethyl)-5-nitroimidazole, in place of l-( 21 -ethylsulfonylethyl) -5-nitroimidazole, . ' 1 propyl) -5-nitroimidazol-2-yimethyl N-meth Icarbamate, 2 l-(4'-e.thylsulfonylbutyl)-5-nitroimidazol-2-ylmethyl N- 3 methylcarbamate, 1~( 2 ' -methylsulfonylethyl) -5-nltroimidazol- 2-ylmethyl N-methylcarbamate, l-(2 ' -propylsulfonylethyl) -5- 5 nitroimidazol-2-ylmethyl N-methylcarbamate, l-(2'-phenyl- 6 sulfonylethyl)-5-nitroimidazol-2-ylmethyi N-methylcarbamate, 7 and l-(2'-benzylsulfonylethyl)-5-nitrolmidazol-2-ylmethyl 8 N-methylcarbamate. 9 EXAMPLE 33 0 l-(l>-Methy -5,~Nitroimldazol-2'-yl)Ethyl Carbamate . 1 A solution of 0.01 moles of l-methyl-2-( 1' -2 hydroxyethyl) -5-nitroimldazole in 25 ml. of dry pyridine is 3 stirred at 0°G. and 1.85 g. (0.012 mole) of phenyl chloro-k formate is slowly added. The reaction mixture is stirred 5 for 3-^ hours at room temperature and is poured into about 6 , 200 ml. of water. The mixture is cooled overnight and the 7 precipitate of l-(i '-methy1-5 '-nitroimidazoi-^'-yl) ethyl. 8 phenyl carbonate is separated by filtration. 9 A solution of 0.005 mole of l-( 1 ' -methy1-5 ' -nltro-0 imidazol-21 -yl) ethyl phenyl carbonate in 10 ml. of chloro-1 form is cooled in an ice-bath, and is saturated with 2 dry ammonia. It is allowed to stand for 5 days at 5°C. 3 l-di-Methyl-S1- nitroimidazol-2 ' -yl) ethyl carbamate, in. . k 156.5-l60°C. , is obtained as a crystalline precipitate.

· EXAMPLE 3 k 6 2-( 1 ' -Meth 1-5 ' -Nitroimidazol-2 ' -ypEthyl Carbamate 7 A solution of 0.01 mole of l-methyl-2 '-hydroxy-8 ethyl) -5-nitroimidazole in 25 ml. of dr yridine is stirred slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poure'd into about 200 ml. of water. The mixture -is cooled overnight and the precipitate of 2-(l'-methyl-5' -nitroimidazol-2 '-yl)ethyl phenyl car-. bonate is separated by filtration.

A solution of 0.005 mole of 2-(1· -methyl-5' -nltro-imidazol-2 *-yl) ethyl phenyl carbonate in 10 ml. of chloroform is cooled in an ice-bath, and is saturated with dry ammonia. It is allowed to stand for 5 days at 5°C. 2-(l' -Methyl- '-nitroimidazol-2 '-yl) ethyl carbamate is obtained as a crystal-line precipitate; m.p. 165-166°C.

EXAMPLE 35 3-( 1' -Methyl-5 ' -Nltroimidazol-2 '-y1)Prop-2-en-l-y1 Carbamate A solution of 0.01 mole of l-methyl-2-( 3 '-hydroxy-prop-2' -enyl)-5-nitroimidazole in 25 ml. of dry pyridine is stirred a 0°C. and 1.85 g. (0.012 mole) of phenyl chloro-formate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled overnight and the precipitate of 3-(l'-methyl-5,-nitroimidazol-2,-yl)prop-2-en-l-yl phenyl carbonate is separated by filtration.

A solution of 0.005 mole of 3-(l'-methyl-5'-nitro-imidazol-2 ' -yl)prop-2-en-l-yl phenyl carbonate in 10 ml. of chloroform is cooled in an ice-bath, and is saturated with dry ammonia! It is allowed to stand for 5 days a 5°C. 3-( 1 ' -Methyl- ' -nitroimidazol-2 ' -yl)prop-2-en-l-yl carbamate is obtained as a crystalline precipitate; m.p. 173-175°C.

EXAMPLE 36 l-Methyl-5-Nitroimidazol-2-ylmethyl N-methylcarbamate 2.77 G. , (0.01 mole) of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate Is dissolved In 20 ml. of chloro-form and 0.93 g. (0.03 mole) of methylamine in 20 ml. of chloroform is added at room temperature under a dry ice-cold finger. The mixture is stirred for 7 hours. The solvent is evaporated and the residue slurried with 15 ml. of water. The solid product removed by filtration. Re--crystallization from water yields l-methyl-5-nitroimidazoi-2-ylmethyl N-methylcarbamate; m.p. 99-101°C.

In accordance with the above procedure, but using ethylamine, propylamine, butylamine, pentylamine and hexyl-amine in place of methylamine, and using the liquid amines directly rather than in chloroform solution, there is obtained the corresponding l-methyl-5-nitroimidazol-2-yl-methyl N-ethylcarbamate, l-methyl-5-nitroimidazol-2-yl-methyl N-propylcarbamate, l-methyl-5-nitroimidazol-2-yl-methyl _ N-butylcarbamate, l-methyl-5-nitroimidazol-2-yl-methyl N-pentylcarbamate and l-methyl-5-nitroimidazol-2-yl-methyl -hexylcarbamate .

EXAMPLE 37 l-Methyl-5-Nltrolmidazol-2-ylmethyl N,N-dimeth lcarbamate 7.8 G. of dlmethylamlhe is added to a solution of l-methyl-5-nitroimidazol-2-ylmethyl chloroformate (prepared from 11.0 g. of l-methyl-2-hydroxymethyl-5-nitro-imidazole as described in Example 1). The temperature of the reaction mixture rises to about 24°C. The mixture Is 1 dryness under reduced pressure. 100 ml. of water and 800 2 ml. of ethyl acetate are added "to the residue. The ethyl 3 acetate layer is separated and the aqueous layer extracted k with two 200 ml. portions of ethyl acetate. The ethyl acetate extracts are combined and evaporated to dryness. On 6 addition of 10 ml. of ethyl acetate to the residue, 1-methyl- 7 ' 5-nitroimidazol-2-ylmethyl Ν,Ν-dimethylcarbamate crystal-. 8 lizes and is recovered by filtration to give 5.3 g.; m.p. 9 91-9^°C. Recrystallization from a benzene-hexane mixture 0 yields substantially pure material; m.p. 92-92f°C. 1 In accordance with the above procedure, but using 2 diethylamine, dipropylamine and diphenylamine, in place of 3 dimethylamine, there is obtained the corresponding 1-methyl-k 5-nitroimidazol-2-ylmethyl N,N-diethylcarbamate , 1-methyl-5 5-nitroimidazol-2-ylmethyl Ν,Ν-dipropylcarbamate, 1-methyl-6 5-nitroimidazol-2-ylmethyl N,N-diphenylcarbamate . 7 EXAMPLE 38 ama e 8 l-Methyl-5-Nitroimidazol-2-ylmethyl 4-Morpholinecarbo¾yi.-fet-e 9 A cold solution of the chloroformate ester of 0 l-methyl-2-hydroxymethyl-5-nltroimidazole is prepared as in 1 Example 1 (using 11.0 g. of l-methyl-2-hydroxymethyl-5-2. nitroimidazole) . To this solution there is added rapidly 3 with stirring 15.6 g. of morpholine. The temperature rises 4 from 0°C. to 15°C. The reaction mixture is cooled in a 5 ice-bath and stirred for one hour. The tetrahydrofuran 6 is evaporated under reduced pressure and the gummy residue 7 extracted with a mixture of 100 ml. of water and 1 liter of 8 ethyl acetate. The ethyl acetate layer is separated, back- The resulting residue is dissolved in a minimum volume of benzene. The benzene solution is concentrated to a volume of about 20 ml. An equal volume of diethyl ether is added to the benzene. l-Methyl-5-nitroimidazol-2-ylmethyl 4-morpholinecarboxylate precipitates. There is obtained 7.3 g. of crude product which is recrystallized three times from benzene to give substantially pure material; m.p. 108-110°C.

In accordance with the above procedure, but start-ing with pyrrolidine, piperidine, N-methyl piperazine, and thiamorphollne, in place of morpholine, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl i-pyrrolidinecarboxylate, l-methyl-5-nitroimidazol-2-yl-methyl 1-piperidinecarboxylate, l-methyl-5-nitroimidazol-2-ylmethyl N^-methyl-N^-piperazinecarboxylate, and l-methyl-5-nitroimidazol-2-ylmethyl-4-thiamorpholine-carboxylate.

EXAMPLE 39 l-Methyl-5-Nitrolmidazol-2-ylmethyl N-Chloroethylcarbamate A cold solution of the chlorofor ate ester of l-methyl-2-hydroxymethyl-5-nitroimidazole is prepared as in Example 1 using 11.0 g. of l-methyl-2-hydroxymethyl-5-nitroimidazole. To this solution is added 14.4 g. of 2-chloroethylamine . The mixture is stirred with cooling for one hour and then evaporated to dryness under reduced pressure. 100 Ml. water and 800 ml. of ethyl acetate are added to the residue. The ethyl acetate layer is separated and the aqueous layer extracted with two 200 ml. portions of ethyl acetate. The ethyl acetate extracts are combined and evaporated to dryness. On addition of ethyl acetate and to the residue, l-methyl-5-nitroimidazol-2-ylmethyl N-2-chloroethylcarbamate crystallizes.

In accordance with the above procedure, but start-ing with 2-bromoethylamine, 2, 2,2-trifluoroethylamine, 2- luoroethylamine, 3-chloropropylamine, and 3-bromopropyl-amine, in place of 2-chloroethylamine, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-2'-bromoethylcarbamate, l-methyl-5-nitroimidazol-2-ylmethyi N-2« ,2' ,2'-trifluoroethylcarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-2 '-fluoroethylcarbamate, l-methyl-5-nitro-imidazol-2-ylmethyl N-3 '-chloropropylcarbamate and 1-methyl-5-nitroimidazol-2-ylmethyl N-3 '-bromopropylcarbamate . , . EXAMPLE 40 l-Methyl-5-Nitroimidazol-2-ylmethyl Hydroxymethylcarbamate A mixture of 2.0 g. (0.01 mole) l-methyl-5-nitroimidazol-2-ylmethylcarbamate, 0.6 g. (0.02 mole) of paraformaldehyde and 6 ml. of dimethyl sulfoxide is heated at 100°C. in a sealed tube for 24 hours. Evaporation of the solvent leaves a viscous residue which is dissolved in 3 ml. of dimethyl formamide. After the addition of 5 ml. of water and standing for 2k hours, a crystalline pre-cipitate is obtained which is separated by filtration, air dried, and recrystallized from ethyl acetate to yield l-methyl-5-hitroimidazol-2-ylmethyl N-hydroxymethyl- carbamate.

EXAMPLE 41 l-Methyl-5-Nitroimidazol-2-ylmethyl 2 » ,2 ' ,2 '-Trichloro- hydroxyethylisocyanate is dissolved in 50 ml. of dioxane and a solution of 1.57 g. (0.01 moles) of l-methyl-2-hydroxy-methyl-5-nitroimidazole in 200 ml. of dioxane is added. The mixture is left to stand for 48 hours at 15°C. The solution is concentrated to 25 ml. and the crystalline residue removed by filtration. The residue is recrystallized from ethyl acetate to yield l-methyl-5-nitroimidazol-2-ylmethyl 2' ,2' ^'-trichloro-l'-hydroxyethylcarbamate.

EXAMPLE 4.2 l-Methyl-5-Nitrolmidazol-2-ylmethyl N-( 2 » ,2 » ,2 •-Trichloro-1' -Hydroxyethfrxy) Carbamate · A mixture of 2.16 g. (0.01 mole) of l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxycarbamate , 1; 81 g. (0.011 mole) chloral hydrate and 2.00 g. of anhydrous magnesium sulfate are heated at reflux for 8 hours. The "reaction mixture after cooling is filtered and the filtrate evaporated to dryness to yield l-methyl-5-nitroimidazol-2-ylmethyl N-( 2 ' ,2 ' ,2 · -trichloro-1 ' -hydroxyeth&ey-carbamate .

In accordance with the above procedure, but start-ing with bromal hydrate or trifluoro acetaldehyde hydrate, in place of chloro hydrate, there is obtained the corres-ponding l-methyl-5-nitroimidazol-2-ylmethyl N-(2,,2,,2»- yi tribromo-1 ' -hydroxyeth-e*y-)carbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-(2' ,2· ,2 '-trifluoro-l' -hydrox - yi ethexy)carbamate .

EXAMPLE 3 l-Methyl-5-Nitroimidazol-2-ylmethyl Ν-2' -hydroxy Ethylcarbamate ; " 1.22 G. of ethanolamlne is added at 15°C. to a solution of 2.93 g. of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate in 10 ml. of chloroform. The mixture is stirred for 7 hours and at the end of this time, the solid product is removed by filtration. Recrystallized from ethyl acetate gives l-methyl-5-nitrolmidazol-2-ylmethyl N-2 »-hydroxyethyl carbamate; m.p. 132-135°C.

In accordance with the above procedure, but start-ing with propanolamine, butanolamine, in place of ethanol-amine, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-3 '-hydroxypropylcarbamate, and l-methyl-5-nltroimidazol-2-ylmethyl N-hydroxybutylcarbamate .

EXAMPLE 44 N-e l-Methyl-5-Nitroimidazol-2-ylmethyl gfthoxymethylcarbamate A mixture of 1.15 g. (.005 mole) of l-methyl-5-nitroimidazol-2-ylmethyl hydroxymethylcarbamate , .05 g. of p-toluenesulfonic acid and 20; ml. of ethanol is allowed to stir overnight at room temperature. After evaporation, the residue is dissolved in 50 ml. of chloroform and t e-chloroform solution washed with dilute sodium bicarbonate solution. The chloroform solution, after drying over, sodium sulfate, is evaporated to dryness. The residue is recrystallized from ethyl acetate to yield l-methyl-5-nitroimidazol-2-ylmethyl N-ethoxymethylcarbamate .

In accordance with the above procedure, but using n-propanol, n-butanol or n-pentanol in place of ethanol, there is obtained the corresponding l-methyl-5-nitroimida-zol-2-ylmethyl N-propoxymethylcarbamate, . l-methyl-5-nitroimidazol-2-ylmethyl N-butoxymetnylcarbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-pento.xymethylcarbamate .

EXAMPLE 45 l-Methyl-5-Nitroimidazol-2-ylmethyl N-Ethoxyethylcarbamate 1. 78 G. , ( 0 .02 mole) of 2-ethoxyethylamlne is added at 15°C to a solution of 2 . 93 g. of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate in 10 ml. of chloroform. The mixture is stirred for 7 hours and at the end of this time, the solution is evaporated to dryness.

The residue is slurried with water and the solid product after filtration, is recrystallized from ethanol-water to give l-methyl-5-nitroimidazol-2-ylmethyl N-ethoxyethyl-carbamate.

In accordance with the above procedure, but start-ing with 3-ethoxypropylamine, 4-ethoxybutylamine, 5-ethoxy-pentylamine, and 6-ethoxyhexylamine, in place of 2-ethoxy-ethylamine, there is obtained the corresponding 1-methyl- 5-nitroimidazol-2-ylmethyl N-3-ethoxypropylcarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-4-ethoxybutylcarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-5-ethoxypentylcar-bamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-6-ethoxy-hexylcarbamate. , ■ > EXAMPLE 46 l-Methyl-5-Nitroimidazol-2-ylmethyl N-2-oxopropylcarbamate To a solution of . 05 mole of l-methyl-5-nitro- imidazol-2-ylmethyl chloroformate in 50 ml. of tetrahydro- furan (anhydrous) at 0°C. is added .15 mole of triethylamine . To this solution is added dropwise, «05 mole o aminoacetone hydrochloride in 100 ml. of dr tetrahydrofuran . After stirring for 4 hours at 15°C, the triethylamine hydro- . chloride is removed by filtration and the filtrate is con- centrated under reduced pressure. The. residue is recrystal- lized from ethyl acetate-benzene to yield l-methyl-5- nitroimidazol-2-ylmethyl N-2-oxopropylcarbamate .

In accordance with the above procedure, but start- ing with l-amino-2-oxobutane hydrochloride, l-amino-2-oxo- pentane hydrochloride and l-amino-2-oxo-2-phenylethahe in place of aminoacetone, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-(2T-oxobutyl)- carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-(2'-oxo- pentyl) carbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-( 2* -oxo-2 '-phenylethyl) carbamate.

- EXAMPLE 7 N-(l-Methyl-5-Nltroimidazol-2-ylmethoxycarbonyl) Glycine To a cold tetrahydrofuran solution (100 ml.) of l-methyl-5-nltroimidazol-2-ylmethyl chloroformate (prepared as described in Example 1 from 3· 12 g. of l-meth l-2- hydroxymethyl-5-nitroimidazole) is added 1.50 g. (0.02 mole) of glycine. Triethylamine (1.0 g., 0.01 mole) is added and the mixture stirred for 2k hours < with cooling in an ice- bath. It is then evaporated under reduced pressure to a gummy residue. This residue is washed with 20 ml. of water, the water is removed and about 100 ml. of ethyl acetate added to the remaining residue. The ethyl acetate addition - - - - m z -2- ylmethoxycarbonyl) glycine which is separated by filtration, dried, and recrystallized from- ethyl acetate.

In accordance with the above procedure, but start-ing with a-alanine, β-alanine, serine, and γ-amino butyric . acid in place of glycine, there is obtained the correspond-ing N-(l-methyl-5-nitroimidazol-2-ylmethoxycarbonyl)-a-alanine, N-(l-methyl-5-nitroimidazol-2-ylmethoxycarbonyl)-β-alanine, N-(l-methyi-5-nitroimidazol-2-yimethoxycarbonyl)-serine, and N-(l-methyl-5-nitrdimidazol-2-ylmethoxycarbonyl)-γ-aminobutyric acid.

