CS244146B2 - Method of beta-lactam antibiotic production - Google Patents

Abstract

.beta.-Lactams having a sulfonic acid substituent in the 1-position and an amine function in the 3-position and having the formula: (see fig. I) wherein R1 is H or acyl derived from a carboxylic acid; R2 is H or alkoxy; R3 and R4, the same or different, are H, alkyl, cycloalkyl, phenyl or substituted phenyl, or one of R3 and R4 is H and the other is alkoxycarbonyl, alken-1-yl, alkyn-1-yl, 2-phenylethenyl or 2-phenylethynyl; and X is H or SO3X is SO3-M+ wherein M+ is a cation, and the use of said .beta.-lactams as antibiotics.

Description

The present invention relates to a new class of beta-lactam antibiotics, to a process for their production as an antibacterial agent. It has been found that the beta-lactam nucleus can be biologically activated by a substituent consisting of a sulfonic acid salt moiety attached to the nitrogen atom of the nucleus.

The beta-alkyls bearing the 1-position substituent of the sulfonic acid salt moiety (including internal salts) and the 3-position acylamine substituent show activity against gram-negative and gram-positive bacteria.

The present invention provides a process for the preparation of compounds of the general formula I

Rj-KH-CH · ---- C-Rj (I) in which

Znamená, represents a hydrogen atom or an ethyl group as defined below,

R 8, which may be the same or different, each represent hydrogen, a C 1 -C 10 alkyl group, a C 3 -C 7 cycloalkyl group or a phenyl group optionally substituted by one, two or three substituents selected from the group consisting of amino, halogens, hydrooylacetin, trifluoroethyl, alkyl groups and 1 to 4 carbon ethoxy groups of 1 to 4 carbon atoms, or one of R e R 6 is hydrogen and the other is an alkoxycarboinyl group with 1 to 10 carbon ethers in the alkoxy moiety, 1-alkenyl of up to 10 carbon atoms, 1-alkynyl of up to 10 carbon atoms, 2-phenylethyl or 2-phenylethyl and

M &^lt; ⁺ &^gt; sulfonic acid residue.

These meanings include, but are not limited to, the following general symbols throughout.

Thus, in addition to the above-mentioned beta-lakaams containing a sulfonic acid salt substituent at the 1-position and a 3-methyl-amino acid substituent at position 3, the invention also encompasses betamectamides containing a sulfonic acid salt (including the internal salts) at position 1 and an amine αinový at position 3. ^ '.

Preferred compounds of this type odpooídaaí formula Ia ^"4" TF-R (Ie)

N-SOjM *

These compounds are intermediates used in the preparation of the corresponding 3-acyl amino acids.

The term scyl, as defined by R, includes all organic moieties derived from an organic acid (i.e., carboagrelic acid) by cleavage of the tyrolol group. Certain acyl groups are _also -iochuoitelně preferred scope of the invention but in no way limited to these preferred groups. As examples of acyl groups, the acyl groups that tulle have hitherto been used to acylate beta-lacaam antibiotics, including 6-amino-enalenic acid and its derivatives and 7-amino-oleospoic acid and its derivatives - see, for example, CeplMiaosporins and Peenccilins [ed. Flynn, Academic Prese (1994)], DOS No. 2,716,677, published October 10, 1978, Belgian Patent No. 867,994, issued December 11, 19718, U.S. Patent No. 4,152,432, Issued May 1, 1979, U.S. Pat. U.S. Patent No. 3,971,778, issued July 27, 1976, U.S. Patent No. 4,172,199, issued October 23, 1979, and British Patent Publication, March 27, 1974. In these sections, describing various acyl groups, references herein.

Suitable acyl groups R @ 1 are:

(a) Clic groups of the formula

Ukde

R 1 represents an alkyl group, a cycloalkyl group, an alkoxy group, an alkenyl group, a cycloelkenyl group, a cyclohexadienyl group or an alkyl or alkenyl group having one or more substituents selected from halogen ethers, cyano nitro groups, amino groups and amino groups; ;

(b) ааrЫ) cyclic aroma groups corresponding to the formulas

24414b in which

or

has a value of 0, 1, 2 or 3; »8 each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 atoms and is an amino, hydroxyl, carboxyl salt, protected carboxyl, formyloxy, sulfo salt, sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino thio or [(alkylthio) thio] .

Preferred kerbocyclic aromatic acyl groups include radicals corresponding to the formulas

НО

O ₂ CH ₂ -CCH ₂ -CH ₂ nh ₂

-C-

wherein R 8 is preferably a carboxyl group in the form of a salt or a sulfo group in the form of a salt, and _O

CH-11

Λ wherein Bg is preferably a carboxyl group in the form of a salt or a sulfo group in the form of a salt:

R ₁₀ - (CH ₂ 11 _n -C (s) heteroaromatic groups of formula)

Even in which

AND

R ₁₀ -O-CH ₂ -CΪ

R θ — S — CHg — C—

Ϊ5

R _a -C-C or a «9 й has the value 0,1,2 or 3» on the abovementioned meaning and represents an optionally substituted five-, six- or seven-membered heterocyclic ring containing 1,2,3 or 4 (preferably 1, and or 2) nitrogen, oxygen and / or sulfur atoms ·

Examples of heterocyclic rings include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, morpholinyl, pyrimidinyl and tetresolyl rings. Examples of substituents include halogen atoms, hydroxyl, nitro, amino, cyano, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.

Preferred heteroaromatic acyl groups include those groups of the above formulas in which R @ _o is 2-amino-4-thiazolyl radical, the 2-amino-5-halo-4-thiazolyl radical, a 4-aminopyrimidine-2-yl, 5-amino A 1,2,4-thiadiazol-5-yl, 2-thienyl or 2-furanyl residue;

(d) [(4-Substituted-2,3-dioxo-1-piperazines1/carbonyl)amino]arylacetyl groups of the general formula wherein:

means an aromatic group, including aromatic kerbocyclic radicals, such as those of the formula

and the heteroaromatic radicals mentioned in the definition of the meaning of the symbol Rq,. K12 represents an alkyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, cyano, nitro, amino, mercapto, aralkyl, -N = CH-R1, where R | is as defined above, an arylcarbonylamino group, i.e., a group of formula 'O', wherein - R 1, i

-NH-C-R 1 is as defined above, or an alkylcarbonylamino group.

Among the above withdrawn ^{h [(E} /ě-uutat.-S,3-dioo--l-pi erzzinyl / carboxylic ^{o y} l) ^aminojar, y ^l ace ^t yl group taležejí those in which R₆ is an ethyl group, feoylmetylelamioosktpinu or 2-furylmethyloamino;

(e) (C sttttimimimimimim a) arylacetyl groups of the general formula

wherein - is as defined above and represents a hydrogen atom, an alkyl group, a cyclostyl group, an alkyleminocarbinyl group, an aryl group or a vinyl group (i.e. a group of the formula -g-NH-R wherein R 1 is as defined above) or a substituted alkyl group which it contains one or more Sttatitteot selected. from the group consisting of halogen atoms, cyano, C 1 -C 00, C 10 -C 10 amino, mercapto, alkyl C 1-4 aromatic (as defined in the meaning of R p> carboxyl (including its soH), emido, alkooycarboxoyl, phioylmetooykerSioyl, diphenylmethylmethyoylSioyl, hydroisoylphosphoryl, dihydrioylphisphioyl, hydrofunctional and dialkiophosphioyl.

Preferred (sthioimio) arylacetyl groups are those wherein R ₁ is 2-amino-13-thiazilyl. Also preferred are those in which R 1 represents a methyl group, a stylish group, a caroylmethyl group or a 2-cardoyisopropyl group;

(f) (acylamino-aryl-acetyl groups of the general formula I)

O-O-CH-NH4-O; ⁴ in which

is as defined above and represents the remainder of the formula

R

. alkylamino, (cyanalkyl) amino, amido, alkylamido, (cyanalkyl) amido, radical of the formula

CH ₂ - NH

nh ₉ I ² -CH-CR o

_Í_NH_CH ₃ ,

SO ₂ -H (CH ₂ -CH 3 -OH) 2, v = n \ = /

OH

or

OH

More preferred (ecylaminedairecetyl groups of the above formula) include those in which R ₄ is amino or emido purchased. Also preferred are those in which the phenyl or 2-thienyl radical is;

(g) [(3-Substituted-22-oxo-1-methoxysolldiyyl/carbolyl) carbonyl </RTI> group] of the formula (c)

1-CH-NH-N-N-H-R.

I I I

R _n QR-CH ₂ wherein ^{R 11} is as defined above and represents a hydrogen atom, an alkylsulfolyl group, an arylmethylexaamino group (ie, -NaCH-Rf, wherein Rf- is as defined above, -C- ^Rfg)

- O (wherein R 8 represents a hydrogen atom, an alkyl group or a halogen-substituted alkyl group), an aromatic group (as defined above for R f), an alkyl group or an alkyl group substituted with one or more substituents selected from the group consisting of halogen atoms, cyano, nitro, atm, or mercapto.