EXAMPLE 48 l-Methyl-5-Nitroimidazol-2-ylmethyl N-carbethoxymethyl-carbamate 13.8 G., (0.05 mole) of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate is dissolved in 100 ml. ethanol containing .05 mole of glycine ethyl ester. To this solu-tion is added 10 g. (0.05 mole) of triethylamine . After standing for 24 hours, at 15°C. the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and the solution washed with water, dried and the solvent removed under reduced pressure. The residue is re-crystallized from ethyl acetate/ether to yield l-methyl-5-nitroimidazol-2-ylmethyl N-carbethoxymethylcarbamate.

In accordance with the above procedure, but start-ing with glycine propyl ester, glycine butyl ester, c-alanine methyl ester, a-alanine pentyl ester, and β-alanine. ethyl ester, in place of glycine ethyl ester, there is obtained the corresponding l-methyl-5-nitroimidazol-2-yl-methyl N-carbopropoxymethylcarbamate, l-methyl-5-nitro- -nitroimidazol-2-ylmethyl N-l-carbomethoxyethylcarbamate , l-methyl-5-nitroimidazol-2-ylmethyl N-l-carbopentoxyethyl-carbamate, and l-methyl-5-nitroimidazol-2-ylmethyr N-2-carbethoxyethylcarbamate.

EXAMPLE 9 l-Methyl-5-Nitroimidazol-2-ylmethyl N-carbamoylmethyl-carbamate . . 13.8 G . , (0.05 mole) of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate Is dissolved in 100 ml. ethanol containing .05 mole of glycine amide. To this solution is added 10 g. (0.05 mole) of triethylamine . After standing for 24 hours, at 15°C. the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried and the solvent removed under reduced pressure. The residue is recrystallized from ethyl acetate/ether to yield l-methyl-5-nitroimidazol-2-yl-methyl N-carbamoylmethylcarbamate .

In accordance with the above procedure, but start-ing with -alanine amide and β-alanine amide, in place of glycine amide, there is obtained the corresponding 1-methyl-5-nitroimldazol-2-ylmethyl N-l-carbamoylethylcarbamate and l-methyl-5-nitroimidazol-2-ylmethyl N-2-carbamoylethyl-carbamate.

' EXAMPLE 50 ' l-Methyl-5-Nitroimidazol-2-ylmethyl N-carbamoylmethyl-N-ethylcarbamate \ 13.8 G., (0.05 mole) of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate is dissolved in 100 ml. ethanol containing .05 mole of glycine N-ethylamide. To this solu- standing for 24 hours, at 15°C. the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried and the solvent removed under reduced pressure. The residue is recrystallized from ethyl acetate/ether to yield l-methyl-5-nitroimidazol-2-yl-methyl N-carbamoylmethyl -ethylcarbamate .

In accordance with the above procedure, but start-ing with glycine N-propylamide, glycine N-butylamine, glycine N-phenylamide, or glycine N-benzylamide, in place of ethyl glycine amide, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-carbamoylmethyl N-propylcarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-carbamoylmethyl N-butylcarbamate, l-methyl-5-nitroimidazoi-2-ylmethyl N-carbamoylmethyl N-phenylcarbamate , l-methyl-5-nitroimidazol-2-ylmethyl N-carbamoylmethyl N-benzylcarbamate.

EXAMPLE 51 l-Methyl-5-Nitroimidazol-2-ylmethyl N-Pormyloxymethyl-carbamate A mixture of 2.3 g. (0.01 mole) of l-meth l-5-nitroimidazol-2-ylmethyl N-hydroxymethylcarbamate and 90% formic acid (10 ml.) is heated on a steam-bath for 2 hours. After evaporation to dryness the residue is slurried with saturated aqueous sodium bicarbonate solution, and filtered. The product is l-methyl-5-nitroimidazol-2-ylmethyl N-formyloxymethylcarbamate.

EXAMPLE' 52 l-Methyl~5-Nitroimidazol-2-ylme.thyl N-acetoxymethylcarbamate 0.05 Mole of l-methyl-5-nltroimidazol-2-ylmethyl N-hydroxymethylcarbamate is dissolved in 25 ml. of pyridine and 0.055 moles of acetyl chloride introduced dropwise into the stirred solution. After 30 minutes stirring, the solu-tion is allowed to stand at 15°C. for 4 hours. The solvent is removed under reduced pressure. The residue is extracted with ethyl acetate, washed with water, dried, and the solvent removed under reduced pressure. The residue is recrystallized from acetone or ethyl acetate to yield l-methyl-5-nitroimidazol-2-ylmethyl N-acetoxymethylcarbamate .

In accordance with the above procedure, but starting with propionyl chloride, butyryl chloride, valeryl chloride, or benzoyl chloride, in place of acetyl chloride, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-propionoxymethylcarbamate, l-methyl-5-nitro-imidazol-2-ylmethyl N-butyroxymethylcarbamate, l-meth l-5-nitroimidazol-2-ylmethyl N-valeroxymethylcarbamate and ■ l-methyl-5-nitroimidazol-2-ylmethyl N-benzoyloxymethyl-carbamate.

EXAMPLE 53 l-Methyl-5-Nitroimidazol-2-ylmethyl N-carbamoyloxymethyl-carbamate ; 0.05 Moles of l-methyl-5-nitrolmidazol-2-ylmethyl N-hydroxymethylcarbamate is dissolved in 25 ml. of pyridine and the 'mixture is cooled in an ice-salt bath while .055 mole of gaseous carbamyl chloride is introduced into the stirred solution. The solution is allowed to stand at 15°C. extracted with ethyl acetate. The ethyl acetate . solution is washed with ice water, dried, and concentrated. Re- crystallization from ethyl acetate or acetone yields 1- methyl-5-nitroimidazol-2-ylmethyl N-carbamoyloxymethyl- carbamate.

In accordance with the above procedure, but start- ing with l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxyethyl- carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxy- propylcarbamate, or l-methyl-5-nltroimidazol-2-ylmethyl N- hydroxybutylcarbamate, in place of l-methyl-5-nitroimidazol- 2-ylmethyl N-hydroxymethylcarbamate, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-car- bamoyloxyethylcarbamate, l.-methyl-5-nitroimidazol-2-yl- methyl N-carbamoyloxypropylcarbamate, and l-methyl-5- nitroimidazol-2-ylmethyl N-carbamoyloxybutylcarbamate .

EXAMPLE ^ l-Methyl-5-Nitroimidazol-2-ylmethyl N-(Dimethylcarbamoyloxy- methyl) carbamate , 0.05 Moles of l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxymethylcarbamate is dissolved in 25 ml .. of . pyridine ; and the mixture is cooled in an ice-salt bath while .055 mole of dimethyl carbamoyl chloride is introduced . into the , stirred solution. The solution is allowed to stand at 15°C. for 24 hours. It is then concentrated and the produc · extracted with ethyl acetate.. The ethyl acetate solution is washed with water, dried and concentrated. Recrystal- lization from ethyl acetate or acetone yields l-methyl-5- nitroimidazol-2-ylmethyl N-( dimethylcarbamoyloxymethyl)- carbamate.

In accordance with the above procedure, but start-ing with l-methyl-5-nitroimida'2ol-2-ylmethyl N-hydroxyethyl-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxy-propylcarbamate , or l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxy utylcarbamate, in place of l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxymethylcarbamate, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyi N-(dimethylcarbamoyloxyethyl) carbamate, l-methyl-5-nitro-imidazol-2-ylmethyl N-(dimethylcarbamoyloxypropyl) carbamate., and l-methyl-5-nitroimidazol-2-ylmethyl N-(dimethyl-carbamoyloxybutyl) carbamate.

EXAMPLE 55 l-Methyl-5-Nitroimidazol-2-ylmethyl N-2 *-Sulfonamidoethyl-carbamate - .05 Mole of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate is dissolved in ethanol containing .05 mole of 2-aminoethylsulfonamide and 0.05 mole triethylamine.

After 24 hours at 15°C, the solution is evaporated.

Trituration with water causes the crystallization of 1-methyl-5-nitroimidazol-2-ylmethyl N-2 •-sulfonamideethyl-carbamate.

In accordance with the above procedure, bu using 3-aminopropylsulfonamide, 4-aminobutylsulfonamide and -aminopentylsulfonamide, in place of 2-aminoethyls.ulfon-r amide, the.re is obtained the corresponding l-methyl-5--nitroimidazol-2-ylmethyl N-3 '-sulfonamidopropylcarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-4 '-sulfonamidobutyl-carbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-5 sulfonamidopentylcarbamate.

EXAMPLE 56 l-Methyl-5-Nitroimidazol-2-ylrtethyl N-2 '-(Ν' ,N» -Diethyl-sulfonamido) ethylcarbamate <_ ' .05 Mole of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate Is dissolved in ethanol containing .05 mole of 2-aminoethylsulfonic acid diethylamide, and 0.05 mole triethylamine. After 24 hours at 15°C, the solution is evaporated. Trituration with water causes the crystalliza-tion of l-methyl-5-nitroimidazol-2-ylmethyl 2,-(N,,N'-dlethylsulfonamido)ethylcarbamate.

I accordance with the above procedure, but start-ing with 2-aminoethylsulfonic acid dipropylamide, 2-amino-ethylsulfonic acid diphenylamide, or 2-aminoethylsulfonic acid dibenzylamide, in place of 2-aminoethylsulfonic acid diethylamide, there is obtained the corresponding 1-methyl-5-nitroimidazol-2-ylmethyl 2 '-(Ν' ,Ν'-dipropylsulfonamido)-ethylcarbamate, l-methyl-5-nitroimldazol-2-ylmethyl 21-(N* , '-diphenylsulfonamido)ethylcarbamate, and l-met yl-5-nitroimidazol-2-ylmethyl 2 *-(Ν' ,Ν' -dibenzylsulfonamido)-ethylcarbamate.

EXAMPLE 57 l-Methyl-5-Nitroimidazol-2-ylmethyl N-Mercaptoethylcarbamate I. G., (0.02 mole) of 2-mercaptoethylamine is added at 15°C. to a solution of 2.77 g. of l-meth l-5-nitroimidazol-2-ylmethyl phenylcarbonate in 10 ml. of chloroform. The mixture is stirred for 7 hours and at the end of this time, the solid product is removed by filtration. Recrystallizatlon from ethanol gives l-methyl-5-nitroimida-zol-2-ylmethyl N-2 '-mercaptoethylcarbamate.

In accordance with the above procedure, but start-ing with 3-mercap op op lamine and 4-mercaptobutylamine, in place of 2-mercaptoethylamine, there is obtained the corres^-ponding l-methyl-5-nitroimidazol-2-ylmethyl N-3 '-mercapto-propylcarbamate and I-methyl-5--nitroimidazol-2-ylmethyl N-4 '-mercaptobutylcarbamate .

EXAMPLE 58 l-Methyl-5-Nitroimidazol-2-ylmethyl N-Ethylthioethyl-carbamate 2.12 G. , (0.02 mole) of ethylthioethylamine is added at 15°C. to a solution of 2.77 g. of l-methyl-5-nitro-imidazol-2-ylmethyl phenylcarbonate in 10 ml. of chloroform. The mixture is stirred for 7 hours and then evaporated to dryness. The residue is triturated with ether and the solid . product is removed by filtration. Recrystallization from ethanol gives l-methyl-5-nitroimidazol-2-ylmethyl N-2'-ethylthioethylcarbamate.

In accordance with the above procedure, but start-ing with 2-methylthioethylamine, 2-propylthloethylamine, 2-butylthioethylamine, or 2-benzylthioethylamine, in place of 2-ethylthioethylamine, there is obtained the correspond-ing l-methyl-5-nitroimidazol-2-ylmethyl N-2 '-methylthio- th ethylcarbamate, l-me¾¾yl-5-nitroimidazol-2-ylmethyl N-2 '-propylthioethylcarbamate, l-methyl-5-nitroimidazol-2-yl-methyl N-2 '-butylthioethylcarbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-2 ' -benzylthioethylcarbamate .

EXAMPLE 59 l-Methyl-5-Nitroimidazol-2-yimethyl N-Thioi?carbamoylmethyl-carbamate _^ ' 13.8 G., (0.05 mole) of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate is dissolved in 100 ml. ethanol containing gl cinethioamide ( .5 g. , 0.05 mole) , and 5.1 g. (0.05 mole) of triethylamine . Afte standing for 24 hours, at 15°C. the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried. The solvent is removed under reduced pressure and the residue is recrystallized from ethyl acetate/ether to yield l-methyl-5-nitroimidazol-2-ylmethyl N-thion¾ar-bamoylmethylcarbamate .

In accordance with the above procedure but start-ing with a-alaninethioamlde , or β-alaninethioamide, in place of glycinethioamide, there is obtained the correspond-ing l-methyl-5-nitroimidazol-2-ylmethyl N-l ' -thioncarbamoyl-ethylcarbamate and l-methyl-5-nitroimidazol-2-ylmethyl -2'-thioncarbamoylethylcarbamate.

EXAMPLE 60 l-Methyl-5-Nitroimidazol-2-ylmethyl N-( T -EthyIthio-car amo lmeth l) car amate 13.8 G. , (0.05 mole) of l-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate is dissolved in 100 ml. ethanol containing .05 mole of -ethyl .glycinethioamid . To this solution is added 5.1 6· (0.0-5 mole) of triethylamine.

After ^standing for 24 hours, at 15°C. the solution is con-centrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried. The solvent is with water and ethyl acetate. The ethyl acetate extract Is evaporated and the residue re'orystalllzed from ethyl acetate/ ether to yield l-raethyl-5-nltrolmidazol-2-ylmethyl N-(N -ethylthiocarbamoylmethyl) carbamate.

In accordance with the above procedure, but start-ing with N-propyl glycinethioamine, N-butyl glycinethioamide , N-phenyl glycinethioamide, or N-benzyl glycinethioamide, in place of N-ethyl glycinethioamide, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-(N'-propylthiocarbamoylmethyl) carbamate, l-me.thyi-5-nitroimida-zol-2-ylmethyl N-(N* -butylthiocarbamoylmethyl) carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-(N* -phenylthiocar-bamoylmethyl) carbamate, and l-methyl-5-nitroimidazol-2-yl-methyl N-(N'-benzylthiocarbamoylmethyl) carbamate.

EXAMPLE 61 l-Methylr-5-Nitroimidazol-2-ylmethyl N-(N' -dimethyldithio-carbamoylmethyl) carbamate ' 1.1 ml. of ^0% aqueous dlmethylamine and 37% aqueous formaldehyde (1.0 ml.) is added to a solution of . 2.0 g. (0.01 mole) of l-methyl-5-nitroimidazol-2-ylrethyl carbamate in 5 ml. of dimethyiformamide. To the mixture is added carbon disulfide (1.0 g.). The reaction mixture is stirred for 2k hours at 15°C. Water (10 ml.) is added and the mixture stirred an additional 2 hours. The precipitate is removed b ' filtration and washed with water to yield l-methyl-5-nitroimidazol-2-ylmethyl N-(N' -dimeth ldithio-carbamoylmethyl) carbamate.

In accordance with the above procedure, but start-with diethylamine, dipropylamine, dibutylamine, diphenyl- is obtained, the corresponding l-methyl-5-nitroimidazol-2-ylraethyl N-(N ' -diethyldithiocarbamoylmethyl) carbamate , l-methyl-5-nitroimidazol-2-ylmethyl N-(N' -dipropyldithio-carbamo lmeth l) carbama e, l-methyl-5-nitroimidazol-2-yl methyl N-( '-dibutyldithiocarbamoylmethyl) carbamate, 1-methyl-5-nitroimidazol-2-ylmethyl -(NT -diphenyldithio-carbamoylmethyl) carbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-( ' -dibenzyldlthiccarbamoylmethyl) carbamate .

EXAMPLE 62 l-Methyl-5-Nitroimidazol-2-ylmethyl N-(aminoethyl) carbamate .5 G., (0.02 mole) of l-methyl-5-nitroimidazol-2-methyl phenylcarbonate is dissolved in 70 ml. of chloro-form and 0.06 moles of ethylene diamine is added. The mixture is heated under reflux for 5 hours, cooled and allowed to stand for 18 hours. 170 ml. of chloroform is added and the mixture extracted with saturated aqueous potassium bicarbonate solution. The chloroform extract is washed with water and the solvent removed under reduced pressure. A portion (0.1 g.) of the residual brown oil is dissolved in methyl ethyl ketone. A solution of 8.53 g. of p-toiuenesulfonic acid in 80 ml. of methylethyl ketone is prepared. An excess of the p-toluenesulfonic acid solution (i.e. more than 2 moles per mole of concentrate derivative) is added and the mixture allowed to cool. The solution 'is evaporated to dryness, 5 ml. of methylethyl ketone added. After standing at 0°C. the. di-p-toluene-sulfonic acid salt of l-methyl-5-nitroimidazol-2-yimethyl N-(aminoethyl) carbamate is obtained.

EXAMPLE 63 l-Methyl-5-Nitroimldazol-2-ylmethyl Ν-(Ν' ,Ν' -Diethylamino-ethy])carbamate . ' . 15.5 G, (0.02 mole) of l-methyl-5-nitroimidazoI-2-methyl phenylcarbonate is dissolved in 70 ml. of chloro-form and 2.68 g. (.023 moles) of diethylaminoethylamine is added. The mixture is heated under reflux for 5 hours , cooled and allowed to stand for 18 hours. Chloroform (170 ml.) is added and the mixture extracted with saturated aqueous potassium bicarbonate solution. The chloroform extract washed with water and the solvent removed; under reduced pressure. A portion (0.1 g.) of the residual .brown oil is dissolved in methylethyl ketone. A solution of 8.53 g. of p-toluenesulfonic acid in 80 ml. of methylethyl ketone is prepared. An excess of the p-toluenesul onic acid solution (i.e. more than 2 moles per mole of carbonate derivative) and the mixture allowed to cool.. The solution is evaporated to dryness, 5 nil. of methylethyl ketone added. After standing at 0°C. the di-p-toluenesulfonic acid salt of l-methyl-5-nitroimidazol-2-ylmethyl N-(N' ,Ν'-diethyl-aminoethyl) carbamate, m.p. 101-103°C, is obtained.

In accordance with the above procedure, but start-lng with 3-dimethylaminopropylamine and dibenzylaminoethyl-amine, in place of diethylaminoethylamine, there is. obtained the corresponding l-methyl-5-riltrOimidazol-2-ylmethyl N-(3'- '-dimethylaminopropy])carbamate, and l-methyl-5-nitro-imidazol-2-ylmethyi -(N'-dibenzylaminoethyl) carbamate.

EXAMPLE 64 l-Methyl-5-Nitroimidazol-2-ylmethyl N-(Morpholln- » -y1 methyl) carbamate , 12 . 0 G. , (0.01 mole) of l-methyl-5-nitroimic.azol-2-ylmethyl carbamate, 0.3 g. (0.01 mole) of para ormalo.e-hyde, and 0.86 g. (0.01 mole) of morphollne In 6 ml. of dimethyl formamide is heated at 100°C. in a sealed tube for 2 hours. After evaporation of the solvent under reduced pressure, the residue is dissolved in 20 ml. of nethylethyl ketone. A solution of . g. of p-toiuenesul onic acid in 20 ml. of methylethyl ketone is added to yield a precipi-tate of the di-p-toluenesulfonic acid salt of l-methyl-5-nitroimidazol-2-ylmethyl N-(morpholln-½ ' -ylmethyl) carbamate .

In accordance with the above procedure, but start-ing with N-methylpiperazine, pyrrolidine and thiamorpholine, in place of morpholine, there is obtained the corresponding di-p-toluenesulfonic acid salt of l-methyl-5-nitroimidazoi-2-ylmethyl N-( 4-methylpiperazin-l-ylmethyl) carbamate, 1-methyl-5-nitroimidazol-2-ylmethyl N-(pyrrolidin-l-ylmethyl) carbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-thia-morpholine-4 ' -ylmethyl) carbamate .

EXAMPLE 65 l- ethyl-5-Nitroimidazol-2-ylmethyl Phenylcarbamate To a solution of l-methyl-2-hydroxymethyl-5-nitroimidazole chloro ormate prepared as in Example 1 (from 11.1 g. of l-methyl-2-hydroxymethyl-5-nitroimidazole there is added.16.3 g. (0.175 mole) of aniline. The tem-perature of the mixture rises' from 0°C. to about lo°C. The mixture is stirred for 90 minutes with cooling in an ice- gummy residue. This residue is washed with 100 ml. of water, the water is removed and about 100 ml. of ethyl acetate added to- the remaining residue. The ethyl acetate addition causes crystallization of l-methyl-5-nitrolmidazol-2-ylmethyl phenylcarba ate. The crystalline product is.. removed by filtration and dried to give 12.3 g.; m.p. 136-142°C. Recrystallization from methylene chloride and then from ethyl acetate affords substantially pure 1-methyl-5-nitroimidazol-2-ylmethyl phenylcarbamate m.p. 1/15.5-148°C.

In accordance with the above procedure, but start-ing with p-fluoroaniline, p-chloroaniline. and p-nitro-aniline, in place of aniline, there is obtained the corres-ponding l-methyl-5-nitroimidazol-2-ylmethyl p-fluorophenyl-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl p-chloro-phenylcarbamate, and l-methyl-5-nitroimidazol-2-ylmethyl p-nitrophenylcarbamate .

EXAMPLE 65 l-Methyl-5-Nitroimidazol-2-ylmethyl' Methylohenylcarbamate A solution of chloroformate ester of l-methyi-2-hydroxymethyl-5-nitroimidazole is prepared, as in. Example 1 (from 11.1 g. of i-methyl-2-hydroxymethyl-5-nitroimidazole) I8.7 G. of N-methylanlline is added to this solution, and the resulting mixture stirred, with ice cooling, for one hour! The mixture is evaporated to dryness in vacuo to a gum which is extracted with 200 ml. of water and 60C ml. of ethyl acetate. The ethyl acetate extracts are separated and evaporated to dryness. The residue is crystal- N-l-methyl-5-nitroimidazoI-2-ylmethyl/methylphenylcarbamate m.p. 93-95°C. Recrystallizatlon from 50 ml. of a 1:1 benzene-hexane mixture affords substantially pure material; m.p. 9 .5-98°C.

In accordance with the above procedure, but start-ing with prop-2-en-l-ylamine, but-2-en-l-ylamine, but-3-en-1-ylamine, pent-2-en-l-ylamine and pent-3-en-l-ylamine , in place of N-me hylaniline, there is obtained the corres-ponding l-methyl-5-nitroimidazol-2-ylmethyl N-( 2-propenyl)-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-(2-butenyl ) carbamate, l-methyl-5--nitroimidazol-2-ylmethyl N-( 3-butenyl) carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-(2-pentenyl) carbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-( 3-pentenyl) carbamate.

EXAMPLE 67 . l-Methyi-5-Nltroimidazol-2-ylmethyl N-Ethoxymethylene-carbamate ; ■ 2.0 G., (0.01 mole) of l-methyl-5-nitroimidazol-2-ylmethyl carbamate, 1.33 ml. (0.01 mole) of boron fluoride etherate and 25 ml. of triethylorthoformate is heated on a steam bath overnight. The excess triethylortho ormate is removed under vacuum. To the oily residue is added 100 ml. of chloroform and 10 ml. saturated sodium bicarbonate solution. The chloroform solution is separated, washed with 2 x 10 ml. of water, and dried, over anhydrous sodium sulfate. Evaporation of the chloroform solution gives l-methyl-5-nitroimidazol-2-ylmethyl N-ethoxymethylene-carbamate.

In accordance with the above procedure, but start- tribenzylorthoformate, and triphenylorthoformate, in place of triethyiorthoformate, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-methoxymethylene-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-propoxy-methylenecarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-benzyloxymethylenecarbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-phenyloxymethylenecarbamate . .

EXAMPLE 68 l- ethyl-5-Nitroimidazol-2-ylmethyl N-(Diethylaminomethylene) carbamate A mixture of 2.56 g. (0.01 mole) of l-methyl-5-nitroidazol-2-ylmethyl ethoxymethylenecarbamate , and 0.73 g. (0.01 mole) of diethylamine in 25 ml. of 1,2- . dimethoxyethane is refluxed for 2 hours. After cooling, the addition of 3. g. (0.02 mole) of p-toluenesulfonic acid results in the separation of the di-p-toluenesulfonate salt of l-methyl-5-nitroimidazol-2-ylmethyl N-(diethylamino-methylene) carbamate.

In accordance with the above procedure, but start-ing with dimethylamine, dlbutylamine, dipropylamine, dibenzylamine, and dlphenylamine, in place of diethylamine, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-dimethylaminomethylenecarbamate , l-methyl-5-nitroimidazol-2-ylmethyl. N-dibutylaminomethylenecarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-dipropylaminomethylene-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-dibenzyl-aminomethylenecarbamate, and l-methyl-5-nitroimidazol-2-yl-methyl N-diphenylaminomethylenecarbamate . 1 EXAMPLE 69 2 l-Methyl-5-Nitroimidazol-2-ylmethyl N-(l'-carbethoxyprop- 3 2-ylidine) carbamate ; ' · i» 4.0 G. , (0.02 mole) of l-me hyl-5-nitroimidazol- 5 2-ylmethyl carbamate, 150 ml. of ethyl acetoacetate and 6 0.02 g. of p-toluenesuifonic acid (anhydrous) are heated on 7 a steam bath for days. The solvent is removed by evapora- 8 tion under reduced pressure. The residue is slurried with 9 1,000 ml. of ether and the mixture filtered. The ether 0 - extract is evaporated to dryness under reduced pressure. 1 The residue, in 300 ml. of ether, is refluxed with activated 2 charcoal for 30 minutes. The mixture is filtered and the 3 filtrate concentrated to about 100 ml. The ether solution is cooled to -40°C. and a crystalline precipitate of l-methyl-5-nltroimidazol-2-ylmethyl N-( 1 ' -carbethoxyprop-6 2-ylidene) carbamate , m.p. 117-120°C., is obtained. 7 In accordance with the above procedure, but start-8 ing with methyl acetoacetate or benzyl acetoacetate, in 9 place of ethyl acetoacetate, there is obtained the corres-0 ponding l-methyl-5-nitroimidazol-2-ylmethyl N-(l'-carbo-1 methoxy-prop-2-ylidene) carbamate or l-methyl-5-nitroimidazol-2 2-ylmethyl N-( 1 ' -benzyloxycarbonylprop-2-ylidene) carbamate . 3 EXAMPLE 70 11 N-(l-Methyl-5-Nitroim±dazol-2-ylmethyloxycarbonyl)-5 ' , ' -Dimethylfor a idinlum Chloride Hydrochloride .. 6 ·' 0.2 G. (0.001 moles) of l-methyl-5-nitroimidazoi-7 2-ylmethyl carbamate is dissolved in 2 ml. of dimethyl-8 formamide and 0.1 ml. of thionyl chloride added. The mix-9 ture is allowed to stand for 18 hours . Removal of the ' V with ether yields N-( l-methyl-5-nitroimida"ol-2-ylmethyi-oxycarbonyl Nl jN'-dimethylformamidinium chloride hydro-chloride; m.p. 147-151°C. (dec).

' EXAMPLE 71 l-Methyl-5-NitroiTnida2ol-2-ylmethyl Formylcarbamate 3.28 G. (0.01 mole) of -(l-methyl-5-nitroimidazol-2-ylmethoxycarbonyl) NT ,Ν' -dimeth l ormamidinium chloride hydrochloride is dissolved in 20 ml. of water containing .84 g. of sodium bicarbonate. The solution is allowed to stand overnight. The product is l-methyl-5-nitroimidazol-2-ylmethyl formylcarbamate . The same compound is obtained on heating on a steam bath l-methyl-5-nitroimidazol-2-ylmethyl carbamate in an excess of 90i¾ formic acid over-night.

EXAMPLE 72 l-Methyl~5-Nitroi.idazol-2-ylmethyl N-Acetylcarbama e 2 G. of l~methyl-5-nitroinidazoi-2-ylmethyl carbamate is added to a mixture of 40 ml. of acetic anhydride and drops of concentrated sulfuric acid. The solution is heated for 13 hours on a steam bath. The solvent is re-moved under reduced pressure and the residue triturated with petroleum ether and the mixture filtered. The residue is taken up in hot benzene, the. mixture filtered and the filtrate 'concentrated under reduced pressure to a snail volume.. After standing at 5°C. for 12 hours, l-methyl-5-nitroimidazol-2-ylmethyi N-acetylcarbamate, m.p. 140-142°C, is obtained on filtration.

In accordance with the above procedure, but using propionic anhydride, butyric -anhydride, or chloroacetic anhydride, in place of acetic anhydride there is obtained the corresponding l-methyl-5-nltroimidazol-2-ylniethyl N-proplonylcarbamate, l-methyl-5-nitroimidazol-2-ylmethyi N-butyrylcarbamate, and l-methyl-5-nitroimidazol-2-yl methyl N-chloroacetylcarbamate.

EXAMPLE 73 N-l-Methyl-5-Nitrolmidazol--2-ylmethyl/Acetylcarbamate .9 G. of l-methyi-2-hydroxymethyl-5-nitro-imidazole and about 0.5 ml. of pyridine are added to a solution of acetyl isocyanate prepared by refluxing a solution of 15.9 g. oxalyl chloride, and 5.9 g. of aceta-mide in 300 ml. of 1, 2-dichloroethane for 16 hours and the mixture re luxed for 80 minutes . The solvent is then re-moved by concentration in vacuo to give an oil which crystallizes on standing. The crystals are slurried with 50 ml. of benzene and then recovered by filtration. Washing with a mixture of 50 ml. of benzene and 85 ml. of ether leaves crude l-methyl-5-nitroimidazol-2-ylmethyl acetyl-carbamate; m.p. i08-132°C. On recrystallization from benzene-hexane , substantially pure material is obtained; m.p. 132-135°C In accordance with the above procedure, but using benzoylisocyanate or phenylacetylisocyanate, in place of acetylisocyanate, there is obtained the corresponding 1-methyl-5-nitroimidazoi-2-ylmethyl N-benzoylcarbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-phenylacetylcarbamate.

Similarly, in accordance with the above procedure, but using l-methyl-2-mercaptdmethyl-5-nitroimidazole and l-ethyl-2-hydroxymethyl-5-nitroimidazole, in place of l-methyl-2-hydroxymethyl-5-nitroimidazole and utilizing benzoylisocyanate, there is obtained the corresponding o l-methyl'-5-nitroimidazol-2-ylmethyl N-benzoylthio3carbamate and l-ethyl-5-nitroimidazol-2-ylmethyl N-benzoylcarbamate .

EXAMPLE 7 l-Methyl-5-Nltroimidazol-2-ylmethyl N-Cyanoacetylcarbamate 2 G. (0.01 mole) of l-methyl-5-nitroimidazol-2-yl carbamate, 0.93 g. (0.011 mole) of cyanoacetic acid and 10 ml. of acetic anhydride are heated on a steam bath for 3 hours. On cooling, a crystalline product is obtained.

Recrystallization from ethanol gives l-methyl-5-nit o-imidazol-2-ylmethyl N-cyanoacetylcarbamate .

EXAMPLE 75 l-Methyl~5-Nltroimidazol-2-ylmethyl N-Acryloylcarbamate To a solution of 2.0 g. (0.01 mole) of l-methyl-5-nitroimidazol-2-ylmethyl carbamate in 5 ml. of dimethyl-formamide at 0°C. is added slowly 1.13 g. of acryloyl chloride. The mixture is allowed to warm to room tempera-ture and stand for 8 hours. 10 Ml. of water is added slowly and the product l-methyl-5-nitroimidazol-2-ylmethyl N-acryloylcarbamate is removed by filtration. k In accordance with the above procedure, but using crotonoyl chloride, in place of acryloyl chloride, there is obtained the corresponding l-methyl-5-nltroimidazol-2-yi- V EXAMPLE 76 l-Methyl-5-Nltroimidazol-2-ylmethyl Allophanate 3 G · of a solution of l-methyl-5-nitroimidazoi-2-yl methanol in 75 ml. of 1,2-dimethoxy ethane is added to 4 ml. of cyanic acid at dry ice temperature. The cyanic acid is obtained by heat depclymerization of cyanuric acid. The reaction mixture is tightly stoppered and allowed to stand at about 0°C. for 48 hours. The solids which are formed are filtered. Extraction of the solids with 300 ml. of boiling water followed by filtration gives, within a few minutes., in the filtrate a first crop of solids which is filtered. The filtrate then deposits 1.0 g. of the desired allophanate which on recrystallization from- boiling water gives analytically pure l-methyl-5-nitroimidazol-2-ylmethyl allophanate; m.p. 210-211°C. (dec).

EXAMPLE 77 l-Methyl-5-Nitroimidazoi-2-ylmethyl 4 ' , ? -dimethylallophanate .05 Mole of l-methyl-5-nitroimidazol-2-ylmethyl carbamate is dissolved in 25 ml. of pyridine and cooled in an ice-water bath. To this stirred solution is added .055 mole of dimethylcarbamyl chloride. After the initial re-action, the mixture is allowed to stand for 24 hours and is then concentrated under reduced pressure. The residue is extracted with ethyl acetate ... The ethyl acetate extract is washed with ice water, and the dried solution is reconcen-trated. The residue is recrystallized from ethyl acetate to yield l-methyl-5-nitroimidazol-2-ylmethyl 4 · ,4 '-dimethyl-allophanate.

In accordance with the above procedure, but start-ing with diethylcarbamoyl chloride, dipropylcarbamoyl chloride, dibutylcarbamoyl chloride, dibenzylcarbamoyl chloride, or diphenylcarbamoyl chloride, in place of dimethylcarbamoyl chloride, there is obtained the corres-ponding l-methyl-5-nitroimidazol-2-ylmethyl 4 ' , 4 ' -diethyl-allophanate, l-methyl-5-nitroimidazol-2-ylmethyl.4 * ,4 dipropylallophanate , l-methyl-5-nitroimidazol-2-ylmethyl 4 ' ,4 '-dibutylallophanate, l-methyl-5-nitroimidazol-2-yl-methyl 4' , ' -dibenzyiallophanate, and l-methyl-5-nitroimida-zol-2-ylmethyl 4 » , 4 ' -diphen lallophanate .

EXAMPLE 78 l-Methyl-5-NitroimldagQl-2-ylmethyl 2 '-Meth lallophanate .05 Mole of l-methyl-5-nitroimidazol-2-ylmethyl N-methylcarbamate is dissolved in 25 ml. of pyridine and the mixture is cooled in an ice-salt bath while .055 mole of gaseous carbamyl chloride is introduced into the stirred solution. After 30 minutes, the solution is allowed to stand at 15°C. for 24 hours. It is then concentrated and the product extracted with ethyl acetate and washed with ice water. The solution is dried and concentrated. Re-crystallization from ethyl acetate or acetone yields 1-methyl-5-nitrolmldazol-2-ylmethyl 2 '-methylallophanate .

In accordance with the above procedure, but start-ing with' l-methyl-5-nitroimidazol-2-ylmethyl N-ethyl-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-propyl-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-butyl-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-phenyl- V N-methylcarbama e, there Is obtained the corresponding l-methyl-5-nitroimidazoI-2- lmethyl 2 '-ethylallophanate , l-methyl-5-nitroiinidazol-2-ylmethyl 2 '-propylallophanate , l-methyl-5-nitroimidazol-2-ylmethyl 2 '-butylallophanate, l-methyl-5-nitroimidazol-2-ylmethyl 2 '-phenylallophanate , and l-methyl-5-nitroimidazol-2-ylmethyl 2 '-benzylallophanate .