Preferred C ([beta] -benzyl-2-oxo-1-inidezidlidyl (carbonyl) amino) eryl acetyl groups of the above formula include those in which R1 is phenyl or 2-thienyl. Also preferred are those in which R 1 represents a hydrogen atom, a methylsulfonyl group, a phenylmethylmethylamino group or a 2-fuzyrlmethylnamino group;

Unless expressly stated otherwise, the terms "alkyl" and "alkoxy" as used herein are intended to denote both straight and branched chain groups. Preferred are those groups having 1 to 10 carbon atoms.

The terms cycloalkyl and cycloelkenyl mean cycloalkyl and cycloalkenyl groups having from 3, 4, 5, 6 or 7 carbon atoms.

The term "alkenyl" refers to both straight-chain and branched-chain groups. Preferred are those groups containing 2 to 10 carbon atoms.

The term halogen refers to! fluorine, chlorine, bromine and iodine.

As used herein, the term cations * means a free, positively charged atom or group of atoms.

^ ^ T ^ bb IIT aspen atom oe '^ te-varnish-Mu ^P ccording tynálezu ztytky soUÍ includes all sulfonic acids. Preferred are pharmaceutically acceptable salts, although other salts are useful for the purification of the products of the present invention or as intermediates for the preparation of pharmaceutically useful salts. The free moiety includes, but is not limited to, the following ions:

ammonium ion, substituted ammonium ions, such as alkylammonium ions (e.g., tetra-n-butyeammonium ion, hereinafter referred to as tetrabutylammonium ion), alkali metal ions such as lithium, sodium and potassium, alkaline earth metal ions such as calcium and magnesium, pyridinium ion, dicyclohexylammonium ion, tydrabammonium ion, benzzinium ion, and N-meet-1-D-glycol ammonium ion.

As mentioned above, M ⁺ may be hydrogen

As will be described below, the beta-lactams of the invention may be prepared synthetically. Non-spicy, unsubstituted betl-lacquers of formula (I) at position 4, i.e., those compounds of formula (I) in which R8 and R6 are not hydrogen, can be prepared using 6% of an acid or 6% of an acid; -acylliinupenoic acids as starting materials. The β-lactams of formula (I) in which R 8 represents an TTKys ^^ l l can be prepared from the corresponding non-alkoxylated β-alkams. Certain of the compounds of the present invention may be crystallized or recrystallized from water-containing solvents. In these cases, hydrates may be formed. The invention encompasses both stearate tyrates and compounds containing various water options that may be formed by processes such as lyophilization.

The bi-lalamines containing at position 1 a substituent consisting of a sulfonic acid salt moiety and an amino or acylimine autsaituant at position 3 containing at least one center of the carbon atom (at the 3-position of the beta-alkaloid nucleus) to which the amine or acylamine albusaituant. The invention relates to those described above in which steraochemistry at the center of the chute at the 3-position of the bβta-at stove core is the same as the corornigation at and the carbon atom at the 6-position of natural pexocillins (e.g. penocilli G). cefamfcin C).

With respect to the preferred beta-lakes of the formulas I and Ia, their structural formulas were drawn to show stereo. at the center of the ch-reHty at position 3. Due to ^ τ ^^ θΙώ ^ convention m)! those compounds of the formulas i and Ia in which Rg represents a hydrogen atom, the S configuration and those compounds of the formulas i and le in which Rg represents an alkoxy group, Kunigurici R.

Also within the scope of the present invention is recemic amines containing the above-described beta-lactobatalacts (1 at position 1) of the sulfonic acid salt of tartaric acid and acyl or acyl. The aubsaituent at the 3 * bc, 1-lakaam core position has shown a potent activity to a wide variety of glycolytic organisms and gram organisms. in which R1 or R1 is hydrogen or an alkyl group, especially a methyl group.

The compounds of the present invention can be used to drink baaterial infections (including urinary tract infections and respiratory tract infections) in a variety of mammalian species, such as dornmai animals (e.g., dogs, cats, cows, marten, etc.) and humans.

To combat bacterial infections in mammals, the compound of the invention may be administered to a mammal in need of such treatment at a level of from about 1.4 mg / kg / day to about 350 mgk / day, preferably from about 14 m / kg / day to about 100 m / day. All routes of administration that have hitherto been used to bring peidcilins and cefelosporins to the point of infection can also be used for the new class of beta-lectems of the invention. These delivery methods will render oral administration, intramuscular administration, intremissmarinic administration and suppository administration.

The bromothecaem derivatives of formula (I) are generally prepared by introducing the sulfonic acid residue (sulfo group -SOy-) to the nitrogen atom at the 1-position of the beta-1-BkaMo-O nucleus or its open-chain precursor followed by cycles to form bet1. -l8 key core · This latter procedure. is an object of the invention. This sulphonation reaction is readily accomplished by reacting beta-α-icaica or the aforementioned procurate with a sulfur trioxide complex or an equivalent sulphonating agent such as chlorosulphorate.

Sulfur trioxide-containing complexes used are the complexes of pyddine-sulfur trioxide, lutidine-sulfur trioxide, dimethylfoxaeemide-sulfur trioxide and picoline-sulfur trioxide. Instead of using the previously prepared complex, the complex can be prepared in situ, for example using chlorine-3-methylsilyl silicon and pyridine as reagents. Alternatively, the sulfonation may be accomplished via a suitable intermediate, such as by first silylating the nitrogen atom of the beta-11-nucleus core and then silylating the silylated compound by reaction with triethylsilyl Cchossulfonyl or a similar reagent. Examples of suitable silylating agents include the moonsils 1, 4, 4, 4, 4, 4, 4-tamidide, trimetylsyl chloride-triethylamine, and bis (triethylsilyl) triloyloneolide.

In general, the sulfonation reaction is carried out in the presence of an organic solvent, such as pyridine, or a network of organic solvents, preferably a mixture of a polar solvent, such as dimethylformamide, and a halogenated hydrocarbon, such as dichloxmethane.

The product which is primarily formed in the sulfonation reaction is the salt of a .alpha.-olefinic bett-1θkteíj · When the sulfonation complex is killed with pyridine and sulfur trioxide, the primary product is the pyridinium salt of sulfonated beta-aaltam of the formula below.

These comlexes can be converted to other sulfonic acid salts by conventional techniques, for example, by ionomidindes, crisellization or ion pair extraction. Conversion of the pyridinium salt to the potassium salt with potassium phosphate or potassium hexanodate, not with tetrabutonium thiobonium boronium methanesulfonate or potassium phosphate to the zwitterion (M * hydrogen) using formic acid.

It will be appreciated that the sulfonation reaction to introduce the sulfo group and the nitrogen atom of the beta-alkali nucleus can, as mentioned above, be carried out at various stages of the synthesis, including the introduction prior to the formation of the beta-lekaam nucleus, this process. is carried out as described below. The sulfonation reaction is carried out in the presence of the solvents described above, usually at room temperature. In the case of the presence of the amine function, it is advantageous to work to protect the amine function. ’

The beta-18-ring may be formed by a purification reaction, wherein the sulfonyl reaction may be carried out either before or after the cyclization. The first of the present invention is illustrated by the following reaction scheme:

244Г46

-cyclization

всу1-НН

M-SOi (III)

The acyl group in this reaction may also be an easily cleavable group which acts as a protecting group and which, upon cleavage, yields an amine-containing product.

The basic starting material for the preparation of the compounds of formula I is an amino acid amide corresponding to formula IV

(IV)

A protected amino group by a classical protecting group, for example a benzyloxycarbonyl group (hereinafter referred to as Z) or a tert-butoxycarbonyl group, and by converting a hydroxyl group to a leaving group V such as an alkyl, phenyl or substienylphenylsulfonyl group (hereinafter referred to as Me) to give a compound of formula V

(V) in which it represents a protecting group, including an aso group ·

Sulfonation of the compound of formula V yields the compound of formula VI

AHH-CH

(VI)

0 '

Compound (VI) is cyclized by treatment with a base such as potassium carbonate. The reaction is preferably carried out under reflux of water and an organic solvent (such as a halogenated hydrocarbon such as 1,2-dichloroethane) to form a compound of formula VXI ^K 4

(VII)

Deprotection of the sulfonated azetidinone of formula VIX in which A is a protecting group by catalytic hydrogenation affords a compound of formula VIII

HgN

N-SO ₃ M * (VIII) which can be converted by the action of an acid such as formic acid into a zwitterionic ion of the formula IX

(IX) .beta.-SO3 The invention is illustrated by the following non-limiting examples.

Example 1 (S) -3-Amino-2-oxo-1-azetidine sulfonic acid

A) L-tert-Butoxycarbonyls erinemide mesylate

A partial suspension of 16.2 g of L-tert-butoxycarbonylserinamide in 250 ml of ethylene chloride was cooled to -10 ° C and 10.4 ml of triethylamine was added thereto. 4.25 ml of ethanesulfonyl chloride was added dropwise over 15 minutes and after heating to 0 ° C another 0.425 ml of methanesulfonyl chloride was added dropwise. The reaction mixture was stirred at 0 ° C for 0.5 h and then poured into 1 L of ethyl acetate and 250 mL of cold sodium chloride solution was added. The organic layer is washed twice with 200 ml of 1N hydrochloric acid each, saturated with sodium chloride, dried in magnesium sulphate and concentrated to a volume of 100 ml. The resulting suspension was diluted with 300 mL of diethyl ether and filtered to give 10.73 g of the desired product. Concentration of the mother liquors and recrystallization of the residue gave longer 1.67 g of product, m.p. 105 DEG-107 DEG C. and optical rotation. [α] 6.4 ° (c = 2, methanol).

8) L-Tetra-n-butylsmonium-tert-butoxycyclonylserine sulfamate mesylate

Following the procedure of Example 2B below, the title compound was obtained using L-tert-butoxycarbonylserinamide mesylate instead of L-tert-butoxycarbonylltreonine bromide mesylate.

C) (S) -3 - [(tert-Butoxycarbonyl) amino] -2-oxo-1-azetidine sulfonic acid tetra-n-butylammonium salt

The title compound was obtained as in Example 20 below using L-tetra-n-butylammonium t-butoxycarbonylserine sulfamate mesylate instead of L-tetra-n-butylammonium t-butoxycarbonyl threonine sulfamate mesylate.

D) (S) -3-Amino-2-oxo-1-azetidine sulfonic acid

3.06 Tetra-n-butylammonium salts of (S) -3 - [(tert-butoxycarbonyl) amino] -2-oxo-1-azetidine sulfonic acid are dissolved in 18 ml of 97% formic acid, the solution is stirred for 4 hours and the mixture is stirred Dilute with ethylene chloride. The mixture is filtered and after washing the residue on the filter is dried. 0.52 g of the title compound melted with decomposition at 208-210 ° C. Wp ^{1 with} -39.9 ° (c = 2, water).

Example 2 (3S-trans) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid

A) L-tert-butoxycarbonyl threoninamide mesylate

The title compound was prepared according to the procedure described in Example 1A) except that L-tert-butoxycarbonyl-threoninamide was used instead of L-tert-butoxycarbonylserinamide. The product melted at 129-131 ° C and having an optical rotation [ «* Jp ¹ = 18.9 ° (c = 10, methanol).

B) L-Tetra-n-butylammonium tert-butoxycarbonyltreonine sulfamate mesylate

A solution of 2.8-methylpyridine (17.8 mL) in methylene chloride (90 mL) was cooled to -50 ° C at a rate such that the temperature inside the reaction mixture did not exceed 5 ° C, 5.97 mL of chlorosulfonic acid was added dropwise. The resulting solution was stirred for 15 minutes, then a solution was added

8.9 g of L-tert-butoxycarbonyltreoninamide mesylate in 30 ml of methylene chloride. The resulting solution was stirred at reflux for 16-20 hours, then poured into 500 mL of a 0.5 M potassium dihydrogen phosphate solution and diluted with 120 mL of methylene chloride. The organic layer was separated and washed with an additional 100 mL of potassium dihydrogen phosphate solution. The aqueous phases are combined, 10.2 g of tetra-n-butylammonium hydrogen sulphate are added and the mixture is extracted once with 300 ml and twice with 150 ml of methylene chloride. The organic extracts were dried over sodium sulfate and concentrated. 17.2 g of the foamed title compound are obtained.

C) (3S-Trans) -3 - [(tert-butoxycarbonyl) amino] -4-methyl-2-oxo-1-azetidine sulfonic acid tetra-n-butylammonium salt

13.0 g of potassium bicarbonate are dissolved in 320 ml of water, 220 ml of 1,2-dichloroethane are added, and the mixture is heated to reflux. A solution of 20.0 g of L-tetra-n-butylammonium tert-butoxycarbonyltreonine sulfamate mesylate in 100 ml of 1,2-dichloroethane is added, the mixture is stirred vigorously at reflux for 15 minutes, then added to a separatory funnel. the lower organic layer was separated. The aqueous layer is extracted with an additional 200 ml of methylene chloride, the organic phases are combined and, after drying over sodium sulfate, concentrated. 18 g of the crude title compound, mp 144 DEG-146 DEG C. and an optical rotation [a] ² ' »-14.6 ° (c" 2, methanol).

244146 12

(R) (3S-trans) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid

6.3 g of (3S-trenes) -3 - ((tert-butoxycarbonyl) amino] -4-methyl-2-oxo-1-azetidine sulfonic acid tetra-n-butylammonium salt are dissolved in 30 ml of 97% formic acid and the solution The resulting suspension was diluted with 30 mL of methylene chloride and filtered, and the solid was dried after washing with methylene chloride for a long time to give 1.53 g of analytically pure product with optical rotation. ⁹ -41.0 ° (c = 1, water).

Example .3 (3S-Trans) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid

A) Threonine methyl ester hydrochloride

A flask containing 500 ml of methanol was cooled in an ice-salt bath at -5 ° C under nitrogen and charged with 130 ml (excess) of thionyl chloride at such a rate that the temperature of the mixture was maintained between 0 and 10 ° C. After re-cooling to -5 ° C, 59.5 g of 1-threonine is added, the mixture is allowed to warm to room temperature and stirred at this temperature for 16 hours. The reaction mixture was concentrated and evacuated at 13 Pa for 2 hours to give a viscous oil which was used directly in the next step.

B) Threoninamide

The crude product from Part A was dissolved in 2.5 liters of methanol, cooled to -5 ° C in an ice / sodium chloride cooling bath, saturated with ammonia gas, the cooling bath was removed and the sealed reaction vessel was allowed to stand for 3 days. . After removing most of the unreacted ammonia with the aid of an aspirator, 100 g of sodium bicarbonate and 50 ml of water are added, and the mixture is evaporated to a viscous oily residue.

C) Benzyloxycarbonylthreoninamide

The crude product from paragraph V (already containing the necessary amount of sodium bicarbonate) was diluted to 1 liter with water and a solution of 94 g (88 ml of 90% pure material) of benzyloxycarbonyl chloride in 80 ml of tetrahydrofuran was added over 1 hour with vigorous stirring. The reaction mixture was stirred for a further 16 hours and then extracted once with 500 mL and twice with 250 mL of ethyl acetate. The combined extracts were dried (MgSO4) and concentrated. The crystalline residue is dissolved in 250 ml of hot ethyl acetate, 300 ml of hexane are added and the mixture is boiled until a clear solution is obtained. After cooling and filtering the crystalline material, 104 mg of the title compound is obtained after drying.

D) Benzyloxycarbonyltreoninamide O-mesylate

100 g of benzyloxycarbonyltreoninamide are dissolved in 400 ml of anhydrous pyridine under argon, cooled in an ice-salt cooling bath, and 36.8 ml (54.5 g) of methanesulfonyl chloride are added with stirring over 15 minutes. After stirring for 2 hours, an additional 0.3 equivalents of methanesulfonyl chloride was added, the reaction mixture. The mixture was poured into a mixture of 1.5 liters of ice and 2 liters of water. The resulting suspension is stirred for about 30 minutes, then filtered and the solid product is dried in a vacuum oven at 60 ° C for about 16 hours. 109 g of the title compound are obtained.

E) N-Sulfonylbenzyloxycarbonyltreoninamide O-mesylate tetrabutylammonium salt

A solution of 17.8 mL of 2-picoline in 90 mL of methylene chloride was cooled to -5 ° C in an ice / salt cooling bath and 5.97 mL of chlorosulfonic acid was added thereto at a rate to maintain the temperature below the reaction mixture. Low: 14 ° C.

The resulting solution was added to a suspension of 7.56 g of benzyloxycarbonyl-threoninamide O-mesylate in 120 ml of methylsulfide via a tube. The resulting heterogeneous mixture was heated at reflux for about 16 hours while passing a clear solution. This solution is taken up in 500 ml of phosphate buffer pH 4.5 (0.5 M) and further diluted with 120 ml of maeyl chloride. The separated orgenic layer is washed once with 100 ml of buffer solution, 10.2 g of tetrotriyldylsulphonic acid are added to the aqueous phases, and the mixture is extracted once with 300 ml with twice 150 ml of methylsulfide. After drying the combined organic extracts with sodium sulfate, the organic solution was concentrated to give 12.7 g of a pan product.

(F) (3S-taars) -3-ω-thio-4 · · methyl-2-oxo-1-azetidinesulfinic acid

A mixture of 5.52 g of potassium carbonate in 20 ml of water and 160 ml of 1,2-dichloroethene is heated to reflux and treated with 15.5 ml of tetrabutylammonium salt of O-mesylate O-mesylate. Ethanol (20 mL of 1,2-dichloroethane was flushed to wash the above solution). After three refluxing, the mixture is introduced into a separatory funnel, diluted with 50 ml of water and 100 ml of methylene chloride, and the phases are separated. The organic phase was dried over sodium sulfate and concentrated to give the crude (3S-trichloro) -3-benzylo-phenyl-lainil-4-aeyl-2-axyl-1-azetidine-8-salic acid. 0.8 g of 5% palladium / carbon catalyst is added to the isodium dioio derivative (250 ml) in the catalyst and hydrogen gas is added to the mixture. After 90 minutes, the mixture was filtered through 50 mL of stem to rinse the reaction vessel. After addition of 1.2 ml of formic acid to this solution, the zwitterionic title ion is clearly present. After one-time stirring, the mixture is separated off slightly after drying for one hour in a vacuum of 13 Pi to give 1.1 g of the desired product.