EXAMPLE 79 l-Methyl-5-Nitroimidazol-2-ylmethyl N-(Piperidinocarbonyl) carbamate 0.05 Mole of l-methyl-5-nitroimidazpl-2- lmethyl carbamate is dissolved in 25 ml. of pyridine and cooled in an ice-water bath. To this stirred solution is added 0.55 mole of piperidino carbonyl chloride. After the initial reaction, the mixture is allowed to stand for 24 hours and is then concentrated under reduced pressure. The residue is extracted with ethyl acetate. The ethyl acetate is washed with ice water and the dried solution is re-concentrated. The residue is recrystallized from ethyl acetate or acetone to yield l-methyi-5-nitroimidazol-2-yl methyl N-(piperidinocarbonyl) carbamate; m.p. 78.5-30.5°C.

In accordance with the above procedure, but start-ing with 4-methyl-piperazinocarbonyl chloride, morpholino-carbonyl chloride and thiamorpholinocarbonyl. chloride, in place of piperidinocarbonyl chloride, there is obtained the corresponding l-nethyi-5-nitroimidazol-2-ylmethyl N-( ' -methyl piperidinocarbonyl) carbamate , m.p . 101-104°C, l-methyl-5-nitroimidazol-2-ylmethyl N-(morpholinocarbonyl) carbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-(thiamorpholinocarbonyl) carbamate.

EXAMPLE 80 ο l-Methyl-5-Nitroimidazol-2-ylmethyl 3 '-Thion4llophanate 0.1 Mole of l-methyl-5-nitroimidazol-2-ylmethyl chloroformate Is dissolved in 200 ml. of benzene and stirred with 10.6 g. of anhydrous potassium thiocyanate for four days at 20-40°C. This mixture is treated with an excess of anhydrous gaseous ammonia. On cooling, the 1-methyl-5-nitroimidazol-2-ylmethyl 2 ' -thionallophanate separates in crystalline form.

In accordance with the above procedure, and utilizing a benzene solution of l-methyl-5-nitroimidazol-2-ylmethoxycarbonyl isothiocyanate as produced above but using methylamine, ethylamine, butylamine, benzylamine, phenylamine, dimethylamine, diethylamlne, dibutylamine, dibenzylamlne, and diphenylamine, in place of gaseous ammonia, there is obtained the corresponding l-methyl-5- o nitroimidazol-2-ylmethyl '-methy1-3 '-thionallophanate, l-methyl-5-nitroimidazol-2-ylmethyl ' -methy1-3 ' -thiori¾-allophanate, l-methyl-5-nitroimldazol-2-ylmethyl 4†- o butyl-3 '-thionallophanate, l-methyl-5-nitroimidazol-2-yl methyl 4 ' -benzyl-3 ' -thioi$_.llophanate, 1-methy1-5-nitro- o imidazol-2-ylmethyl 1 -phenyl-3 ' -thion&llophanate , 1-methyl-5-nitroimidazol-2-ylmethyl 4 ' ,4 '-dimethyl-3 '-thlon©-allophanate, l-methyl-5-nitroimldazol-2-ylmethyl 4',4·-diethyl-3'-thion llophanate, l-methyl-5-nitroimidazol-2-yl o methyl 4 '',4 '-dibut l-3 '-thion llophanate, l-methyl-5- o nitroimidazol-2-ylmethy1 4 ' , r -dibenzy1-3 ' -thionallophanate , and l-methyl-5-nitroimidazol-2-ylmethyl 4' , '-diphenyl-3 '- o thionallophanate.

EXAMPLE 81 l- ethyl-5-Nitroimidazol-2-ylmethyl N-Nitrocarbamate .05 Mole of l-methyl-5-nitroimidazol-2-ylmethyl carbamate is dissolved in .066 mole of acetic anhydride and treated with .05 mole of 95% nitric acid over a period of 2 minutes. After 11 minutes, it is poured into an equal volume of saturated sodium chloride solution. After completion of the decomposition of the acetic anhydride, the solution is extracted with ethyl acetate and the ethyl acetate extract washed with water. The dried ethyl acetate solution is saturated with ammonia gas to give the ammonium salt of l-methyl~5-nitroimidazol-2-ylmethyl N-nitrocarbamate.

EXAMPLE 82 l-Methyl-5-Nitroimidazol-2-ylmethyl Carbazate A mixture of 5 g. of l-methyl-5-nitroimidazol-2-ylmethyl phenyl carbonate, 0.5 ml. of 95% hydrazine and ml. of chloroform is stirred at room temperature for one hour. At the end of this time . the solid is removed by filtration to give 3.3 g. of material; m.p. 101-105°C.

This product is dried in vacuo at 68°C. to remove phenol and then recrystallized from water to give substantially pure l-methyl-5-nitroimidazol-2-ylmethyl carbazate; m.p. 135-1 0°C.

' EXAMPLE 83 l-Methyl-5-Nitroimidazol-2-ylmethyl Carbazate To a solution of l-methyl-2-hydroxymethyl-5-nitroimidazole chloroformate in dioxane as prepared in V "1 hydrazine. The mixture is stirred for 90 minutes with 2 cooling in an ice bath. The. mixture is evaporated under 3 reduced pressure, and the residue washed with water and 4 dissolved in ethyl acetate. The ethyl acetate solution after drying over sodium sulfate, is concentrated to 6 yield l-methyl-5-nitroimidazol-2-ylmethyl carbazate. 7 EXAMPLE 84 8 l-Methyl-5-Nitroimidazol-2-ylmethyl N ' -Methylcarbazate 9 .05 Mole of l-methyl-5-nitroimidazoi-2-ylmethyl i0. chloroformate is dissolved in 50 ml. of anhydrous tetra- 11 hydro uran and added to a solution containing .15 mole of 12 methylhydrazine in 50 ml. of tetrahydrofuran at 15°C. 13 After 2 hours, the methylhydrazine hydrochloride is re- 14 moved by filtration. The tetrahydrofuran is removed under reduced pressure and the residue is recrystallized from 1β ethyl acetate to yield l-methyl-5-nitroimidazol-2-ylmethyl 17 N^-methylcarbazate . 18 In accordance with the above procedure, but start- 19 ing with ethylhydrazine, propylhydrazine, or benzylhydrazine , in place of methylhydrazine, there is obtained the corres- 21 ponding l-methyl-5-nitroimidazol-2-ylmethyl N^-ethyl- 22 carbazate, l-methyl-5-nitroimidazol-2-ylmethyl .N -propyl- 23 carbazate, and l-methyi-5-nitroimidazol-2-ylmethyl N - 24 benzylcarbazate .

EXAMPLE 85 26 l-Methyl-5-Nitroimidazol-2-ylmethyl N -Isopropylidinyl- 27 carbazate · 28 200 Mg. of l-methyl-5-nitroiraidazol-2-ylmethyl V reflux for 10 minutes. The solvent is removed under reduced pressure and the residue recrystallized from a 1:1 mixture of benzene and hexane to yield l-methyl-5-nitroimidazol-2- 2 ylmethyl N -isopropylidenylcarbazate; m.p. 160-162°C.

In accordance with the above procedure, but using methylethyl ketone, benzaldehyde , acetaldehyde, in place of acetone, there is obtained the corresponding 1-methy1-^5- 2 nitroimidazol-2-ylmethyl N -2"-butylidenylcarbazate, 2 l-methyl-5-nitroimidazol-2-ylmethyl N -benzylidenylcarbazate, 2 and l-methyl-5-nitroimidazol-2-ylmethyl N -ethylidene-carbazate.

EXAMPLE 86 2 l-Methyl-5-Nitroimidazol-2-ylmethyl N -Benzoylcarbazate .1 Mole of l-methyl-5-nitroimidazol-2-ylmethyl-carbazate is dissolved in 50 ml. of dry pyridine and cooled in ice.. 0.1 Mole of benzoyl chloride is added dropwise.

After standing for 1 hour at 15°C, the solution is quenched with ice and water. The precipitated l-methyl-5-nitroimidazol-2-ylmethyl N -benzoylcarbazate is filtered, washed well with water and recrystallized from ethanol.

In accordance with the above procedure, but using acetic anhydride in place of benzoyl chloride, there is obtained the corresponding l-methyl-5-nitroimidazol-2-yl 2 methyl N -acetylcarbazate .

Similarly, but using propionic anhydride, valeric anhydride, butyric anhydride or phenylacetic anhydride, in place of acetic anhydride, there is obtained the corres- 2 ponding l-methyl-5-nitroimidazol-2-ylmethyl N -propionyl- 2 - - - - V 2 carbazate, and l-methyl-5-nitroimidazol-2-ylmethyl -phenylacetylcarbazate . - EXAMPLE 87 N^-( 1 ' -Methyl-5 ' -Nitroimidazo -2 ' - lmethoxy ) Semicarbazide To . 05 mole of l-methyl-5-nitroimidazol-2-ylmethyl chloroformate in 50 ml. of dry purified tetrahydrofuran is added . 05 mole of semicarbazide hydrochloride. To this mixture is added . 3 mole of triethylamine. The mixture is stirred vigorously for 2 hours. The solid precipitate is filtered. The tetrahydrofuran filtrate is removed under reduced pressure and the residue is well washed with water. The combined water insolubles are recrystallized from il ethanol to yield N -( i'-methy1- '-nitroimidazol-2 '-ylmethoxy carbonyl) semicarbazide .

In accordance with the above procedure, but using thiosemlcarbazide hydrochloride in place of semicarbazide 4 hydrochloride, there is obtained the corresponding N -( 1 ' -methyl- ' -nitrolmidazol-2 ' -ylmethoxycarbony1) thio-semicarbazide.

EXAMPLE 88 l-Methyl-5-Nitroimidazol-2-ylmethyl -Hydroxycarbamate 0 . 386 G. of sodium is dissolved in 40 ml. of methanol and the solution cooled in an ice bath. 1.17 G. of hydroxylamine hydrochloride is added to the cold methanol solution. To the resulting mixture there is added over a period of minutes 2 . 33 g. of l-methyl-5-nitroimidazol-2-ylmethyl phenyl carbonate in 60 ml. of methanol. The resultin mixture is held for 15 hours at refrigerator present is removed by filtration. The solid is washed with alcohol and then with hexane^ and dried to give l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxycarbamate; m.p. 189-190°C.

In accordance with the above procedure, but start-ing with N-methylhydroxylamine hydrochloride, N-propyl-hydroxylamine hydrochloride, N-phenylhydroxylamine hydro-chloride, and N-benzylhydroxylamine hydrochloride, in place of h droxylamine, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-methyl-N-hydroxy-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-propyl-N-hydroxycarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-phenyl-N-hydroxycarbamate, and l-methyl-5-nitroimidazol-2-ylmethyl N-benzyl-N-hydroxycarbamate.

EXAMPLE 89 l-(2'-Acetoxyethyl)-5-Nitroimidazol-2-ylmethyl N-Hydroxy carbamate 3.66 G. of l-(2†-acetoxyethyl)-5-nitroimidazol-2-ylmethyl phenyl carbonate is dissolved in 20 ml. of methanol and treated with freshly prepared hydroxylamine from .72 g. of hydroxylamine hydrochloride and .6 g. of sodium methoxide in 20 ml. of methanol. The residue is recrystallized from ethanol to yield l-(2 '-acetoxyethyD-5-nitroimidazol-2-ylmethyl N-hydroxycarbamate m.p. 153-155°C.

EXAMPLE 90 l-Methyl-5-Nitroimidazol-2-ylmethyl N-Hydroxythionfcarbama e 0.56 G. (0.005 mole) of potassium t-butoxide is dissolved in 20 ml. of ethanol and 0.35 g. (0.005 mole) of for 5 minutes. 0.732 G. (0.0025 mole) of l-meth l-5-nitroimidazol-2-ylmethyl phenyl thion¾arbonate is added and the mixture allowed to stand for 1 hour. The solvent is removed under reduced pressure, and water added to the residue to yield l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxythiox^carbamate; m.p. 94-95°C. (dec).

In accordance with the above procedure, but start-ing with N-methylhydroxylamine, N-propylhydroxylamine, N-phenylhydroxylamine, and N-benzylhydroxylamine, in place of hydroxylamine, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-methyl-N-hydroxy- o thioncarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-propyl-N-hydroxythion¾arbamate, and l-methyl-5-nitroimida-zol-2-ylmethyl N'-benzyl-N'-hydroxythiorcarbamate.

EXAMf¾E 9ί bio- (1 Methyl 5 Nl oimida--ol-2-ylmethoxy M-Hydro¾yimino EXAMPLE 92 l-Methyl-5-Nltroimidazol--2-ylmethyl N-Methoxycarbamate After cooling the solution is treated with an excess of an ether solution of diazomethan-e. At first, decolorization of the diazomethane . is rapid, but later it is very low.

After several hours, the colorless solution is filtered from starting material. The residue from the solution is chromatographed over a column of silica gel in ethyl acetate solution. The 0-methyl derivative comes directly through the column and is non-crystalline . This material is treated with one equivalent weight of p-toluenesulfonic acid in methyl ethyl ketone to give the p-toluenesulfonic acid salt of l-methyl-5-nitroimidazol-2-ylmethyl N-methoxy carbamate in 17$ overall yield; m.p. 113-115°C.

In accordance with the above procedure, b t starting with l-methyl-5-nitroimidazol-2-ylmethyl N-methyl-N-hydroxycarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-propyl-N-hydroxycarbamate, l-methyl-5-nitroimidazol-2-yl methyl -phenyl-N-hydroxycarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-benzyl-N-hydroxycarbamate, in place of 1-methyl-5-nitroimidazol-2-ylmethyl N-hydroxycarbamate, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-methyl-N-methoxycarbamate, l-methyl-5-nitro-imidazol-2-ylmethyl N-propy1-N-methoxycarbamate , 1-methyl-5-nitroimidazol-2-ylmethyl N-phen 1-N-methoxycarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-benzy1-N-methoxy carbamate.

' In accordance with the above procedure, but using diazoethane, diazopropane, diazobutane, and phenyldiazo-methane, in place of diazomethane, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-ethoxy m te -meth l- -nitroimidazol-2- lmeth l N- ro ox carbamate, 1-methyl-5-nitroimidazol-2-ylmethyl N-butoxy carbamate, and 1-methyl-5-nitrolmidazol-2-ylmethyl N-benzyloxycarbamate .

EXAMPLE 93 l-Meth l-5- i rolmidazol-2-ylmethyl Acetoxycarbamate To a solution of 2.22 g. (0.01 mole) of 1-methy1-5-nitroimidazol-2-ylmethyl hydroxycarbamate in 10 ml. of pyridine, cooled in an ice bath, is added slowly 1.12 g. acetic anhydride. The mixture is allowed to warm to room temperature. The solvent is evaporated at reduced pressure leaving a residue which is slurried in ether and filtered giving 1-methyl-5-nltroimidazol-2-ylmethyl acetoxycarbamate.

In accordance with the above procedure, but start-ing with propionic anhydride, butyric anhydride, valeric anhydride or phenylacetic anhydride, in place of acetic anhydride, there is obtained the corresponding 1-meth 1-5-nitroimidazol-2-ylmethyl N-propionoxycarbamate, 1-methyl-5-nltroimidazol-2-ylmethyl N-butyroxycarbamate, 1-methyl-5-nitroimidazol-2-ylmethyl N-valeroxycarbamate, and 1-meth 1-5-nitroimldazol-2-ylmethyl N-phenylacetoxycarbamate .

In accordance with the above procedure, but start-ing with trifluoroacetic anhydride, in place of acetic anhydride, there is obtained. the corresponding 1-meth 1-5-nitroimidazol-2-ylmethyl N-trifluoroacetoxycarbamate .

EXAMPLE 94 l-Methyl-5-Nitroimidazol-2-ylmethyl N-Benzoylox carbamate 1 G. of 1-meth l-5-nitroimldazol-2-ylmethyl h drox carbamate in 1 ml. of IN sodium h droxide is stirred is repeated with 0.5 ml. of benzoyl chloride and additional sodium hydroxide. 25 Ml. of benzene is added and the benzene layer separated, washed with water and dried over sodium sulfate. Evaporation yields l-methyl-5-nitro-imidazol-2-ylmethyl N-benzoyloxycarbamate; m.p. 147-151°C.

EXAMPLE 95 l-Methyl-5-Nitroimidazol-2-ylmethyl N-acetyl-N-Acetoxy carbamate 0.22 G. (0.001 mole) of l-methyl-5-nitroimldazol-2-ylmethyl hydrox carbamate, 0.1 g. of potassium acetate and 5 ml. of acetic anhydride are heated on a steam bath for 3 hours. The reaction mixture is evaporated to dryness at reduced pressure and 5 ml. of water and 50 ml. of chloroform added to the residue. The chloroform extract ; on evaporation gives a crystalline product which is slurried in ether and filtered to yield l-methyl-5-nitroimidazol-2-ylmethyl N-acetyl-N-acetoxycarbamate.

In accordance with the above procedure, but using propionic anhydride and potassium propionate, butyric anhydride and potassium butyrate, valeric anhydride and potassium valerate, phenylacetic anhydride and potassium phenyl acetate in place of acetic anhydride and potassium acetate, there is obtained the corresponding l-methyl-5-nitroimidazol-2-ylmethyl N-propionyl-N-propionyloxycarbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-butyryl-N-butyryloxy-carbamate, l-methyl-5-nitroimidazol-2-ylmethyl N-valeryl-N-valeryloxycarbamate, and l-methyl-5-nitroimidazol-2-yl methyl N-phenylacetyl-N-phenylacetoxycarbamate. v EXAMPLE 96 l-Methyl-5-Nitroimidazol-2-ylmethyl Sulfamoylcarbamate . 0.1 Mole of 1-methyl-2-hydroxymethyl-5-nitro-Imidazole in 100 ml. of methylene chloride is treated with .1 mole of chlorosulfonylisocyanate with heating at 50°C, until all of the starting material is dissolved. On cool-ing the intermediate, 1-methyl-5-nitroimidazol-2-ylmethyl carbamate-N-sul onyl chloride crystallizes. This product in methylene chloride is treated with methylene chloride containing an excess of ammonia while cooling to -20°C.

After 2 hours the excess ammonia and solvent are removed by evaporation. The product is washed with water. The l-methyl-5-nitroimidazol-2-ylmethyl sulfamylcarbamate is recrystallized from methanol or ethanol.