A second sub-product is obtained by concentrating the filtrate by adding further formic acid. ^Z £ ^ka with ^{1.3 g of} ion obojstmáho title ^ zi melting detuning nid ² 18 ° C.

_ = ⁴¹ 1 ° (c. · ^1, water).

NMR (CDCl 3): δ 1.58 (d, 3H, J = 7 Hz), 4.80 (m, 2H).

EXAMPLE 4 4 (3S-trlit) - 3-Alyio-4-pyridyl-2-oxo-1-azetidin-10-yl acid

A) Phenylacetyl tsoonin · aid-azylate

16.9 g of L-ss feilllcetylteoiniiaaidU by heating to reflux for 5 dissolved in ⁰⁰ ml tetral ^ld ro ^f srlis ^- ss solution was cooled to -35 ° C ni and ^p RID ^and SS ^ к it therefrom at ^{15.0 -} ml trielyl8aiis i peak in 1 hour 7.1 ml - aeealnsSphonilchlog. The reaction mixture was stirred for 1 hour then diluted with 400 ml of water and the organic layers were separated. The aqueous layer was extracted three times with 300 ml of ethyl acetate each time, the combined organic phases were washed with 0.1N hydrochloric acid in brine, dried over magnesium sulfate. After filtration, the filtrate is concentrated to about 200 ml volume to dry the product. The suspension is diluted with an equal volume of hexane and filtered. There was obtained 19.2 g product of product, mp ¹ 3 ^{3 2-13} ° C and optical rotation ^{+ 1} = 19.25 ° ^{- (c "2,} meta).

(B) L-tetгvi-suyllaaliiua-fe] n-ethyltreo-III-tulaaate

The title compound is obtained according to the procedure of Example 2B) except that L-phthalcetyltelonineaid-mmes is used instead of L-tert-butyl-tert-butyl-aesylate.

C) Tetríbuty aaliilv ^{R and} S salts □ gastrin) · ^ - ^{[(FEI IL} · l ^c e l ^tl) e ^{e βaiio0-4-yl-2-oxO11} azeeidiisuSfonové acid.

The title compound ae was prepared by repeating the procedure described in Example 2C, substituting L-tetra-n-butylammonium phenylecetyltreonine sulphate mesylate instead of L-tetre-n-butylammonium tert-butoxycarbonyltreonine sulfemate mesylate.

D) (3S-trans) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid

3.79 g of (3S-trsns) -3 - [(phenylethyl) emino] -4-methyl-2-oxo-1-azetidine sulfonic acid tetra-n-butylanonium salt are dissolved in 70 ml of methylene chloride, cooled to -15. ° C and 2.3 ml of pyridine are added thereto. 5.8 ml of 12% phosgene in benzene are added to the cold mixture and the resulting mixture is stirred at -10 ° C for 90 minutes. After addition of 35 ml of methanol, the mixture was stirred for 30 minutes, 1.62 ml of trifluoroacetic acid was added, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The precipitated material is filtered off after washing with methylene chloride and dried. 0.43 g of the title compound is obtained, having an optical rotation of [α] D -41.0 ° («1, water).

Example 5 (2S-cis) -3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid

A) L-tert-butoxycarbonyl-allotreoninamide mesylate

The procedure described in Example IA) was repeated except that L-tert-butoxycarbonyl-allotreoninamide was used instead of L-tert-butoxycarbonylserinamide. The title compound melted at 124 ° C with an optical rotation of [α] D = + 16.9 ° (c = 2, methanol).

B) L-Tetra-n-butylammonium tert-butoxycarbonyl-allotreonine sulfamate mesylate

The title compound was obtained according to the procedure of Example 2B) except that L-tert-butoxycarbonyl-threoninemide mesylate was replaced with L-tert-butoxycarbonyl-allotropionone mesylate.

C) Tetra-n-butylammonium di (3S-cis) -3 - [(tert-butoxycarbonyl) emino] -4-ethyl-2-oxo-1-azetidine sulfonic acid

The title compound is obtained according to the procedure of Example 2G) except that L-Tetra-n-butylammonium tert-butoxycarbonyl-ellotreonine sulfamate mesylate is used instead of L-tetra-n-butylammonium tert-butoxycarbonyltreonine sulphate mesylate.

D) (3S-C 18) -3-Amino-4-methyl-2-oxo-1-azetidine sulfonic acid

The procedure described in Example 2D) was repeated using tetrabutylammonium salt (3S) instead of (3S-trans) -3 - [(tert-butoxycarbonyl) amino] -4-methyl-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt. -cis) -3 - [(tert-butoxycarbonyl) amino] -4-methyl-2-oxo-1-azetidine sulfonic acid. Give the title compound, melting at 200 DEG C., [.alpha AJP ¹ «* -61.8 ° (c» 5.1, water)

Example 6 (3S-trans) -3-Amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid

A) .alpha .- (tert-Butoxycarbonylamino) -beta-cyclohexyl-beta-hydroxy-threopropionic acid g .beta.-cyclohexyl-.alpha.-amino-.beta.-hydroxy-threopropionic acid is suspended in 150 ml of acetonitrile and 70 ml of water. After addition of 17.8 g of triethylamine, the mixture was heated to 60 ° C with stirring. A clear solution is formed at this temperature, to which 21.0 g of di-tert-butyl-pyrocarbonate is added and stirring is continued at 60 DEG C. for a further 1.5 hours.

The solvent is removed in vacuo and 50 ml of water are added to the residue. The aqueous layer was adjusted to pH 2 with 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The crystalline residue is stirred with petroleum ether and filtered off. 20.4 g of the title compound of melting point 113 DEG-115 DEG C. are obtained.

B) Alpha- (t-butoxycarbonylamino) -beta-cyclohexyl-beta-hydroxy-threopropionamide

20.2 g of alpha (tert-butoxycarbonylamino) -beta-cyclohexyl-beta-hydroxy-threopropionic acid are suspended in 350 ml of water and 175 ml of tert-butanol. The pH of the mixture was adjusted to 4 with potassium carbonate, 16.4 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide was added, and the mixture was stirred for 1.5 hours while maintaining the pH at 4. The tert-butanol was evaporated in vacuo. The aqueous solution was saturated with sodium chloride and extracted with ethyl acetate (2.times.100 ml). The organic layers were combined, dried over sodium sulfate and evaporated to dryness to give the title compound.

C) Alpha- (tert-butoxycarbonylamino) -bet8-cyclohexyl-betB- (methanesulfonyloxy) -treopropionamide

18.3 g of alpha- (tert-butoxycarbonylamino) -beta-cyclohexyl-beta-hydroxy-threopropionamide are dissolved with stirring in 100 ml of dry pyridine, the solution is cooled to 0 DEG C. while stirring and 9.3 g of methanesulfonyl chloride are added dropwise. After one hour at 0 ° C, a further 3.3 g of methanesulfonyl chloride was added and stirring continued for 1 hour. The reaction solution is poured into 300 ml of ice-water, 200 ml of ethyl acetate are added and the pH is adjusted to 3 with dilute sulfuric acid. The organic layer is separated, dried over sodium sulfate and the solvent evaporated in vacuo to give the title compound. .

O) Tetra-n-butylammonium salt of .alpha .- (tert-butoxycarbonylamino) -beta-cyclohexyl-beta-methanesulfonyloxy-threopropionyl sulfamate

A solution of 2-methylpyridine (17.8 mL) in methylene chloride (90 mL) was cooled to -50 ° C and 5.97 mL of chlorosulfonic acid was added thereto at a rate that kept the temperature inside the reaction mixture below 5 ° C. The resulting solution was stirred for 15 minutes and then a solution of 12 g of alpha- (tert-butoxycarbonylamino) -beta-cyclohexyl-beta- (methanesulfonyloxy) -treopropionamide in 30 ml of methylene chloride was added. The reaction mixture was refluxed for 16-20 hours, then poured into 500 mL of 0.5 M potassium dihydrogen phosphate and diluted with 120 mL of methylene chloride. The separated organic phase is washed with a further 100 ml of potassium dihydrogen phosphate solution, the aqueous phase and combined, 10.2 g of tetre-n-butylammonium hydrogen sulphate are added and the mixture is extracted once with 300 ml and twice with 150 ml of methylene chloride each time. sodium sulfate and concentrated. The resulting foamed title compound is obtained.

E) Trans-3 - [(tert-butoxycarbonyl) amino] -4-cyclohexyl-2-oxo-1-azetidine sulfonic acid tetra-n-butylammonium salt

13.0 g of potassium hydrogen carbonate are dissolved in 320 ml of water, 220 ml of 1,2-dichloroethane are added, the mixture is heated to reflux and a solution of 20 g of tetra-n-butylammonium salt of alpha- (tert-butylamine) is added. butoxycarbonylamino) -beta-cyclohexyl-beta-methanesulfonyloxy-threopropionylsulfemate in 100 ml 1,2-dichloroethane. The reaction mixture was stirred vigorously at reflux for 15 minutes, then added to a separatory funnel and the lower organic layer was separated. The aqueous layer was extracted with an additional 200 mL of methylene chloride and the combined organic phases were dried over sodium sulfate. After concentration of the organic solution, the title compound is obtained in the form of a crude masterlike material.

F) Trans-3-Amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid

3.8 g of tetrebutylemmonium salt of trans-3- (tert-butoxycarbonylamino) -4-cyclohexyl-2-oxo-1-ezetidine sulfonic acid was stirred in 20 ml of formic acid for 3 hours. 20 ml of methylene chloride are added to the reaction and the title compound is filtered off. 1.0 g of product is obtained, m.p. 217-219 ° C.

Example 7

TгθnssЗ-amino-44 _β ett-2-txoazetidine-1-Sulfonic acid

The procedure described in Part A) of Example 6 was followed, but instead of beta-cyclohexyl-beta-1-tetrahydro-tyropto-troopropionic acid, bete-et-1-all-amino-beti-hydron-threopropionic acid was used. The title compound was obtained as a solid melting from decomposition at 185 ° C.

P Peak la d 8 '

TraansЗ-emino-4-phenyl-11-azetyl-sulfonic acid

The procedure described in Part A) of Example 6 is followed, but substituting beta-cyclohexyl-11aaerinx-β-tydrxoyl-thiophoxoxoxacetic acid is ethyl-allyl-alpha-amino-betl-hydrony-threopropionic acid, followed by the subsequent treatment. ^ aici. of the reaction described in Example 6. The title compound was obtained as a reddish brown solid.

Example 9

(S) -N- (2-ooo-1-sblfo-3-azetidiyyl) potassium salt ---- fetllccelaDidb

To a solution of 121 mg of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt (see Example 6A) in 3 mL of dry methylene chloride was added 40 mg of lenylacetic acid and 61 mg of dicycloxheoylklrexdiiride.

After stirring at room temperature for 48 hours, the dicyclohenyurea was filtered off, the solvent was evaporated in vacuo and the residue was taken up in acetone. The solution is filtered and the title compound is precipitated by the addition of 5 ml of acetone saturated with potassium iodide. The supernatant was decanted, the residue was washed three times with acetone and dried. 48 mg of the desired product are obtained, which after agglomeration. of methanol and ether melts at 210 DEG C. with decomposition.

Ainlýza: for C ^ R jNgS KC.I / 2HgO Calculated 39.86 _C 3.65% H 8.45 "N, 9.68" 11.80% K;

found 40.0 1 * C 3.37% H 8.59% N 9.59 »S 11.98% K.

NMR (CDCl3): 3.66 (singe t, 3H), 3.67 (doublet of doublets, J = 6.4), 3.90 (triplet),

4.90 (doublet J = 6.4), 7.36 ppm (mUltplet, 5H).

Example 10

(S) -3 - [(22-Dioxo-4-thiazxlyl-ethoxy) -lactriox] -2-oxo-L-azetidone-oxalic acid potassium salt

To a mixture of 2 g of tetrabutylammonium salt of (S) -3-lrinx-2-xxx-1-azetidiosulphonic acid, 0.5 g of erinoxiazole oxetic acid and 0.4 g of hydroxybenzenesulfonate are added dropwise at 0 DEG C. in 100 ml of dry dimethyiorramide. solution of 0.7 g of dicyclohenylcarbodiimide in 10 ml of dimethylxime. After complete addition, the mixture is stirred for 12 hours at 20 DEG C. under stirring, then the insoluble urea is filtered off and the solvent is evaporated off under vacuum. The oily residue is treated at room temperature for 15 minutes with a solution of perlluoro17444146 potassium butelphonate in 20 ml of acetone. After addition of 200 ml of dimethyl ether, the title compound precipitates and is filtered off. The product was dried and purified by chromatography on a 300 ml column of HP-20 adsorbent using water as the eluent. There were obtained 850 mg slouieniny Uve ^ not in the title, melting above ⁰⁰ ° C 3.

They did

Dresel 'salt [ЗS (*)] - 3 - ^[(fo ORC ^{y' ft} yloxy EI rlecttyl ^s) 8min] - · 2ooxo-Ί azttidin8U ^F0-sulfonic acid

A mixture of 1.5 g ^^ ^ 0 ^ 8 '^ sooi (S) -3-amino-2-oxo-1 -ezetá ^ d ^ i ^ M ^ X ^ ^ ulfo oic acid, ¹⁰⁰ ml of ^di meth ^y l ^o ORMA ^id UA 2 ml ^p ro ^py Lenox ^id for not cooled 0 ° C and stirring ae к thereto of a solution of O-formylrandlové chloride acid in 10 L acc ^ onttilu. The temperature is maintained for 1 hour and the solvent is removed in vacuo. The oily residue is treated with a solution of 2 g of potassium perfluorobutanesulfonate in 15 ml of acetone and then 200 ml of ether are added to the mixture, which crystallizes the title compound, which is collected in a yield of 1.5 g. MTO-r8t1í to adsorb ^^ with HP-20 melts protakt for extended ^ ACLU at ^{180 ≥ 18} and 5 ° C.

Example 12

Dras salt of ^{[3S (+} J - ³ - [(/ FOM ^yl- oз ^Y R ^1e CCE ^y el ^YLT yl) θmin -] - 2-oxo - ^1-e θztt Diss ^1- on-Mo-tyseli

The procedure is analogous to that in Example 11 except that DO-1-methyl-butyric acid chloride is used instead of O-formylmandelic acid chloride. After lyophilization from ^I compound with a ^K ^ Ni ^ Measured UV HV ^and invite the ^ ^th the fence ^{120 to 125} ° C.

P Pikl a d 13

^I3 Dras salt of S ^(-)] зЗ - ((/ FOM ^yl- o; ^y r e ^Yia ctetyl ^ft) θminoJ ^{ox---2-one 1-} -aztt ^e dilsзu on KYSE-inflammatory ^{and y} in

The procedure is analogous to that of Example 11 except that L-formylmandelic acid chloride is used instead of O-formylmandelic acid chloride. Give the title compound, 1 mole obsstauící vodb temperature for ^counting e ^{203? 2} ° 5 ° C. ^p ^ oo ^p atrnám drying melts ^P ro ^du ct at ²²⁸ and ²³ ° C.

Example

The potassium salt of ^(S) - ^{2-oxo-3- I (1} 1ooxoюki ^yl; EI) ^{amino] -1-e} tztt dilsul ^{io alkyl} noové Selin ^y

A mixture of 1.5 g tttrabutytamoni-inflammatory sooi (S) -3-Arino-2-oxo-1-azttidiIsufOonové to the acid, ¹⁰⁰ ml '^ fomnamito lip and 2 mL of ^p ro ^py Lenox ^d u is cooled to 0 ° C, at which A solution of 0.8 g of caprylic acid chloride in 20 ml of dry acetone is added dropwise to the temperature, and stirring is continued for 30 minutes. Rozpouutědlo the odppří in vacuo and the oily residue was treated with 2 g _of potassium perfluorbutansullonátu in 15 ml of acetone. The acetone is removed in vacuo, the residue is dissolved in 5 ml of water, and the clome-gafuite is dissolved in 300 ml of HP-20 resin using a 9: 1 mixture of water and acetone as eluent. After ^ looks' is obtained 0.9 g of the ^ title Nina Taj ^ s at ^{173 1} and ⁸ ° C.

He said 15

The potassium salt of [3S (Z)] - 3- [[(2 - ^^ 0-4 tioazol ^{yl) [[(ye} dгo :: Y (t n ^{f e y} lrβ tx ^y) foofin ^yl] methoxy imino] tcet ^{yl] 0} Tiina ^{-2-oxo-1--azttidixs} s1fnш) as tyseHny

A mixture of 0.8 g of tetrabutylammonium ^y tθíoniovά sooi (0-3 - ^. ^ - 2 ^ 0-1 azetidiMufo »dreamy acid in 30 ml diretylf отютЫи, ^{0.9 g of (Z)} - ² -arino-alpha- [ ^[[YDD oo lmttox ^Y1, ey ^{y y) y} L ^R fotfi MTT x ^y] líino0-4-ttazoloctové acid 0.3 g hydroJýbetno-rlazolu eicykloheχylkerboeiirieu and 0.7 g of 24 hours at ambient rístnoosi.