, In accordance with the above procedure, but using methylamine, dimethylamine, ethylamine, propylamine, aniline or benzylamine, in place of ammonia, there is obtained the corresponding l-methyi-5-nitroimidazol-2-ylmethyl N-(N'-methylsulfamoyl)carbamate, l-methyl-5-nitroimidazol-2-yl methyl N-(N' , ' -dimethylsulfamoyl)carbamate, 1-methy1-5-nitrolmidazol-2-ylmethyl -(N' -ethylsulfamoyl) carbamate, 1-methyl-5-nitroimldazol-2-ylmethyl N-(N'-propylsulfambyl) carbamate, 1-methyl-5-nltroimldazol-2-ylmethyl N-( '-phenylsulfamoyl) carbamate, and 1-meth l-5-nitroimicat-ol-2-ylmethyl N-(N* -benzylsulfamoyl) carbamate .

EXAMPLE 97 l-Methyl-5-Nitroimidazol-2-ylmethyl N-(p-toluenesulfonyl) carbamate ' .1 Mole of 1-meth l-5-nitrolmidazol-2-yl v •1. added to 200 ml. of benzene containing 0.5 ml. of pyridine. 2 The resulting mixture is heated under reflux until complete - 3 solution is obtained. The solvent is then removed b 4 evaporation under reduced pressure. The partially crystal- . .5 line material thus obtained is recrystallized from ethyl- acetate or acetone to yield l-methyl-5-nitroimidazol-2-yl- 7 methyl N-(p-toluenesulfonyl) carbamate; m.p. 159-172°C. (dec. ) . 8 In accordance with the above procedure, but start- 9 ing with methanesulfonylisocyanate in place of p-toluene-: 0 sulfonylisocyanate, there is obtained the corresponding 1 l-met.hyl-5-nitroimidazol-2-ylmethyl N-methanesulfonyl 12 carbama e. 13 in accordance with the above procedure, but start- 14 ing with the corresponding isothlocyanates there are obtained the corresponding l-methyl-5-nitroimldazol-2-ylroethyl 6 N-substltuted sulfonylthiocarbamate . 17 EXAMPLE 98 18 l-Methyl-5-Nitroimidazol-2-ylmethyl N-Diaminophosphoryl 19 carbamate .1 Mole of dichlorophosphoryl isocyanate is added 21 to an ice cold solution of .1 mole of l-methyl-2-hydroxy- 22 methyl-5-nitroimldazole dissolved in anhydrous tetrahydro- 23 furan. After standing 18 hours at 0°C, this solution is 24 added to an excess of ammonia gas dissolved in tetrahydro- 25 furan. After two hours at 15°C, the mixture is filtered 26 from ammonium chloride and the tetrahydrofuran is removed 27 under reduced pressure. The ammonium chloride is dissolved 28 in water and any insoluble material is combined with the 29 residue from tetrahydrofuran. After washing with water, v ,1 In accordance with the above procedure, but using : 2 methylamine, dimethylamine, ethy.lamine, propylamine, aniline 3 and benzylamine, in. place of gaseous ammonia, there is " 4 obtained the corresponding l-methyl-5-nitroimldazol-2-yl methyl N-[bis(methylamino)phosphoryl]carbamate, l-methyl-5- 6 nitroiraidazol-2-ylmethyl N-[bis(dimethylamino)phosphoryl] 7 carbamate, l-methyl-5-nitroimidazol-2-ylraethyl N-[bis- 8 (ethylamino)phosphoryl]carbamate, l-methyl-5-nitroimidazol- ,9 2-ylmethyl N-[bis(propylamino)phosphoryl]carbamate, 1-methyl- 10 ' 5-nitroimidazol-2-ylmethyl N-[bis(anilino)phosphoryl] ,11 carbamate, and l-methyl-5-nltroimidazol-2-ylmethyl N-[bis- 12 (benzylamlno)phosphoryl]carbamate. 13 EXAMPLE 99 14 4-Phenyl-5-Nltroimldazole 1. 56 G. of 4-p-acetylarainophenyl-5-nitroimldazole 16 is suspended in 50 ml. of ethanbl and 13 ml. of concentrated 17 sulfuric acid added dropwise with cooling and stirring, 18 temperature being maintained below 10°C. An aqueous solu- 19 tion containing 1. 03 g. of sodium nitrite is cooled to below 10°C. and added slowly to the ethanolic solution. The 21 reaction mixture is maintained at a temperature of less than 22 10°C. and stirred for 1 hour. A further aqueous solution 23 of sodium nitrite containing 1. 03 g. of sodium nitrite is 24 added and the reaction mixture stirred for a further hour. 252 Mg. of'finely divided copper bronze alloy is added and 26 the mixture warmed on a steam bath for 15 minutes until 27 effervescence ceases . The reaction mixture is filtered and 28 the filtrate added to a mixture of ethyl acetate and water separated and the aqueous layer further extracted with ethyl acetate. The combined ethyl acetate extract is dried and the solvent removed by evaporation under reduced pressure. The residue is combined with the residues from the previous two filtrations . The mixture is sublimed in vacuo at an oil bath temperature of circa 200°C. The sublimate is taken up in acetone, filtered, concentrated and cooled to yield 4-phenyl-5-nitroimidazole; m.p. 284-288°C. (dec).

EXAMPLE 100 l-Methyl- -Phenyl-5-Nitrolmidazole 100 g. of 4-phenyl-5-nitroimidazole and 0.06 g. of dimethyl sulfate are warmed to 145°C. over 45 minutes.

The homogenous mixture is cooled in an ice bath, aqueous sodium hydroxide solution added and the mixture poured into excess water.

The mixture is filtered and the residue, after air drying, is recrystalllzed from ether ether/petroleum ether to yield l-methyl-4-phenyl-5-nitroimidazole ; m.p. 74.5-75.5°C.

In accordance with the above procedure, but start-ing with 4-chlorophenyl-5-nltroimidazole and 4-nitrophenyl-5-nitrolmidazol, in place of 4-phenyl-5-nitroimidazole , there is obtained the corresponding l-methyl-4-chlorophenyl-5-nitroimidazole and l-methyl-4-nltrophenyl-5-nitroimidazole .

EXAMPLE 101 l-Methyl-4-Phenyl-5-Nltrolmidazol-2-ylmethyl Carbamate A mixture of 2 g. of l-methyl-4-phenyl-5-nitro-imidazole 15 g. (0.05 mole) of paraformaldehyde and 15 ml. v ; of diraethylsulfoxide Is heated In a sealed tube overnight at 110-150°C. The diraethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl , acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields l-methyl-2-hydroxymethyl- -phenyl-5-nitroimidazole .

A solution of 2.33 g. (0.01 mole) of 1-methyl- 2-hydroxymethyl-4-phenyl-5-nitrolmidazole i 25 ml.' of dry pyridine is stirred at 0°C. and 1.85 g. (0.012 mole), of phenyl chloro ormate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled over- night and the precipitate of l-methyl-4-phenyl-5-nitro- imidazol-2-ylmethyl phenyl carbonate is separated by filtration. 0.005 Mole of l-methyl-4-phenyl-5-nitroimidazol- 2-ylmethyl phenyl carbonate is dissolved slowly in 50 ml. 'of liquid ammonia. After solution is complete, the ammonia ' is permitted to evaporate. The residue is washed with water and recrystallized from methanol to yield l-methyl-4- phenyl-5-nitroimidazol-2-ylmethyl carbamate.

In accordance with the above procedure, but start- ing with l-methyl-4-chlorophenyl-5-nltroimidazole or 1- methyl-4-riitrophenyl-5-nitroiraidazole, there is obtained the corresponding l-methyl-4-chlorophenyl-5-nitroimidazol- 2-ylmethyl carbamate and l-methyl-4-nitrophenyl-5-nitro- imidazol-2-ylmethyl carbamate.

EXAMPLE 102 l-Methyl-4-Cyaj-0-5-Nitroimidazol--2-ylmethyl Carbamate A mixture -of 15.2 g. (0.1 mole) of l-methyl-4-cyano-5-nitroimidazole, 15 g. (0.5 mole) of paraformalde-hyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 12.0°C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water arid extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of , the solvent yields l-methyl-2-hydroxymethyl-4-cyano~5-nitroimidazole.

A solution of 1.82 g. (0.01 mole), of l-methyl-2-hydroxymethyl-4-cyano-5-nitroimidazole in 25 ml. of dry pyridine is stirred at 0°C. and 1.85 g. (0.012 mole) of phenyl chloroformate is slowly added. The reaction mixture is stirred for 3-4 hours at room temperature and is poured into about 200 ml. of water. The mixture is cooled over-night and the precipitate of l-methyl-4-.cyano-5-nitroimida-zol-2-ylmethyl phenyl carbonate is separated by filtration. 0.005 6. of l-methyl- -cyano-5-nitroimidazol-2-ylmethyl phenyl carbonate is dissolved slowly in 50 ml. of liquid ammonia. After solution is complete, the ammonia is permitted to evaporate and the, residue washed with water and recrystallized from methanol to yield l-methyl-4-cyano-5-nitroimidazol-2-ylmethyl carbamate.

EXAMPLE 103 3-Nltro-5 , 6-Dihydroimidazo-[1.2 :-α]-pyrrol-7-y1 Carbama e A mixture. of 1.67 g. (0.01 mole) of 3-nitro-7-oxo-5,6-dihydroimidazo-[l,2:a]-pyrrole, 0.39 g. (0.01 mole) of sodium borohydride and 100 ml. of ethanol is allowed to stand at 15°C. for 6 hours. After addition of a few drops of acetic acid to decompose the excess borohydride, the solution is evaporated to a small volume, and 50 ml. of water added slowly with stirring. The product, 3-nitro-7-hydroxy-5,6-dihydroimidazo-[l,2 : ]-pyrrole Is filtered and dried.

To a solution of 1.69 g. (0.01 mole) of the above product in 10 ml. of pyridine, cooled in an ice bath, is added 1.57 g. of phenyl chloroformate dropwise over a period of 20 minutes. The mixture is allowed to warm to room temperature and held for 48 hours. The reaction mixture is quenched in 60 ml. of Ice water and the resulting solid recovered by filtration. After drying, the 3-nitro-5>0-dihydroimidazo-[l,2a]-pyrrol-7-yl phenyl carbonate is dissolved in 50 ml. of chloroform and the resulting solution added dropwise to 20 ml. of liquid ammonia, cooled In dry ice bath. After stirring for 30 minutes, the mixture is allowed to warm gradually to room temperature. The chloro-form is removed by evaporation and the residue slurried with water. 3-Nitro- ,6-dIhydroimidazo-[l,2a]-pyrrol-7-yl carbamate is obtaine iquid ammonia an amine of the formula s defined here ed carbamates 4 obtained.

EXAMPLE 104 l-Methyl-2~Hydroxymethyl-4-Nitrolmidazole To a mixture of 1.4 . of 2-h drox meth l-4- v is added 0.2*1 g. of sodium hydride. 1.26 G. of dimethyl sulfate is added and the mixture- s refluxed for 2 hours.

After cooling, the solvent is evaporated under reduced ' pressure. 10 Ml. o 4N ammonium hydroxide solution is added and the mixture extracted with 2 x 75 ml. of ethyl acetate. The ethyl acetate extract is evaporated to dryness to give l-methyl-2-hydroxymethyl-4-nitroiraidazole; m.p. 166-163°C.

EXAMPLE 105 l-Methyl- ~Nltroimldazol-2-ylmethyl Carbamate . * ' ■ 3 G. of l-methyl-2-hydroxymethyl-5-nitroimidazole are heated under reflux with 10 ml. of methyliodlde in 20 ml. of benzene for 4 days. The solvent is removed to yield the methiodide which is not further purified. The l-methyl-2-hydroxymethyl-5-nitroimidazole methiodide thus obtained is heated to circa 250°C. under .01 mm. pressure to yield l-methyl-2-hydroxymethyl-4-nitroimidazole as a crystalline sublimate which is recrystallized from acetone and ether to give a product having a melting point 168-172°C, A solution of 1.43 g. (.0091 mole) of 1-methyl-2-hydroxymethyl-4-nitroiraidazole> in 10 ml. of dry pyridine is stirred at 0°C. and 2.7 ml. of phenyl chloroformate is slowly added. The reaction mixture is stirred for 3-hours at room temperature and is poured into about 100 ml. of water. 'The mixture is cooled overnight and the precipi-tate of l-methyl-4-nitroimidazol-2-ylmethyl phenyl carbonate is separated by filtration, (2.1 g., m.p. 105-106°C). 2 G. of l-methyl-4-nitroimidazol-2-ylmethyl ammonia. After solution is complete, the ammonia is per-mitted to evaporate and the residue washed with water and recrystallized from ethanol to yield l-methyl-4-nitroimida-zol-2-ylmethyl carbamate, (1.2 g., m.p. 187-189°C).

V 1 The starting materials used in the aforementioned 2 examples may be prepared in the following manner. 3 Preparation 1 4 l-Butyl-5-Nltroimidazole 24.2 G . , (0.214 moles) of 4(5)-nitroimidazole is 6 heated with 25.0 g. (0.11 mole) of n-butyl tosylate for one 7 hour at 180-190°C. and cooled to give a hard solid. The 8 mixture is shaken with 175 ml. of 2.5 N aqueous sodium 9 hydroxide until it is dissolved and diluted with 175 ml. of water to give an oily precipitate. The mixture is extracted 11 with ether; the ether extract washed with 2.5 N aqueous 12 hydrochloric acid and water. The aqueous acid wash is ^■3 treated with excess aqueous sodium hydroxide and extracted with ether. This latter ether extract is evaporated to dry- !5 ness and recrystallized from petroleum ether to yield 16 l-butyl-5-nitroimidazole, m.p. 51-54°C. 17 In accordance with the above procedure but start- 18 ing with methyl tosylate, ethyl tosylate and propyl tosylate 19 in place of n-butyl tosylate, there is obtained the corres- 20 ponding l-methyl-5-nitrolmidazole, l-ethyl-5-nitroimicazole, 21 and l-propyl-5-nitroimidazole. 22 Preparation 2 23 l-Anyl-5-Nitroimidazole i*j.o g., (0.124 moles) of 4( 5)-nitroimidazoie is heated with 26.3 g. (0.124 moles) of allyl. tosylate at 26 140-150°C. for 15 minutes and cooled. The resultant mixture 27 is dissolved in 150 mi. of 2.5 N sodium hydroxide and diluted hydrochloric acid. The acid extracts are made basic by the addition of excess aqueous sodium hydroxide and extracted with ether. This latter ether extract is evaporated to ' dryness to give l-allyl-5-nitroimidazole as an oil. The l-allyl-5-nitroimidazole is dissolved in 50 ml. of dry ether and added to a solution of 4.01 g. of p-toluene sulfonic acid hydrate and 200 ml. of ether, the mixture cooled in an ice bath and the precipitate removed by filtration. The , precipitate is recrystallized from ethyl acetate to yield l-allyl-5-nitroimidazolium-p-toluene sulfonate, m.p.- 145- 1 9°C.

Preparation 3 l-Phenyl-5-Nitroimldazole G. , (.069 mole) of 1-phenylimidazole is dis- solved in 30 ml. of chloroform and the solution is stirred in an ice bath while 5 g. (.037 mole) of nitronium fluoborate is added in small portions over .5 hour. After stirring for .5 hour at room temperature, the two dark phases are diluted with 200 ml. of chloroform and the mixture . extracted with an excess of 1 N hydrochloric acid. The chloroform extract is evaporated and the residue dissolved in acetone-ether (1:1) and chromatographed on 12 g. of a charcoal/Supercel mixture to yield l-phenyl-5-nitroimidazole, m.p. 150-165°C. Sublimation at less than 1 mm. of mercury pressure and 120°C. raises the melting point to 160-170°C.

MeOH U.V. λ 291.0 πιμ max Preparation 4 l-P-Nitrophenyl-5-Nitroimidazole. 1.98 G., (.0137 mole) of 1-phenylimidazole is ' dissolved in 6 ml. of concentrated sulfuric acid and 3·0 ml. (.07 mole) of fuming nitric acid is added slowly. The mixture is heated in an oil bath at 120°C. for 1 hour, cooled and poured into ice water. The mixture is extracted with chloroform to give a partly crystalline mixture. The aqueous acid phase is made basic and extracted with chloro-form to give crystalline 1-p-nitrophenylimidazole . 'The acid insoluble fraction is repeatedly washed with small portions of chloroform, evaporation of the solvent is fol-lowed by filtration of an acetone solution of the residue through celite/charcoal. Evaporation, followed by re-crystallization from methanol gives l-p-nitrophenyl-5-nitroimidazole; m.p. 156.8-158°C.

U.V. λ^®°Η 275.0 ι £.13,100 Preparation 5 l-( ' -Hydroxyethy1)- - itroimidazole 78 G. , (0.615 mole) of 5-nitroimidazole is dis-solved in 1500 ml. of acetic acid upon the addition of 72 ml. (0.57 mole) of boron trifluoride etherate. 175 Ml., (3.5 moles) of ethylene oxide in 175 ml. of hexane, in a dropping funnel topped with a cold finger, is added slowly over 1 hour* to the above solution maintained at 32-35°C. with a water cooling bath. The mixture is concentrated under high vacuum to 100-150 ml. volume. The residue is diluted with 500 ml. of water, neutralized to pH 7 with l-( 21 -hydroxyethyl)-5-nitroimidazole . It is convenient to isolate the compound as the hydrochloride. Hydrogen chloride is passed through the ethyl acetate extract and l-(2'-hydroxyethyl)-5-nitroimidazolium hydrochloride is isolated; m.p. 172-175°C.

In accordance with the above procedure but start-ing with 1,2-epoxypropane, 1,2-epoxybutane, 1,2-epoxypentane, 1, 3-epoxypropane, 1,3-epoxybutane and 1,3-epoxypentane in place of ethylene oxide, there is obtained the corresponding l-(2,-hydroxypropyl)-5-nitroimidazole, l-(2'-hydroxybutyl)-5-nitroimidazole, l-(2 '-hydroxypentyl)-5-nitroimidazole, l-( 3' -hydroxypropyl) -5-nitroimidazole, l-(3'-hydroxybutyl)-5-nitroimidazole, and l-( 3 ,-hydroxypentyl)-5-nitroimidazole .