The precipitated urea ee ^y 'filtered and the solvent evaporated in vacuo. Per oily residue with an equivalent amount of potassium periluorbutansulionate in 10 ml of acetone. The title compound was filtered off. 6 purified by chromatography on HP-20 resin using water as eluent. 500 mg of the desired product melting at 210 DEG-215 DEG C. with decomposition is obtained. F

Example 16 ^[3S (Z)] - 3- [[(2-tainoo4 TITZE ^{FS-l) (n and} m Toor NO) θcet Amino ^{t r} l] ^-2-oxo-1-n tzetid n8ul ⁰ nNew tyselina

A mixture of 1.5 g of tetrabutylamino ammonium (S) -3-amino-2-oxo-1-thiazolidinedioic acid in 100 mL of dimethyioamide, 0.6 g of dibasic tri-azrazole, 1 g of dicyclohexyltrimododimide and 0.8 g of (Z) -2-amino-oxo-amine. of (n-oxyimino) -4-thiazoleacetic acid was stirred at room temperature for 24 hours. The solvent was removed by distillation, the residue was dissolved in 30 mL of acetone, the urea was filtered off and the mother liquor was treated with a solution of 2 g of potassium p-tert-carbuttotulfonate in 20 mL of acetone. After addition of - 200 mL of ether, the title compound precipitates, which is filtered off and dried. After purification by column cta'a1mtograffí using Arabic gum ^^ ice №-20 and water as eluent, 1.1 g of a polyorganosiloxane compound, M.P. dec s ^p 180-185 ° C.

Example 17

The potassium salt of ^[3S (E) J-3- ^{[[(2-amino-4-r} l titzol ^{((TTO: yi imino)} TCE ^those eminoJ L ^e-2-oxo-1 -azetidlnsulfonové acid

The procedure is analogous to that of Example 16 except that (E) -2-amino-β-alpha (eto: 4-amino-4-thiolino) -4-thiazoleacetic acid is used in place of (Z) -titzoloctová acid. After LybfiLizaci gave the title compound, mp 160 ^and 170 ° C Z_.

Example 18

^ Potassium salt of [3S (Z) J-3- [[(2-tmnn ^thiazol-4-L R) - ^{(2,2,2ttriUlueretoř s)} im notθctt ^{n r} l ^t aíinoU-2-oxo-1-acid tzttidnwшlfonové

In a similar manner as following Example 16, by naimsto (Z ^ Z-amino-alfа-tttoз understood as meaning ^yl) -4-teszoloctové tysel ⁱ n ^y mere (Rev--eminn ^ al ^ -J ^^^ - trifluorttox ^yl) imino-4-tiεzoloctová acid. After Lřafiliztci gave the title compound, -tajíc s ^p 160-170 ° C.

He said 19 a d 19

DRAs-salt of (S) -2-oxo-3 t · ^{[(P t} Aoxa ra ^py l) imino] -1-tztt ^{d n} d ^s адu ⁱ⁰ nnav

1.5 g tetαebut ^y αimžoiové scoi (S) -Зaamino-2-oxa-1 -tzttddnnsцffnnavé acid in 10 mL of dry dimetylfrmiamidu ° and 4 ml of ^{p ay} lenžxi RA ^d u from the stirred and cooled to 0 ° C and the p ^ tepLotš 0.5 g of propionic acid chloride in 10 ml of aceeoontril is added dropwise and the resulting mixture is stirred for 2 hours. Solvent. and ^d ddetilujt in vacuo to oily-residue was added with an equivalent mnUžsví perlluorbuttntulfooátu potassium in 5 ml of acetone. After adding. The title compound crystallizes out of ether and is filtered. After Lyo ^^ z ^! of i ^ and ^{0.8 gp} ro ^d uktu mp ¹ 3 ⁵ and ^{from 140} ° C.

PPíkl a d 20

^ Dr Elna salt of [3S ⁽⁺⁾ Jt3 - [(У dгax ^{y y y} FTN ltctt ^yl) amino] -2-axo-1 tfzttid n8U ^{n f s} fnnav tyseliny

1.5 g tltrθbut ^y líífnlové sooi (S) -3-вíino - 2-oxo-1-lzltiiilsžlfonové acid

100 ml of dry ilíetolfomlleíiiu of approximately 16 h with 1, 5 ^'d iiíldž dicyklohlχylklreo g, 0.5 g and 0.6 g hydnoitybeiizooriazolu Manolov acid. Evaporate in vacuo and dissolve the residue in 20 mL of acetone. The urea precipitated is filtered and the liquor is treated with an equivalent amount of potassium perfluorosulfonate. After the addition of ether, the title compound is circulated and the product is discarded. 1.4 g of crude product are obtained. ^p o překystetování of ^t and is ^always in the ^ kt at ¹³⁸ and ¹ 4 ⁰ ° C.

Example 21

The potassium salt of ^(S) -3- ^{[[k (and nmltyl) iO} olalrtyl 8mioo ^l] - ^- Aze oOXO- ¹ ^^ ^ sulfonic Nuu ^to Yae ^e Lina

1.5 g retгэbutylвíoniové sooi (S) -3-eíino-2-oxo-1-lOltidinsžlfonové acid and 0.72 g of ^[(ky иш уО ¹ ^! ^] -Acetic tysel rozkutí ^ with ⁷⁰ ml ^of lcclrf ^for three years and ^ hem MMN was added dropwise a solution of 1.04 g of dicyklohlxyOkareodiiíidž ^ ι ^ ι Ο ^! ^. After about 16 ^hours stirring s temperature range of ⁰ ° C ^to the PA in the ^y SR ^Ái Measured cýlohexylmotavina ^ o ^ ^ filtrate lltauj was evaporated and the oily residue rozpuusí in acetone. After addition of a saturated solution of potassium iodide in acetone under ^{sr <ASI} title compound. 1.1 g iádaného m.p. ¹⁵⁰ and 155 ° C.

Example 22

Potassium salt of (S, -oxo, -CUH-tetrazol-H-ylacetydaminoj-1-azetidiol sulfonic acid)

To a solution of 0.005 mol of tert-butyapionium salt of (S) -3-amino-2-oxo-1-lOtidol] Muffonic acid (see Example 6A) in 70 ml of DMF was added 0.77 g of 1H-tetrao-1-acetic acid and flow stream 1. 13 g, in 5 mL ilcyklohlxylklrboiiiíliu ilíet ^y lfomlaíiiu. The mixture was stirred at room temperature for about 16 hours, the solvent was evaporated in vacuo, the oily residue dissolved in 20 ml of acetone and treated with a solution of 0.006 mol of potassium perfluorobutanesulfonate in acetone. 1.5 g of the title compound melting from pK4 decomposition at 170-175 ° C is obtained.

Example 23

The potassium salt of ^(S) -2-oxo-3- ^{[] (2H-2-yl} tetrlzol lecet ^yl) laminf] -1-azeto ⁱ d ⁱ a5U ^LF-ynoic tyseli

The procedure is analogous to Example 22 except that 2-tetrazole-2-carboxylic acid is used instead of 1H-tetrazole-1-acetic acid. The obtained compound uveůná title melts at ¹⁷⁵ and parted ^from I ⁷⁷ ° C.

Example 24

The potassium salt of ^(S) -2-oxo-3- ^{((2-l yl} aceУ ^e i l ^{y l} θmiio] -1 -azltld xuш ^{of LF-sulfonic} tyseli

The procedure was analogous to Example 22 except that 2-thienoic acetic acid was used instead of 1H acid. The title compound obtained melts at 18 ° C ^{and 190} ° C.

Example 25

The potassium salt of [3S (Z) j * 3- ^{[[(2-imino-4-t} l ⁱ LZO ^{poly ((methoxy} imino ^yl) θce ^ey l] lmilo ^O 2 -> foo1-ezolidiosulfOrnové acid

^Y lamfnlfvá tetrabutylammonium salt (S) -3-Liina-2-oxo-1-azlridioм žffonové acid was cooled to 0 ° 0 О with к pM.dá ketyl 3.53 ^g ^ JS-amino-alpha-Cmetoxyimino ^^ thiazoleacetic ssliny to ^y, and then a solution of 3.27 g in 10 ml iicyklohexjylkarboiiimliu ilmetyiooraamiiu.

244U6

The mixture was stirred at 5 ° C for 16 h, filtered and the solvent was evaporated in vacuo. The residue was dissolved in acetone and the solution was filtered. After addition of 60 ml of a 10% solution of potassium perfluorobutanesulfonate in acetone, the crude product is 4.7 g of crude product. Purification of the crude product by chromatography on HP-20 edsorbent gave 3.0 g of the title compound, melting at 235 ° C.

Example 26

(3S) -α-Q / 2-Oxo-1-sulfo-3-ezetidinyl / emino) carbonyl] benzeneacetic acid dipotassium salt

100 mg of (3S) -α - [([2-oxo-1-sulfo-3-azetidinyl / amino) kerbonyl] benzeneacetic acid phenylmethyl ester potassium salt is dissolved in 20 ml of anhydrous methanol. the mixture was treated with hydrogen for 15 minutes, then the catalyst was filtered off and the methanol was evaporated in vacuo. The residue was dissolved in 5 ml of water and adjusted to pH 6 with 1K potassium hydroxide. After lyophilization, a crude product was obtained, which was chromatographed over HP-20 with water as eluent to give 60 mg of the title compound, m.p. 85 ° C.

Example 1 a d 27

The potassium salt of (S) -2-oxo-3 - [(phenoxyacetyl _z) amino] -1-acid ezetidinsulfonové

A solution of 1.5 g of (S) -3-amino-2-oxo-1-ezethanesulfonic acid tetrebutylammonium salt in 100 ml of dry dimethylformemide is cooled to 0 ° C and 2 ml of propylene oxide are first added thereto while stirring. 1 g of phenoxy-acetyl chloride is added dropwise. The reaction is complete in 1 hour. The solvent was evaporated in vacuo and the residue was treated with an equivalent amount of potassium perfluorobutanesulfonate in 20 ml of acetone. After addition of ether, 1 g of the title compound crystallized. The product is filtered off, dried and recrystallized from boiling water. The title compound obtained has a melting point of 176-180 ° C.

Example 28

[3S (Z)] -3-[[(2-emino-4-thiazolyl) [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] amino] -2-oxo potassium salt -1-azetidine sulfonic acid (1: 1)

To a solution of 0.005 ml of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrebutylammonium salt and 0.006 mol of (Z) -2-emino-alpha - [(2- / diphenylmethoxy) -1,1-dimethyl-2] -oxoethoxy) imino] -4-thiazoleacetic acid in 60 ml of dimethylformemide was added 0.7 g of hydroxybenzotriazole and 1.13 g of dicyclohexylkerbodiimide. After stirring at room temperature for about 16 hours, the mixture was filtered and the filtrate was evaporated. The residue is dissolved in 30 ml of acetone, the solution is filtered and 20 ml of a 10% solution of potassium perfluorobutanesulfonate in acetone are added thereto. Upon addition of petroleum ether, the title compound precipitated, which after ether work-up and filtration gave 3.6 g of the product melting from decomposition at 190 ° C.

Example 29

[3S (Z)] - 3 - [[(2-Emino-4-thiazolyl) - [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid dipotassium salt g of potassium salt [3S (Z)] - 3- [r (2-Bmino-4-thiazolyl) [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] amino] -2-oxo-1 -azetidine sulfonic acids (see Example 28) and suspended in 5 ml of enisole, and 25 ml of trifluoroacetic acid are added to the suspension at -Ю ° C. The mixture was stirred at -10 ° C for 10 minutes, then 100 ml of ether was added thereto at -10 ° C and then 50 ml of petroleum ether. The precipitate formed is filtered off to give 1.6 g of the trifluoroacetic acid salt which is suspended in 20 ml of water at 0 DEG C. and adjusted to pH 5.5 with dilute potassium hydroxide and purified on a column of edaorbeat HP-20. The title compound is eluted with water and melts with decomposition at 225 ° C ·

Example 30.

D ^ SCIO ¹ salt [33 (2)) 1-3- ^([(3 2зaminii4- azo ^il i ^ ^{l) [(2- (efe} eIylaeOoo ^yl) -2-oxoeOOoy] IAIO] acetyl] AMINO-2- iXO- ¹ зazetid ^i] Cst ^f0 -ones ^é acid-oy

When the same procedure as in Example 28 c that CE instead of (Z ^ Z-amioo3alfa - [[2- / difiyylmeta ^O / -1 - ^e iaatylз2зiOieti2 ^o] iainc0] · 4-tiaziloctové acid ⁽²⁾ and ^f з2зaíin0i3 - [(2з / d ixylaetooy ^fe / - ² -ooieto ^of г) iainoi-4-thiazoleacetic acid ^L. Dozen ^give ^ ^d, quoting EO ^and in tazv ^ mp. detuning at 1 ⁸ ° ^C.

Example 31

Potassium salt ^[з S (+) Jз3з ⁽⁾ a1Sidofeτ ^/ lacety ⁾ ) ali ^] -2iOxi- ^1- azetide

Method I

2.03 g of the (S) 3-allyl-2-eno-2-azo-1-azonic acid salt and 0.9 g of (+) - affa-aza-disintegrating acid are dissolved in 30 ml of acetonitrile and a solution of 1.03 dic / kliheoylcarSiimidimide is added. ml aceeoiitrilt. The mixture was reacted first with 1, Melting Tadino at ⁰ ° ^C and then Tadié I ⁰ when the ODF Tapt ^p ^ i ^ costs of the precipitate was oddeeStluje solvent in vacuo, the oily residue is rozpuutí in 20 ml acetone and treated with 1.70 g potassium v-acetone stearosulfioate. After adding 10 ml of ether vykxysSpaluje composite Uve ^ OA tazvu, melting rozdačlu 'at ¹ 49 ° ^C.

Method II

To a solution of 4.06 g of tetrabutylammonium salt of 3α-aza-12-oxo-1-azetiracetic acid and 5 g of propylene oxide in 30 ml of β-α-β-α is added 2.5. g elfaziaifeo / lacet / lchliriet. After stirring for 2 hours, the solvent is evaporated under vacuum and 1 ml of potassium perfluoroanthiolphiol in acetone is added to the oil. Upon addition of ether, the title compound crystallizes and separates. The product melts at 148-149 ° C with decomposition.

Example 1 and d -32

Potassium salt ^H 33 ⁽ D)] - 3 - [[[([(4зaeto: ^oyf · ^{o /} l) ae'Oo ^{o /} ] ^k ar ^s Oi ^{o /} J amino-phenyitylacetyl] amiioo-2зiOi-1зazetidinstlionic acid

To a solution of 2.03 g ³ SOU 0etrabutyaaaooiivé зaaino- -ixo ^{2-1-azetieiICufOonivé} в acid ^{1.58 g D} -a - [[[(a-ee ⁱ o / ^Fe .mu.l ^{/ l)} L) metho ^/ r] ^{to Ar} oo ^/ l] AAI; oo] taozeooctové ^to yselio ^y acceooitrilu in ⁵⁰ ml of a solution of 1.03 g eicykloheo / lkarSieiiaiet acceooitrilu in 10 ml. ^SME with the OEC ^hook react ^p tearing therein for ¹ hour at ^a temperature of ⁵ ° ^C в then 6 hours at místnooti then precipitated dicykloheoylaočovioa solvent removed в ideeetiltje. A non-oily residue consisting of the o-compound is treated with acetone. ρerftuorbutalадtlLOonátea ^d raseliým в ^{é tere} thereby typist Z ^and 2.4 ^g of protaktu, Melting ^th alpha 1 ° ^{8 and} Я1 ° ^C (dec).

Examples 33 to 37

Works with BO81o ^{g p} rocedure as by the built-in cross-Ladle ³² Hm, ^f E. natasto ⁽⁾⁾⁾ - ^ ^al ^ (^ - [[| ((43 зaeto: ^oyfβo / ^lm eOoo ^yl] Tarta ^ l] ^bííoo] tanzeooctov ^s kyselio ^y Poud in ^ZDY p ^ Dust composite uvedeoá column I oáslecbuící table. In this way, the compounds listed in column II of this table are obtained.

Table

Example number I II 33 (D-ELIFA-f (^ ^s-1 metooqďin! Tamtosxrl ^to artonyl] amino] - ^ - ^ tto N-acetic acid вгшы Rui [3s (()] --- [[[[[(4-methoxybenzoyl ol1lOll) mlto: oyjklrbo] ^ 0] amino] -t ^l or ^l 1 ^{l 8cety] l amino]} - ^2-oxo-1 -izetidinsulfonové acid melting decomposition zi ^P s 144 ^- s 146 ° C 34 ⁽⁺⁾ ^ ^ -Iminoo-l - ^[[[(4-methyl drowning ⁰¹⁾ metojqyJtartoiwljamiooJ -4-thiazoleacetic acid ^d nsilná salt of ^{[3S (+)]} - 3- [[(2-8mino -tiazotyO- ^ ^[[[(4-m ^ 1to: ° ^ J ^ ⁱ ii l) I acetoxy] tor ton 1] amino] thirty ^yl] amino] -2-oχ] -1-8zetid0tuuifonové to the ^y ssiiny toptotě mp 232 - ^and even 234 ° C 35 (+) - ^I and il - [[(^ j th-metozoyfr Dmitox ^{1] to} lrbooy1] aalno ^{0-2 u} -l lrloxoctová ^to ysilina ' -cis-IIU salt & ^{S (J +} -3 ^[[2 -i ^u r ^- '. ⁴ ÍLíX methylethyl; ^NI1 and ^{Oyi) Mitox] tortoвд1]} amino] scat ^1] Amii ^ (^ - ² - oxo ^ - ^ ¹ -lnltld0xsu10onové acid melting zi extended adlu ^ s ^p II 124 126 ° ^C 36 ^(L) -alia- ^[[frémitox ^ in ^ Mitox ^1] tortonyl] amino] tonzsnoctová ^alkyl Silina ΑτιμΙο ^ (3S (L)]] - 3 [[[[β4-methoxy ° / ^{ni i} ii l ^ yonder Jtortoityl] imino] loyllcet ^{1 l l]} imino ^0-2 -] oo - * 1 azetidine sulfonic of the acid melting at 172-175 ° C 37 (R) -81- (4 - [ ^(4- Dimethoxy) -4-dimethoxy] toronylamino) -2-thioctanoic acid 0 [1] salt [3S (L)]] 33 - [[[[(4 -metho-ynyl Jmitox-tort tortones¹] uminoo-²- ^ t^and^ nⁱ¹^ icit^and^^l] amino] - ^ - oxo-¹ m.p. 146-114 ° C Ex 1 and d 38

T-trebutylemmonium salt of thiothio) thioxomethyl] thio] ^phenyl- ethyl] amino] -2-oxo-1-azetidine disulfonic acid,

К solution of ¹ 03 ^{g of} (+) - i1 ⁱ i- ^{[[(methylthio} oxomity ^ t ^ ^ ^ e btanionoctové кузеИ ^1, 63 ^g titrahutyiamoniové SOM 3-imino-2-oxo-1-vi izitidixsuifonové acid 30 ml acelooiirilu a рМ tiplotě při.dá -5 ° ^C 0.8 ^g d ⁱ c ^yk Lohia ^ylk ir ^{and b} Depart bromide dissolved in ¹⁰ ml of acetonitrile • three years. Reakčint a mixture of about 16. h, then the resulting dicyklohioyrlmočovina oddlltruji e mmtičný a liquor The oily residue was chromatographed on a column of 400 g of silica gel, eluting with a mixture of itylacitate, methanol and water (8.5: 1: 0.5) to give 1.3 g of the title compound.