Preparation 6 l-( 2 '-Oxoprop 1)-5-Nitroimldazole 17.1 G., (0.1 mole) of l-(2'-hydroxypropyl)-5-nitroimidazole is dissolved in 500 ml. of dimethylsulfoxide and heated with 8 ml. of dry pyridine and 4 ml. of tri-fluoroacetic acid and 61.8 g. (0.3 mole) of dicyclohexyl-carbo diimide for 8 hours at 15-20°C. The mixture is treated with excess oxalic acid, filtered and the filtrate evaporated to dryness under vacuum of less than 1 mm. of mercury pressure. The mixture 'is taken up in water, neutralized with aqueous sodium' ydroxide to pH 8-9 and extracted thoroughly with ethyl acetate.. The. extract after drying over sodium sulfate, is treated with dry gaseous hydrogen chloride and l-(2'-oxopropyl)-5-nitroimidazolium hydrochloride (m.p. 198-200°C.) is precipitated and re- base (m.p. 100°C.) by stirring with a saturated solution of sodium bicarbonate.

In accordance with the above procedure, but start- ing with l-(2*-hydroxybutyl)-5-nitrolmidazole, l-(2'-hydroxy- pentyl)-5-nitroimidazole, l-( 3 '-hydroxybutyl)-5-nitro- imidazole and l-( 3 '-hydroxypentyl)-5-nitroimidazole, in place of l-(2l-hydroxypropyl)-5-nitroimidazole, there is Obtained the corresponding l-(2'-oxobutyl)-5-nitroimidazole, l-(2'-oxcpentyl)-5-nitroimidazole, l-( 3 '-oxobutyl)-5- nitroimidazole and l-(3 '-oxopentyl)-5-nitroimidazole.

Preparation 7 l-( 2 ' -Acetoxypropyl) ~5~Nitroimidazole 11.2 G. , ( .05¾ mole) of l-( 2 ' -hydroxypropyl)-5- nitroimidazolium hydrochloride is heated under reflux in 100 ml. of acetic anhydride for one hour. The mixture is then concentrated and the residue dissolved in ether. The ether solution treated with anhydrous hydrogen chloride to yield l-(2'-acetoxypropyl)-5~nitroimidazolium hydrochloride; m.p. 165-175°C Preparation 8 : l-(2t-Acetox.yethyl)-5- ltroimidazole 55 G. , (0.35 mole) of; l-(2'-hydroxyethyl) -5- nitroimidazole is dissolved in 200 ml. of pyridine and treated with 50 ml. of acetic anhydride. The solution is heated under reflux for one hour and then concentrated under reduced pressure to yield l-(2'-acetoxyethyl)-5-nitro- imidazole; m.p. 6l-62°C.

In accordance with the above procedure but start-ing with l-( 2'-hydrox butyl)-5-nitroimidazole, l-( 2 '.-hydroxy-pentyl) -5-nitroimidazole, l-(3'-hydroxybutyl)-5-nitro-imidazole, l-( 3 '-hydroxypentyl)-5-nitroimidazole , and l-(3'-hydroxypropyl)-5-nitroimldazole, in place of l-(2'-hydroxyethyi)-5-nitroimidazole, there is obtained the corresponding l-( 2 '-acetoxybutyl)-5-nitroimidazole, l-( 2 '-acetoxypentyl)-5-nitroimidazole, l-(3'-acetoxybutyl)-5-nitroimidazole, l-( 3 '-acetoxypentyl)-5-nitroimidazole , and l-( 3'-acetoxypropyl)-5-nitroimidazole.

In accordance with the above procedure but using propionic anhydride, butyric anhydride or valeric anhydride in place of acetic anhydride together with any of the aforementioned l-(2'-hydroxyalkyl)-5-nitroimidazoles, there is obtained the corresponding l-(2'-alkanoyloxyalkyl)-5-nitroimidazole.

Preparation 9 l-( 2 ' -Benzoylox ethyl)-5-Nitroimidazole 55 G., (0.35 mole) of l-( 2'-hydroxyethyi)-5-nitroimidazole is dissolved in 150 ml. of water and added to a mixture of 100 ml. of benzoyl chloride and 300 ml. of 2.5 N aqueous sodium hydroxide and agitating vigorously for 3 hours . The mixture is then concentrated under reduced pressure, extracted with ether,, the ether extract washed with sodium hydroxide, dried over sodium sulfate and evaporated to yield l-(2'-benzoyloxyethyl)-5-nitroimidazole.

In accordance with the above procedure but start-ing with phenylacetyl chloride, propionyl chloride or obtained the corresponding l-(2 '-phenylacetoxy ethyl)-5-nitroimidazole, l-(2'-propionoxyethyl)-5-nitroimidazole and l-(2'-valeroxyethyl-)-5-nitroimidazole.

In accordance with the above procedure but start-ing with any of the l-(2'-hydroxyalkyl)-5-nitroimidazoles produced in accordance with Preparation 5, there is obtained the corrresponding l-(2'-alkanoyloxyalkyl-5-nitroimidazole.

Preparation 10 l-Ethoxyethyl-5-Nltroimidazole 11.3 G., (0.1 mole) of 5-nitroimidazole is. mixed thoroughly with 24.4 g. (0.1 mole) of β-ethoxyethyl tosylate and heated to between 185-195°C for 30 minutes. The mix-ture is cooled and shaken with a mixture of chloroform and 2.5 N aqueous sodium hydroxide. The chloroform layer is set aside while the aqueous layer is extracted with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and the solvent removed under reduced pressure. The residue is dissolved in ether and washed through a column of alumina using ether as the eluan . Evaporation of the eluate yields l-ethoxyethyl-5-nitro-imidazole, In accordance with the above procedure but start-ing with methoxyethyl . tosylate, propoxyethyl tosylate, butoxyethyl* tosylate and benzyloxyethyl tosylate in place of ethoxyethyl tosylate, there is obtained the corresponding l-methoxyethyl-5-nitroimidazole, l-propoxyethyl-5-nitro-imidazole, l-butoxyethyl-5-nitroimidazole and 1-benzyloxy- PreparatIon 11 1-Ethoxyc "opy1-5-Nitroimidazole ' 11.3 G » •(0.1 mole) of 5-nltroimidazole is mixed thoroughly with 25.8 g. (0.1 mole) of β-ethoxypropyl tosylate and heated to between 185-195°C. for 30 minutes. The mixture is cooled and dissolved in a mixture of chloroform and 2.5 N aqueous sodium hydroxide. The chloroform layer is set aside, and the aqueous layer ex-tracted with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate and the solvent removed under reduced pressure. The residue is dissolved in ether and washed through a cdlumn of alumina using ether as the eluant. Evaporation of the eluate yields l-ethoxypropyl-5-nitroimidazole.

In accordance with the above procedure but start-ing with ethoxybutyl tosylate or ethoxypentyl tosylate in place of ethoxypropyl tosylate, there is obtained the corresponding l-ethoxybutyl-5-nltroimidazole and 1-ethoxy-pentyl-5-nitroimidazole .

Preparation 12 -Nitroimidazol-l-ylacetic Acid 1.5 G., (.01 mole) of l-( 2 ' -hydroxyethyl) -5-nltroimidazole is taken up in 15 ml. of water and treated with 5.2 ml. of a chromic acid/sulfuric acid mixture (composition 27 g. of chromium trioxide, 2.35 ml. of con-centrated sulfuric acid made up to 100 ml. with water). The reaction mixture is heated to 70°C. for one hour and allowed to stand for 18 hours. The mixture is diluted with 200 ml. 1 sodium hydroxide which is extracted with ether. The ether 2 layer is discarded. The sodium' hydroxide extract is acidi- 3 fied with acetic acid, extracted with chloroform and the k chloroform extract evaporated under reduced pressure to yield 5-nitroimidazol-l-ylacetic acid; m.p. 225-230°C. 6 Preparation 13 7 5-Nitrolmidazole-l-ylacetic Acid 8 15.7 G., (0.1 mole) of l-( 2»-hydroxyethyl) -5- 9 nitroimldazole is dissolved in 500 ml. of dimethylsulfoxide 0 and heated with 8 ml. of dry pyridine and k ml. of trifluoro-1 acetic acid and 61.8 g. (0.3 moles) of dicyclohexylcarbo-2 diimide for.8 hours at 15-20°C. The mixture is treated with. · 3 excess oxalic acid, filtered and the filtrate evaporated to k dryness at a temperature of 80-90°C. under vacuum of less 5 than 1 mm. of mercury pressure. The mixture is taken up in 6 water, neutralized with aqueous sodium hydroxide to pll 8-9 7 and extracted thoroughly with ethyl acetate. After drying 8 over sodium sulfate, the ethyl acetate extract is treated 9 with dry gaseous hydrogen chloride and 5-nitroimidazol-l-0 ylacetaldehyde hydrochloride is1 removed by filtration. 1 1.55 G., (0.01 mole) of the aldehyde hydrochloride is dis-2 solved in 30 ml. of water and k- ml. of 2.5 N aqueous sodium 3 hydroxide added. 0.011 Mole of sodium hypochlorite is k added and the mixture allowed to.stand at room temperature 5 for 18 hours. The reaction mixture is then made acid with 6 acetic acid and extracted with chloroform. The chloroform 7 extract, after drying over sodium sulfate, is evaporated 8 under reduced pressure to yield 5-nitroimidazol-l-ylacetic 1 In accordance with the above procedure but start- 2 ing with l-( 3 '-hydroxypropyl) -5-nitroimidazole in place of 3 l-( 2 ' -hydroxyethyl)-5-nitroimidazole , there is obtained the H corresponding 5-nitroimidazol-l-ylpropionlc acid.

Preparation 14 6 Ethyl 5-Nitroimidazol-l-ylacetatie 7 22.6 G., (0.2 mole) of 5-nitroimidazole is dis- 8 solved in 250 ml. of nitromethane and 26 ml. (0.2 mole) of 9 boron trifluoride etherate is added. The mixture is cooled 0 to 0°C. and a solution of 25 ml. of diazoacetic ester in 1 25 ml. of nitromethane is added. An additional 12 ml. of 2 diazoacetic acid is then added and the solution concentrated 3 under reduced pressure. The residue is taken up in ethyl 4 acetate and the ethyl acetate solution washed with ice cold 5 aqueous dilute ammonia. A precipitate of 5-nitroimidazole 6 is formed and is separated by filtration. The filtrate is 7 thoroughly washed with water. After drying the ethyl acetate 8 phase over sodium sulfate, dry hydrogen chloride gas is 9 passed through the solution. Ethyl 5-nitroimidazolr-l-yl-0 acetate hydrochloride; m.p. 165-175°C, is obtained as a 1 crystalline precipitate. 2 The ester hydrochloride is dissolved in water from 3 which ethyl 5-nitroimidazol-l-ylacetate; m.p. 76-77°C. , ''4 crystallizes. in accordance with the, above procedure, but start-6 ing with methyl diazoacetate , propyl dlazoacetate or benzyl 7 diazoacetate in place of diazoacetic ester there is obtained 8 the corresponding methyl, propyl and benzyl 5-nitroimidazol-9 1-ylacetates .

Preparation 15 Ethyl 5-Nitroimidazol-l-ylpropio'nate 22.6 G (0.2 mole) of 5-nitroimidazole is dis-solved in 250 ml. of nitromethane and 26 ml. (0.2 mole) of boron trlfluorlde etherate is added. The mixture is cooled to 0°C. and a solution of 25 ml. of dlazoproplonic ester in 25 ml. of nitromethane is added. An additional 12 ml. of dlazoproplonic acid is then added and the solution concen-trated under reduced pressure. The residue is taken up in ethyl acetate and the ethyl acetate solution washed with ice cold aqueous dilute ammonia. A precipitate of 5-nitro-imidazole is formed and is separated by filtration. The filtrate is thoroughly washed with water. After drying the ethyl acetate phase over sodium sulfate, dry hydrogen chloride gas is passed through the solution. Ethyl 5-nitroimidazol-l-ylpropionate hydrochloride is obtained as a crystalline precipitate.

The ester hydrochloride is dissolved in water from which ethyl 5-nitroimidazol-l-ylpropionate crystallizes .

In accordance with the above procedure but start-ing with methyl diazopropionate, propyl diazopropionate or benzyl diazopropionate in place of dlazoproplonic ester there is obtained the corresponding methyl-5-nitroimldazol-1-ylpropionate, propyl-5-nitrolmidazol-I-ylpropionate , and benzyl-5-nitroimidazol-l-ylpropiQnate .

Preparation 16 -Nltroimidazol-l-ylacetic acid · G. , (.05 mole) of ethyl-5-nitroimidazol-l-yl-acetate dissolved in 50 ml. of methanol is treated with 50 ml. of 1 N potassium hydroxide (.05 mole) in 50 ml. of methanol. After ten minutes the solution is diluted with ether (50 ml.) which causes the potassium salt to crystal-llze. It is filtered, washed with 50% methanol-ether and dried.

This potassium salt is dissolved in 40 ml; of water and acidified slowly with concentrated hydrochloric acid to pH 2 or lower. The crystalline acid is filtered off, washed with water and dried; m.p. 226-228°C.

U.V. λ E 297.5 ιημ, 226.0 ιημ; E ^ 4 8, 199 χ C¾0H/HC1 266<0 πμ; B 335.

Preparation 17 Ethyl 5-Nitroimidazol-l-ylacetate 17.1 G., (0.1 mole) of 5-nitroimidazol-l-ylacetic acid is taken up in 200 ml. of ethanol and heated under re-flux for .5 hours, during which time a slow stream of dry hydrogen chloride is passed through the reaction mixture. The ethanol is then removed by evaporation under reduced pressure and the residue recrystalllzed from acetone to yield ethyl 5-nitroimldazole-l-ylacetaile hydrochloride; m.p. 165-175°C * The ester hydrochloride is dissolved in water. On standing for 10 minutes, ethyl-5-nitroimidazol-l-ylacetate; m.p. 76-77°C, is precipitated in crystalline form and is In accordance with the above procedure, but using methanol, propanol or butanol in" place of ethanol, there is obtained the corresponding methyl, propyl or butyl ester.

In accordance with the above procedure but start-ing with 5-nitrolmidazol-l-ylpropionic acid in place of -nitroimidazol-l-ylacetic acid, there is obtained the corresponding ethyl, methyl, propyl and butyl 5-nitroimida-zol-l-ylpropionates .

Preparation 18 -Nitroimidazol-l-ylacetonitrile 3.4 G., (0.02 mole) of 5-nitroimidazbl-l-ylaceta-mide in 50 ml. of dry benzene and 10 ml. of thionyl chloride are heated under reflux for 6 hours. The solvent and excess thionyl chloride are removed by evaporation under reduced pressure and the residue dissolved in chloroform. The chloroform is washed with dilute sodium carbonate solution and dried over sodium sulfate. Dry hydrogen chloride gas is introduced into the chloroform solution and 5-nitroimidazoi-1-ylacetonitrile hydrochloride is isolated as a crystalline precipitate.

The 5-nitroimidazol-l-ylacetonitrile hydrochloride is treated with sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the ethyl acetate removed under reduced pressure to yield · 5-nitroimidazol-l-ylaceto-nitrile.

In accordance with the above procedure, but start-ing with 5-nitroimidazol-i-ylpropionamide in place of 5-nitro-imidazol-l-ylacetamide, there is obtained the corresponding Preparation 19 1- ( 21 -Ethylthioethyl ) -5-Nitroimidazole A mixture- of 3· 11 g. (0.01 mole) of 5-nitroimida- zol-l-ylethyl p-toluenesulfonate and 1.03 g. (0.012 mole) of the potassium salt of ethanethiol in 20 ml. of dry dimethyl- formamide is heated at about 100°C. overnight. The reaction mixture is cooled and is poured into 500 ml. of ice water containing a slight excess of ammonia. The mixture is ex- tracted with ethyl acetate. The extract is dried and con- centrated leaving a residue of l-( 2 ' -ethylthioethyl) -5- nitroimidazole.

In accordance with the above procedure but start- ing with 5-nitroimidazol-l-ylpropyl tosylate and 5-nltro- imidazol-l-ylbutyl tosylate in place of ethyl tosylate, there ■ is obtained the corresponding l-( 3 '-ethylthiopropyl)-5-nitro- . imidazole, l-( 4 ' -ethylthiobutyl-5-nitroimidazole .

In accordance with the above procedure, but using the potassium salt of methanethiol, propanethiol, thiophenol and benzyl mercaptan in place of ethanethiol, there is obtained the corresponding l-( 2 ' -methylthioethyl-5-nitro- imidazole, l-( 2 ' -propylthioethyl-5-nitroimidazole, l-(2'- phenylthioethyl)-5-hitroimidazole and l-( 2' -benzylthioethyl) - 5-nitroimidazole .

Preparation 2Q l-( 2* -Ethylsulfinylethyl) -5-Nitroimidazole v A solution of 1.0 g. '(0.005 mole) of l-(2'-ethyl- thioethyl) -5-nitroimidazole is. cooled to about -20 to -30°C. and a cold solution of 55 ml. (0.0055 mole) of 0.1 N mono- Preparation 19 1-( 21 -Ethylthioethyl) -5-Nltroimidazole A mixture" of 3.11 g. (0.01 mole) of 5-nitroimida- zol-l-ylethyl p-toluenesulfonate and 1.03 g. (0.012 mole) of the potassium salt of ethanethiol in 20 ml. of dry . dimethyl- formamide is heated at about 100°C. overnight. The reaction mixture is cooled and is poured into 500 ml. of ice water . containing a slight excess of ammonia. The mixture is ex- tracted with ethyl acetate. The extract is dried and con- centrated leaving a residue of l-(2'-ethylthioethyl)-5- nitroimidazole.

In accordance with the above procedure but start- ing with 5-nitroimidazol-l-ylpropyl tosylate and 5-nitro- imidazol-l-ylbutyl tosylate in place of ethyl tosylate, there · is obtained the corresponding l-( 3 '-ethylthiopropyl) -5-nitro- . imidazole, l-( 4 ' -ethylthiobutyl-5-nitroimidazole .

In accordance with the above procedure, but using the potassium salt of nethanethiol, propanethiol, thiophenol and benzyl mercaptan in place of ethanethiol, there is obtained the corresponding l-(2 ' -methylthioethyl-5-ni ro- imidazole, l-(2 ' -propylthloethyl-5-nitroimidazole, l-(2f- phenylthioethyl)-5-hitroimidazole and l-(2'-benzylthioethyl)- ^ 5-nitroimidazole .

Preparation 20 l-(2,-Ethyisulflnyleth.vI)-5- ltroimidazole v A solution of 1.0 g. (0.005 mole) of l-(2*-ethyl- thioethyl) -5-nitroimidazole is. cooled to about -20 to -30°C. and a cold solution of 55 ml. (0.0055 mole) of 0.1 mono- mixture Is kept overnight In the cold room. The mixture Is concentrated to dryness at reduced pressure leaving a residue which, after neutralization with dilute ■ammonia-j is extracted several times with chloroform. Evaporation of the chloroform extract leaves a residue of l-(2'-ethyI-sulfinylethyl)-5-nitroimidazole.

In accordance with the above procedure, but start-ing with l-(2 '-ethylthiopropyl)-5-nitroimidazole, l-(2'-. ethylthiobutyl)-5-nitroimldazole, l-(2 '-methylthioethyl)-5-nitroimidazole, I-(21 -propylthioethyl)-5-nitroimidazole, l-(2'-phenylthioethyl)-5-nitroimidazole and l-( 2 '-benzyl-thioethyl)-5-nitroimidazoIe, in place of l-( 2 -ethylthio-ethyl)-5-nitroimidazole, there is obtained the corresponding l-(2,-ethylsulfinylpropyl)-5-nitroimldazole, l-(2'-ethyl-sulfinylbutyl)-5-nitroimidazole, l-( 2 ' -methylsulfinylethyl)-5-nitroimldazole, l-( '-propylsulfinylethyl)-5-nitroimida-zole, l-( 2 ' -phenylsulfinylethyl) -5-nitroimldazole, and l-(2T-benzylsulfinylethyl)-5-nitroimidazole.

Preparation 21 -Nltroimidazol-l-ylethy ethylsulfone A mixture of 433 mg. (0.02 moles) of l-(2'-ethyl-sulfin le hyD-S-nitroimidazoIe, 2 ml. of glacial acetic acid and 2 ml. of 30% hydrogen peroxide is heated for 8 hours at 100°C. The solution is concentrated under reduced pressure (but not to dryness), water Is added to the residue. 5-Nitroimldazol-l-ylethylethylsulfone which precipitates is separated by filtration, washed with water and air dried.

In accordance with the above procedure but starting with l-(2'-methylsulfinylethyl)-5-nltroimidazoie, l-(2'-propylsulfinylethyl)-5-nitroimidazole, l-( 2 '-butyl- sulfinylethyl)-5-nitroimidazole,- l-( 2 ' -methylsulfinylethyl) - 5-nitroimidazole, i-( 2 ' -ethylsulfinylpropyl) -5-nitroimida- zole, l-(2'-phenylsulfinylethyl)-5-nitroimidazole, and l-( 2 '-benzylsulfinylethyl) -5-nitroimidazole, in place of l-(2'-ethylsulflnylethyl)-5-nitroimidazole, there is obtained the corresponding 5-nitroimidazol-l-ylmethylethyl- ' sulfone, 5-nitroimidazol-l-ylpropylethylsulfone, 5-nitro- imidazol-l-ylbutylethylsulfone, 5-nitroimidazol-l-ylethyl- ■ methylsulfone , 5-nitroimidazol-l-ylethylpropylsulforie:, -nltr imidazol-l-ylethylphenylsulfone, and 5-nitroimidazol- 1-ylethylbenzylsul one.

Preparation 22 l-( 2 ' -p-Toluenesulfonyloxyethyl-5-Nltroimidazole G. , (0.127 mole) of l-(2 '-hydroxyethyl)-5- nitroimidazole in 50 ml. of dry pyridine is reacted with 75 g. of p-toluene sulfonyl chloride at 15°C. for 4 hours. The reaction mixture is poured into ice and water and the crystalline precipitate is separated by filtration, washed : with water and air dried to yield l-( 2 ' -p-toluenesulfonyloxy- ethyl) -5-nitroimidazole; m.p. 126-127°C.

In accordance with the above procedure, but start- ing with l-( 2 '-hydroxy propyl)-5-nitroimidazole, l-(2'- hydroxy butyl) -5-nitroimidazole ·, ■!-( 2 '-hydroxy pentyl)-5- nitroimidazole, l-(3 '-hydroxy propyl)-5-nltroimidazole, l-( 3'-hydroxy butyl) -5-nitroimidazole, and l-(3 '-hydroxy pentyl) -5-nitroimidazole, in place of l-( 2 ' -hydroxy ethyl) - 5-nitroimidazole, there is obtained the corresponding l-(2'- p-toluenesulfonyloxybutyl)-5-nitroimidazole, l-( 2 '-p-toluene-sulfonyloxypentyl) -5-nitroimidazole, l-( 3 '-p-toluene-sulfonyloxypropyl)-5-nitroimidazcle, l-( 3 '-p-toluene-sulfonyloxybutyl) -5-nitroimidazole, and l-( 3 '-p-toluene-sulfonyloxypentyl)-5-nitroimidazole.

Preparation 23 l-(2f-N-morpholinylethyl)-5-Nitroimidazole . 16 G. , (.057 mole) of l-(2'-p-toluenesulfonyloxy-ethyl) -5-nitroimidazole and 9.3 ml. of morpholine are heated at 95°C. for 4 hours. The reaction mixture is taken up in water and extracted with ether.' Evaporation of the ether yields l-(2'-N-morpholinylethyl)-5-nitroimidazole; m.p. 109-110°C.

In accordance with the above procedure, but start-ing with pyrrolidine piperidine, dimethylamine, and diethylamine, in place of morpholine, there is obtained the corresponding l-( 2 '-N-pyrrolidinylethyl)-5-nitroimidazole, l-( 2 '-N-piperiQinylethyl) -5-nitroimidazole, l-( 2 ' -NN-di-methylaminoethyl) -5-nitroimidazole, and l-(2 '-NN-diethyl-aminoethyl) -5-nitroimidazole.

Preparation 24 l- ethyl-2-Hydroxymethyl-5-Nitrolmidazole 27.9 G. of l-methyl-5-hitroimidazole and 30.1 g. of paraformaldehyde are added to 1 4 ml. of dimethylsui-foxide and the resulting solution is sealed into a glass-lined tube. The solution is heated at 110°C. for 24 hours, with shaking. The dimethylsulfoxide is removed by distilla- 150 ml. of hot benzene. The benzene extracts are combined and cooled to room temperature. l-Methyl-2-hydroxymethyl-5-nitroimidazole crystallizes, and is recovered by. filtra-tion. The yield of product is 23 g.; m.p. 112-114.5°C ..

Preparation 25 l-[2'-(Tetrahydropyran-2"-ylox )ethyl]-2-H droxymethy1-5-Nitroimidazole .7 G., (0.1 mole) of l-( 2 » -hydroxyethyl) -5-nitroimidazole is heated under reflux in 200 ml. of. dihydro-. pyran in the presence of 1 g. of p-toluene sulfonic acid for 12 hours. The solvent is removed by evaporation under reduced pressure. The residue is taken up in a mixture of chloroform and aqueous sodium bicarbonate. The chloroform phase after drying over sodium sulfate, is evaporated. The residue is dissolved in 75 ml. of dimethylsulfoxide contain-ing 1 g. of paraformaldehyde, and the resulting solution is sealed into a glass-lined tube. The solution is heated at 110°C. for 24 hours, with shaking. The mass is then re-moved from the reaction vessel and the dimethylsulfoxide removed by distillation at 53-56°C ./2mm. The residue is extracted with 3 x 150 ml. of hot benzene. The benzene extracts are combined and concentrated to a small volume. l-( 2-Hydroxymethyl-5-nitrolmidazol-l-yl) ethyl tetrahydro-pyranyl ether crystallizes and is recovered by filtration.

Preparation 26 l-Methyl-2-Formyl-5-Nitroimidazole 100 Gm. (0.64 mole) of l-methyl-2-hydroxymethyl- - t o midaz le is dissolved in 00 ml. of benzene at 70°C. v tetraacetate (previously washed with glacial acetic acid and air dried in the dark) . The reaction mixture is stirred at 78°C. for 8 hours during which time white, crystalline lead diacetate precipitates from the solution. The mixture is allowed to stand overnight at room temperature, and the lead diacetate then removed by filtration and washed with 2 x 100 ml. of benzene. The combined benzene filtrate and washes are extracted with two 1 liter portions of saturated aqueous potassium bicarbonate, then with 1500 ml. of water. The aqueous extracts are combined and extracted with 3 x 2500 ml. portions of chloroform. The chloroform extracts' are backwashed individually with 500 ml. of water and then combined with the benzene solution and evporated in vacuo to dryness. The residue is dissolved in 500 ml. of. 10$ sulfuric acid and warmed on the steam cone at 75-90°C. for 35 minutes.

The acidic solution is then cooled to room tempera-ture and neutralized with sodium bicarbonate. This aqueous solution is then extracted with k x 2500 ml. portions of chloroform and each extract is backwashed in turn with 500 ml. of water. The organic extracts are combined and evaporated to dryness, in vacuo. The crystalline residue thus obtained is dissolved in a minimum volume of chloroform and filtered over about 250 gm. of silica gel. The silica gel is eluted with 7500 mi. of methylene dichloride. The eluate is evaporated in vacuo to give a residue of suo-stantially pure l-methyl-2-formyl-5-nitroimidazole . Re-crystallization of the product from 500 ml. of boiling hexane affords 79 gm. of l-methyl-2-formyl-5-nitroimidazole; m.p. •v Preparation 27 l- ethyl-2-( 1 T -Hydroxyethyl) -5-Nitroimidazole A solution of methyl magnesium iodide is prepared from 4.5 gm. of magnesium, 26.3 gm. of methyl iodide and 90 ml. of diethyl ether. 2.8 Mg. of this solution is diluted with 15 ml. of ether, and added to a solution of 0.5 gm. of l-methyl-2-formyl-5-nitroimidazole in 20 ml. of diethyl ether. The mixture is refluxed for 20 minutes. An addition-al 15 ml. of diethyl ether is then added, followed by 6.7 ml. of 0.5 N hydrochloric acid. The organic phase is separated, dried over sodium sulfate and evaporated to dryness in vacuo to give 0.27 g. of l-methyl-2-(l' -hydroxyethyl)-5-nitro-imidazole. This material is dissolved in ether, an equal volume of petroleum ether added, and the resulting solution evaporated to give crystalline l-methyl-2-( 1' -hydroxyethyl) -5-nitroimidazole.

The acidic aqueous layer is extracted with an equal volume of methylene chloride. The methylene chloride solution is evaporated to a residue which is dissolved in a minumum volume of methylene chloride. One-half volume of petroleum ether is added and the solution evaporated to give a residue of l-methyI-2-(l' -hydroxyethyl)-5-nltro-imidazole.

The solid products obtained are combined and dls-solved in ethyl acetate. The solution is filtered through acid-washed' alumina, and the filtrate evaporated to a small volume. > l- ethyi-2-(l '-hydroxyethyl) -5-nitroimidazole crystallizes; m.p. l44-l45°C. It is recrystallized from ethyl acetate to give pure l-methyl-2-(l '-hydroxyethyl) -5-nitroimidazole; m.p. 145-147°C Preparation 27 l-Methyl-2-(l' -Hydroxyethyl) -5-Nltroimldazole A solution of methyl magnesium iodide is prepared from 4.5 gm. of magnesium, 26.3 gm. of methyl iodide and 90 ml. of diethyl ether. 2.8 Mg. of this solution is diluted with 15 ml. of ether, and added to a solution of 0.5 gm. of l-methyl-2-formyl-5-nitroimidazole in 20 ml. of diethyl ether. The mixture is refluxed for 20 minutes. An addition-al 15 ml. of diethyl ether is then added, followed by 6.7 ml. of 0.5 N hydrochloric acid. The organic phase is separated, dried over sodium sulfate and evaporated to dryness in vacuo to give 0.27 g. o l-methyl-2-(lT -hydroxyethyl) -5-nitro-imidazole. This material is dissolved" in ether, an equal volume of petroleum ether added, and the resulting solution evaporated to give crystalline l-methyl-2-(l* -hydroxyethyl) -5-nitroimidazole.

The acidic aqueous layer is extracted with an equal volume of methylene chloride. The methylene chloride solution is evaporated to a residue which is dissolved in a minumum volume of methylene chloride. One-half volume of petroleum ether is added and the solution evaporated to give a residue of l-methyi-2-(l' -hydroxyethyl) -5-nitro-imidazole.

The solid products obtained are combined and dis-solved in ethyl acetate. The solution is filtered through acid-washed alumina, and the filtrate evaporated to a small volume. » l- ethyl-2-(l '-hydroxyethyl)-5-nitroimidazole crystallizes; m. . 144-145°C. It is recrystallized from ethyl acetate to give pure l-methyl-2-( 1 ' -hydroxyethyl) -5- - ° Prenaration 2& l-Methyl-2-( 1 ' -Hydroxyethyl) -5-Nitroimidazole To a solution of 1.5 g • (.01 mole) of i-methyl-5-nitroimidazole-2-carboxaldehyde in 15 ml. of 1,2-dimethoxy-methane at 0°C. containing 1.33 ml. of boron trifluoride etherate is added 0.9 g. of diazomethane in 50 ml. of diethyl ether solution dropwise over about 20 minutes .

Nitrogen gas is evolved. After stirring for one hour at 0°C, the solution is allowed to warm gradually to room temperature. The solvent is evaporated. Chloroform (100 ml.) and 20 ml. of water (containing 5 ml. of .N ammonium hydroxide) are added to the residue. The chloro-form layer is separated, washed with 10 ml. of water, dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on silica gel to give l-methyl-2-acetyl-5-nitroimidazole; m.p. 98°C.

To 1.83 g., (0.01 mole) of l-methyl-2-acetyl-5-nitroimidazole dissolved in 50 ml. of ethanol is added 0.38 g. of sodium borohydrlde. The solution is allowed to stand overnight at room temperature. Following the addition of a few drops of glacial acetic acid to destroy unreacted sodium borohydrlde, 20 ml. of water is added and the solu-tion evaporated to about 20 ml. l-Methyi-2-(l ' -hydroxy-ethyl) -5-nitroimidazole is separated by filtration, washed with water and air dried. · , in accordance with the above procedure but using diazoethane, diazopropane or phenyldiazomethane in place of diazomethane, there is obtained the corresponding i-methyl-2-(l'-hydroxypropyl) -5-nitroimidazole, l-methyl-2-(i'-h drox but l)-5-nitrolmidazole, and l-methyl-2-( 1 ' -hydrox - Preparation 29 α-( l-Meth.yl-5-Nltroimidazol-2-yl) Benzyl Alcohol 6 G. of 2-benzylimidazole is added to 17 ml. of concentrated nitric acid in 75 ml. of acetic anhydride and cooled in an ice bath. The reaction mixture is warmed on a steam bath for 30 minutes, and then poured into crushed ice. The crude product is extracted with 3 x 100 ml. of chloroform. The combined chloroform extract is washed with 3 x 15 ml. water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue dissolved in 50 ml. acetone. The addition of diethyl ether to the cloud-point results in the crystallization of 2-benzyl-4( 5)-nitro-imidazole. 2.03 G. of 2-benzyl-4(5)-nltroimidazole and 1.3 g. of dimethyl sulfate are heated for 30 minutes at 120°C.

After cooling, 100 ml. of chloroform and 10 ml. of 4 N sodium hydroxide solution are added. The chloroform extract; after washing with 3 x 10 ml. of water is dried over anhydrous sodium sulfate and evaporated. The crude 1-methyl-2-benzyl-5-nitroimidazole is purified by recrystallization from ethanol. 3.22 G. of i-methyl-2-benzyl-5-nitroimidazole is dissolved in a mixture of 4 ml. of water and 15 ml. of sulfuric acid. .25 G. o .sodium dichromate dihydrate in 30 ml. of water is added. 75 Ml. of sulfuric acid is added so as to maintain the temperature between 75 and 90°C. Heating is continued for one hour at about 70°C. The reaction mixture is poured onto crushed ice and concentrated sodium h droxide is added to neutrali . The roduct l-meth i-2- benzoyl-5-nitroimidazole, is filtered.

To 2.15 g. of l-methyl-2-benzoyl-5-nitroimicazole in 100 ml. of ethanol is added 0.28 g. of sodium borohydride . The mixture is allowed to stand .overnight . After the addition of a few drops of glacial . acetic acid, 25 ml. of water is added and the ethanol evaporated. The product, a-( l-methyl-5-nltr0imidazol-2-yl)benzyl alcohol is removed by filtration.

Preparation 30 2-( l-Methyl-5-Nitroimidazol-2-yl) -Ethanol A mixture of 70 g. (0.5 mole) of l,2-dimethyl-5-nitroimidazole, 75 g. (2.5 mole) of paraformaldehyde, and 1 liter of dry dimethylsulfoxide is heated in a glass-lined, rocking autoclave at 120-150°C. overnight. The bulk of the dimethylsulfoxide is removed at reduced pressure.

The residue is dissolved in 400 ml. of 2.5 hydrochloric acid, and the solution is exhaustively extracted with chloroform to remove the rest of the dimethylsulfoxide.

The aqueous phase is adjusted to pH 7.5 by the addition of 50% sodium hydroxide solution, and is again extracted ex-haustively wit chloroform. The extract is dried and con-centrated leaving an oily residue which soon crystallizes. The solid is dissolved in a little ethyl acetate, and the solution is charged to a column Of alumina. Elution with ethyl acetate and evaporation of the solvent yields 2-(l-methyl- -nitroimidazol-2-yl) ethanol; m.p. 149-151°C; λΜβ?Η 310 mu, (£, 8800); 2-( l-methyl-5-nitroimidazol-2-yl)propan-l,3-diol; m.p. 123-125°C; Μβ Η Preparation 31 3-(l- ethyl-5-Nltroimidazol-2-yl)Prop-2-en-l-al A mixture of 0.155 g • » (0.001 mole) l-methyl-2- formyl-5-nitrolmldazole, 0.304 g. (0.001 mole) of formyl- methyltriphenylphosphorane in 6 ml. of benzene is heated under reflux for 18 hours. The solvent is removed under pressure to give a crystalline residue which is dissolved 8 in 75 ml. of ether. ' The solution is washed with 1 N aqueous hydrochloric acid. The hydrochloric acid fraction is made basic by the addition of excess potassium bicarbonate and the resulting aqueous solution extracted with ether.. The ether extract is dried and the solvent removed. The residue 3 is taken up in warm benzene and chromatographed on silica gel. Elution with ether followed by recrystallization ' from ethanol yields 3-( l-methyl~5-nitroimidazol-2-yl) -prop- 2-en-i-al; m.p. 147-149°C. 7 Preparation 32 8 3-( l-Methyl-5-Nltroimidazol-2-yl) Prop-2-en-l-ol 9 8.29 G«> (0.046 mole) 3-(l-methyl-5-nitroimidazoi-0 2-yl)prop-2-en-l-al is taken up in 2.2 liters of ethanol and 1 0.97 g., (.026 mole) of sodium borohydride in 20 ml. of water 2 is added and the mixture allowed to stand for 5 hours. The 3 reaction mixture is then made neutral to pH paper by the k addition o 7 ml. of glacial acetic acid, and concentrated 5 under reduced pressure to 35 nil. The. solids are separated 6 by filtration. The product is recrystallized from butanol 7 to yield 3-( l-methyl-5-nitroimidazol-2-yl)prop-2-en-l-ol ; 8 m.p. 132-134°C.

Preparation 33 3- ( l-Methyl->5-Nitroimidazol-2-yi) Propanol A mixture" of 200 mg. (0.001 mole) of 3-(l-methyl-5-nitroimidazol-2-yl)-prop-2-en-l-ol and 430 mg. (0.0022 mole) of potassium azodicarbox late in 15 ml. of methanol is stirred under nitrogen at 15°C. Glacial acetic acid (0.264 ml., 0.0044 mole) is added and the resulting solution is stirred overnight. ''The solvent is removed at reduced pressure. The residue is dissolved in 5 ml. of water and the solution is extracted continuously with chloroform for 1-2 hours. The extract is dried and concentrated leaving . a residue. The residue crystallizes on addition of water to yield 3-(I-methyl-5-nitroimidazol-2-yl)propanol; m.p. 170-175°C Preparation 34 l- ethyl-2-Chloromethyl-5-Nitrolmidazole 1.0 Gm. (0.0064 mole) of l-methyl-2-hydroxymethyl-5-nitroimidazoie is dissolved in 100 ml. of refluxing ben-zene. To this hot solution is added 20 ml. of thionyl chloride. The solution is warmed on a steam cone for 20 minutes and then evaporated to dryness in vacuo. The residue of l-methyl-2-chloromethyl-5-nltroimidazole hydrochloride thus obtained is flushed several times with benzene to re-move traces of thionyl chloride (The l-methyl-2-ch oro-methyl-5-nitroimidazole hydrochloride prepared in this manne is suitable for synthetic purposes without further purification). It is further purified as follows: It is dissolved in 25 ml. of water and the solution made slightly combined, backwashed with water and evaporated in vacuo to dryness to give . substantially pure l-methyl-2-chloromethyl-5-nitroimidazol .

The l-methyl-2-chioromethyl-5-nitroimidazole is characterized as the p-toluene sulfonic acid salt: To a % (W/W) solution of the imidazole in chloroform there is added a solution of excess p-toluene sulfonic acid in ether.

The l-methyl-2-chloromethyl-5-nitroimidazole. p-toluene sulfonic acid salt, precipitates and is recovered by filtra-tion and dried to substantially pure material; m.p . 153-155°C .

In accordance with the above procedure, but using thionyl bromide in place of thionyl chloride, there is obtained the corresponding l-methyl-2-bromomethyl-5-nitro-imidazole. ι Preparation 35 l-Methyl-2-p-Toluenesulfonyloxymethyl-5-Nltroimidazole To a solution of 1.57 g. (0.01 mole) of 1-methyl-2-hydroxymethyl-5-nitroimidazole in 10 ml. of dry pyridine, cooled to -20°C, is added 1.90 g. (0.01 mole) of p-toluene-sulfonyl chloride. The mixture is kept at -20°C. overnight.

After the addition of 20 ml. of ice-water, the solid product is removed by filtration.

In accordance with the above procedure, but start-ing with methane sulfonyl chloride in place of p-toluene sulfonyl chloride, there is obtained the corresponding 1-methyl-2-methanesulfonyloxymethyl-5-nitroimidazole .

Preparation 36 l- ethyl-2-Mercaptomethyl-5-Nitroimidazole combined, backwashed with water and evaporated in vacuo to dryness to give substantially pure l-methyl-2-chloromethyl-5-nitroimidazole . ! The l-methyl-2-chloromethyl-5-nitroimidazole is characterized as the p-toluene sulfonic acid salt: To a % (W/W) solution of the imidazole in chloroform there is added a solution of excess p-toluene sulfonic acid in ether. The l-methyl-2-chIoromethyl-5-nitroimidazole p-toluene sulfonic acid salt, precipitates and is recovered by flltra-tion and dried to substantially pure material; m.p . '·' 153-155°C .

In accordance with the above procedure, but using thionyi bromide in place of thionyl chloride, there is obtained the corresponding l-methyl-2-bromomethyl-5-nitro-imidazole.

Preparation 35 l-Methyl-2-p-Toluenesulfonyloxymethyl-5-Nltroimidazole To a solution of 1 . 57 g. ( 0 . 01 mole) of 1-methyl-2-hydroxymethyl-5-nitroimidazole in 10 ml. of dry pyridine, cooled to -20°C, is added 1 . 90 g. ( 0 . 01 mole) of p-toluene-sulfonyl chloride. The mixture is kept at -20° C. overnight. After the addition of 20 ml. of ice-water, the solid product is removed by filtration.

In accordance with the above procedure, but start-ing with methane sulfonyl chloride in place of p-toluene sulfonyl chloride, there is obtained the corresponding 1-methyl-,2-methanesulfonyloxymethyl-5-nitroimidazole .

Preparation 3 l-Meth l-2-Mercaptomethyl-5-Nitrolmidazole and the resulting mixture refluxed for 17 hour3. At the end of this time the mixture is- cooled to about 15°C. and the solid material -removed by filtration. , 1.26 g. of l-methyl-5-nitroimidazol-2-yl-methyl isothiouronium chloride is added to 20 ml. of water and -2 ml. of 2.5 N sodium hydroxide in a nitrogen atmosphere.

The mixture is heated at 55°C. for 15 minutes. At the end ■ of this time the mixture is cooled to room temperature and extracted with three 10 ml. portions of chloroform. The chloroform extracts are combined and concentrated to dryness to give l-methyl-2-mercaptomethyl-5-nitroimidazole suitable for use in making carbamates .

Preparation 37 l- ethyl-5-Nitroimidazol-2-ylmethyl Phenyl Carbonate -9 ml. dry pyridine and 4.87 g. (0.031 mole) of l-methyl-2-hydroxymethyl-5-nitroimidazole are added to a flask fitted with a stirrer, thermometer and addition funnel. The mixture is stirred at room temperature until the solid dissolves and then cooled to 0°C. 5.05 G. (0.0322 mole) of phenylchloroformate is added to the stirred solution over an 80 minute period, while maintaining the temperature at 5-10°C. with external cooling. On completion of the addition the reaction mixture is stirred at about 25°C. for 2-1/2 hours. It is then poured into -60 ml. of ice-water with good agitation.' The resulting slurry is stirred for 40 minutes and the^ resulting solid l-methyl-5-nitroimidazol-2-ylmethyl , phenyl carbonate collected by filtration. The solid is washed thoroughly with water and dried in vacuo at 50°C. - ° z - In accordance with the above procedure, but start-ing with l-methyl-2-mercaptomethyl-5-nltroimidazoleJ in place of l-methyl-2-hydroxymethyl-5-nitroimidazole, there is obtained the corresponding l-methyl-5-nitroimidazol-2-yl-methyl phenyl thiocarbonate .

In accordance with the above procedure, but start-ing with l-methyl-2-(l-hydroxyethyl)-5-nitroimidazole, l-methyl-2-(2-hydroxyethyl)-5-nitroimidazole and 3-(l-methyl-5-nitroimidazol-2-yl)prop-2-en-l-ol in place of l-methyl-2-hydroxymethyl-5-nitroimidazole, there is obtained the corresponding l-(l-methyl-5-nltroimidazol-2-yl)-ethyl-phenyl carbonate, 2-( I-methyl-5-nitroimidazol-2-yl)-ethyl-phenyl carbonate, and 3-(l-methyl-5-nitroimidazol-2-yl)-prop-2-en-l-yl phenyl carbonate.

I Preparation 38 l-Methyl-5-Nitrolmlaazol-2-ylmethylphenyl Thionocarbonate .17 G. phenoxythiocarbonyl chloride is added dropwise to a cold solution of M.71 g. of l-methyl-2-hydroxymethyl-5-nitroimidazole in 15 ml. of pyridine. Dur-ing addition the pyridine solution is cooled in an ice bath.

After about one-third of the carbonyl chloride is added, ml. of pyridine is added to the reaction mixture. On completion of the addition, the mixture is allowed to warm to room temoerature and stirred. for three and one-half hours. It is then. poured into about an equal volume of a ice-water mixture. A gummy precipitate forms. The water is decanted from this precipitate and the solid triturated with 70 ml. of methanol. Water (70 ml.) is added and the from benzene-hexane to give l-methyl-5-nitroimidazol-2-ylmethyl phenyl thionocarbonate; m.p. 92-98°C. On further recrystalllzation from benzene-hexane the product melts at 103-105.5°C.

In accordance with the above procedure, but start-ing with l-methyl-2-mercaptomethyl-5-nitroimidazole in place of l-methyl-2-hydroxymethyl-5-nitroimidazole, there is obtained the corresponding l-methyl-5-nitroimidazol-2-yl-methyl phenyl dithiocarbonate. -164- 25931/2 *

Claims

1. Compounds having the or alkyl substituted by or wherein the are phenyl or or substituted by phenyl or mono or or a saturated optionally alkyl substituted or 6 serabered heterocyclic amino may contain a further 0 or S Q is or V is ehlorophenyl or hydroge and hydrogen or ni provided that of the groups and is and has the substructure of formula I and compounds of formula where A oxygen or is or and are each substituted wherein the substituents are 165 carboalkox or lkyl phenylcarbamoyl or or or phenyleulfamoyl or or phenylthiocarbamoyl or phenylalkylthiooarbamoyl or or a 5 or 6 membered saturated heterocyclic phenyl optionally substituted by nitro or alkylidene substituted by or cyanoalkanoyl or optionally subetituted by phenylalkanoyl or thiocarbamoyl and or carbamoyl and wherein the substituents are phenylalkyl or heterocycloalkylcarbonyl wherein the heterooycle a saturated optionally 5 or 6 membered amino and or or substituted lower alk 2593 oryl and or and together with the nitrogen atom to which they are attached form an optionally saturated or heterocyclic ring which may contain a further or alkylimino and the terms and alkoxy hereinabove mean and each containing from 1 to 5 carbon and acid addition salts of such Compounds according to Claim 1 wherein is P is ie and T or Compounds according to Claim 1 having the wherein is loweralkylf Q is or A oxygen or sulfu and is sulfur or according to 1 wherein P is is and T is and have the MM meaning as in Claim Compounds according to Claim 1 wherein is A and are oxygen or and are each or e hydrox loweralkylidinylamino or provided that only one of tht groups and is or taken together are or Compounds according to Claim 1 wherein is P is substituted loweralkyl as defined in Claim and T is or Compounds according to Claim 1 having the wherein is substituted loweralkyl as defined in Claim Q is or A is oxygen or and is sulfur or Compounds according to Claim 1 wherein is P substituted as defined in Claim 1 and T is S and have the same meaning as in Claim according to Claim 1 having the formulat wherein is or and and are each hydrogen or hydroxy provided that only one of the group and Compounds according to Claim substantially as described herein with reference to the A process for the preparation of compounds according to Claim 1 having the formulat which comprises reacting a compound having the formulai a compound having the formulas N C III wherein and have the same meaning as in Claim and where is alkanoylox if with a base to obtain the compound wherein is A process for the preparation of compounds according to Claim having the which comprises reacting a compound having the formulas with A and have the same meaning as in Claim and where ia oxyalkyl or with a base to obtain the corresponding compound wherein is or A process for the preparation of compounds having the formula IV in Claim 26 which reacting a compound having the formula Claim 25 with a compound having the formulas and are hydrogen or both other than and where is alkanoyloxyalkyl or hydrolysing with a base to obtain the corresponding compound wherein is or A process for the preparation of compounds according to Claiffi 1 haying formulas wherein and Q have the same as in Claim which comprises reacting a compound having the formul wherein Q and are as X is alkyleulfonyloxy or with an alkali thlocyanate followed by an A process for the preparation of compounds according to Claim 1 having the formulas which comprises reacting a compound having the formul wherein and have the same meaning as in Claim 1 and X alkyleulfonyloxy or phenylsulfonylox with a B wherein and have the same meaning as in Claim A process for the preparation of a according to Claim 1 wherein has the same meaning as in Claim which comprises reacting a carbamate with a trihalo A process for the preparation of a carbamate according to Claim 1 wherein has the meaning as in Claim which comprises reacting a carbamate with A process for the preparation of a according to 1 wherein has the same meaning as in Claim which comprises reacting a hydroxymethyl carbamate with an alkanol the presence of an A process for the preparation of a kyl according to 1 wherein has the same meaning as in Claim comprises reacting a with a A process for the preparation of compounds according to Claim 1 having the wherein Z is the and phenyl derivatives thereof and Ac Is an aoyl group having the significance o and and and have the as in Claim which a compound having the wherein and the phenylalkyl and phenyl derivatives with a loweralkanoyl a benzoyl alkenoyl halide or a cyano acetic acid in the presence of a dehydrating A process for the preparation of a 2 4 and the N and phenyl derivatives according to Claim wherein is hydrox alkyl or and has the same meaning as Claim and is hydrogen or comprises reacting a wherein and are with a carbamoyl chloride or a phenylalkyl or phenyl substituted carbamoyl chloride and where is alkanoyloxy if desired hydrolyiing with a base to obtain the corresponding compound wherein is hydroxyalk A process for the preparation of a according to Claim 1 wherein is hydroxyalkyl or and has the with a alkali thiocyanate followed by an a or and where Is alkanoylox if with a to obtain the corresponding wherein is hydrox A proceee for the preparation of a according to Claim wherein has the same meaning as in Claim and la or phenyl which comprises reacting a carbamate with an in the presence of an alkanoic aldehyde and carbon A proceae for the preparation of a alkyl according to Claim 1 wherein the same meaning as in Claim and the secondary amino group a or cyclic group containing or provided that at least one of the members of the ring is nitrogen and two are which comprises reacting a ylalkyl carbamate with formaldehyde the presence of a secondary amine including cyclic secondary amines comprising or membered cyclic group containing oxygen or provided that at least one of the of the ring is nitrogen and two are A process for the preparation of a according to Claim wherein has the same meaning as Claim 1 and Rg is alkyl or which reacting a ylalkyl carbamate with a in the presence of boron A process for the preparation of a according to Claim wherein the earae i g as in and is or which comprises reacting a vith an amine wherein and are as A procees for the preparation of an ni halide according to Claim wherein has the same meaning ae in Claim which comprises reacting a ylalkyl carbamate with h in the presence of A thionyl A for the preparation of a according to Claim wherein has the same meaning as in Claim which comprises reacting an halide with a weak aqueous A process for the preparation of a according to Claim wherein has the same meaning as in Claim which comprises reacting a lalkyl carbamate with nitric A procees for the preparation of a N or carbamate to Claim wherein the meaning as Claim which comprises reacting a ylalkyl with an aliphatic aldehyde or aromatic A procees for the preparation of a carbamate according to Claim wherein hae in Claim which comprises reacting a carbamate with an 46 A for the preparation of a according to Claim wherein the as in 1 and amino or phenylalkyl or phenyl substituted amino comprises reacting a with aaffionia or an phenylalkyl or substituted A for the preparation of to 1 wherein has the meaning as in 1 is amino or phenylalkyl or phenyl substituted which comprisee reacting a carbamate with ammonia or an or phenyl substituted A process for the preparation of compounds according to having the which comprises sequentially a yrrole a reducing a phenylhaloformate and an amine the wherein and have the same weaning as in Claim A process for the preparation of compounds according to Claim 1 having the formulaι Q and A have the same in Claim which comprises reacting a compound having the formula II in 25 with one mole of cyanic acid per mole of A process for the preparation of compounds according to Claim 1 having the formulas wherein A and have the meaning as Claim which comprises reacting a compound having the formula II in Claim 25 with at least two moles of cyanic acid per mole of Processes for the preparation of compounds according to Claim substa as described herein with reference to the Compositions useful against trichomoniasis comprising as an active ingredient a compound of Claim 1 distributed in a pharmaceutical A composition according to Claim wherein the active ingredient is Compositions useful enterohepatitis in poultry which comprises an element of poultry sustenance having distributed a minor amount of a compound according to Claim A composition according to Claim 54 wherein the active ingredient is A composition to Claim 54 or 55 wherein the species of poultry is Compositions according to any of Claims 53 and or 54 to substantially as described PCted insufficientOCRQuality