He said 39 i

Drasilná salt of 3 ^(S) -3-C ^[[m mit ltoo ^{l) of} t ox <msiy ^l] thio] ^ nylicetyl] ⁰ imino ^-2-oxo-l 11θls idiosul ^one sulfonic acid ^{1.3 g} titrabutyiemoniové SOH ⁽³ S) -3- ^[[[[(tl ml of LT ⁰⁾ t ⁰ oχometyl] ⁰ o t] FIO llcetyl ^l] ami.no] ^- · -2-oxo-1-azitidniMuioonové ester (see example 38) a rozpuutí in both the acitone and the solution it adds an ilcrivalintic amount of potassium pluorobutanesulfonate. After the addition of the ether, I crystallize the compound seen in the title and filter it out. 0.18 g of product melting at 157 DEG C. decomposes. .

Example 1 and d 40.

The potassium salt of ^[3S (D)] - 3- ^[[[4- 4-ethyl-2,3 ^0iox and ^"p" PlpreennylJkerborxllaminoj Z-thienylacetyl amino] -2-oxo-1-azetidixsulfonové kyselioy

In 25 ml ecetoo ^ Rua is extended ^p usttí 3.25 ^g (β) -81Γ8 - [[(4-ο · ^ of 1,2,3 ^{^]} οχ] -1 - ^^ Γ8ζ1] ° ^ ° carboy ^e] amino] -2- ^ iofeippctové tyselio 4 ^ ²⁰ g ^ tetrebuty Moo-Mo ^Sa] and ³ ^ ι8 .η (· ^ ^^ - αοο- ¹ ι -azet.id Mulfonové ^of sour-e ^{1.3 g of} N ^ ^ -tyúrox eenz- azole. at ^t ep ^l -W OTG ° C during 20 miout solution of 2.06 g in 10 ml dicyklohexelkerbodiimidu aceeooOirilu reakčoí and the mixture was stirred for 16 fits. VznOklá močovioa was filtered and the filtrate in vacuo odppaří solvent. the oily residue was rozpuu! acetoou in 50 ml and treated with elkrivaleotoí ιο ^^ ^ β ^ ί perlluorbutaosullooátu potassium him while you crystallized the osmolality! ^ uvedeoá in oázvu Taj ^Ic detuning ^p rl ^{1 85-187} ° C .

Example 41

Draseloá salt ^£ 3 ³ (+)) - 3- ^[(E гfmfeJ ^not вce ^e yl) amino -21fοo- ^{f 1} -azetidiItóu ^LF onfv ^e ^ selioy

To a solution of 5 Ol tetrabutyaamfniové am.no-2-fχo-1-azetieintulfonfvé kyselioy SOM 31 and 3 g are acteoiáirHu ^p s ^t ep ^l o ^t of ^{the 0th} C ^{p p} e say ^{1.4 g} -bromo ^ al ^ en ^ ^ AECE chloride in 10 ml acCHtoOttilu. After stirring for 3 hours, the solvent was distilled off and the oily residue was dissolved in 30 ml of acetone. To the solution was added an equivalent of potassium bisulfate potassium borate in acetone. After adding! The osmolality ether crystallizes! ^ uvedeoá in oázvu, melting and extended ^{kl d} u ^p s ¹³⁵ and ¹³⁷ ° C.

Example 42

^Q Draselrá salt of S ^{(+)] 1 3} 1 {C ^[a ^ ⁱ ®I Ofkarbeo ^about l) © aino0f2-tie] ^no AEC ^ATE] aвl ^{and nn]] 2-one} oxοf -зezaidiosulfooové kyselihy

Method I

To a solution of 2 g of (S) -3-amino-2-phth-1-esatide-sulfonic acid tetra-butylammonium salt and 1.5 g of propylene oxide in acetic acid is added 1.1 g of (12) 12-amino-4- [4-] -. tiaoУ) 151 (4H) 1> on the ^ο ezolon1h ^{e <f} ro ^d u ¢ chloro. tříhodoověm stirred for ^p! at 0 ° C and stirring for 1 hour at room temperature, the solvent is distilled off. The 8 oily residue is dissolved in 30 ml of acetone. 'After adding! The potassium perllufreutansulloort of potassium in the acetone is crystallized in the salt and introduced in an oasis. After vyčištěoí chrfm8aoor & Ali, oa adsorbent column of HP-20 in water pooustí JEKO e ^ to ^ o čioidla, obtain the compound! ^ Uvedeoá in oázvu, melting rozHaůu ^p s ^{218 and 222} ° C.

Method II ^For suspension. ^{(2 g))} -alf1- ^{e (O} θπ fokθr ^e fo ^{yl) emioo]} -21 t] lfonoctfv tyselio ^é ^ I ⁰ gurgle> l tetrabutya8Иfniové sol.i (S) -3-2-aoinf fOf11-azetedOмulfonfvé kyselioy 8 10 mmol of N-tert.-hydroxytanoz in ⁵⁰ aceetdtrHu ^p s is 0 ° C under stirring pttfó ¹⁰ MSOL DLC ^e] ^ l ^l oi íolςelkareod: ^ limieu dissolving it in 15 ml aceeofOttilu. In míchiáoí continued for 1 Suitable ^p s at -! 5 ° ^C and ^P, and the CDA 16 TODI ^p ^ s Tepo místnooti. ^P o oHiltrovtoí (Hcytlohexylmočovioe odppří the solvent and the oily residue in 50 ml of burst the acetoou. After adding! And ^to vivalaotoíío шю в ^ ^ ^ peгlΊuoreutantullfoátu potassium him in acetoou yielded crystalline produut which upon vyčiětěoí dhromeaooraaií OA column ADS ^^ o ^ HP-20, eluting with water as the eluent, provided an oily compound melting at 220-223 ° C.

Example β d 43

Potassium salt of [3S ( ⁺ ) ^J -3 - [[[pmethylmethyl-arbonyl] amino] -2-4181-4-ethyl-ethyl] -2-oxo-1-o-azide-1-sulfonic acid

0.54 g QMUi- ££ Me ylerninotiff ^{e (t} b ^s 01ocf tyaeliny 1 ¹ tetributylaméniové 00 ^g of (S ^ -iiino - ^ - oxo-izetidirsuioonové acid are dissolved in 20 ol icetoo example, acrylonitrile ⁰ⁱ 'and ^to a solution of ^^ ga at 0 ° C, pM ^ gives 0.5 ^g DLC loheiqflěrtodil.nl.du ^. ^P of eight hour stirring iieyklohaoýLmfčfVin1 oddlužuje, odiistiluje solvent, the oily residue is rozpuusí in 50 ml of acetone and the solution was added к ι ^ The crystalline product was collected by filtration, eluting with HP-20, using water as the eluent to give the desired compound, m.p. roztíadu 2 ⁰ at 5 ° C.

EXAMPLE 44

Dnseln salt ^{and Q} 3 S ^(+)] - 3- [£ (a8oiofoxof1eSy ¹⁾ θminn] -2-thousand ⁿ¹ L1eet ¹ l] 1mlnnf ^{2-0f0f1-i-azetl} iosulf sulfonic acid

A similar procedure as described in Method II of Example 42 with the IE instead of ⁽⁺⁾ -1 ^l1 inhibit the de ^Ss i ^and NO SR ^{b to} f ^{01 l)} silnof- ² -t l ^{f s s} onfctfv tyseHny ^p ou ^teaches Js ^"(+) -1 l ¹ θ [t (θ ^S ^^ nffXfθccS ^y1) 2-1miníf tiofenfctfvá acid. The title compound is obtained, melting at 218-122 ° C.

EXAMPLE 45

The potassium salt of ^[3S (R *)) - 3 - ^(([[(a-ethyl ^^ d ^ oxo-l - ^p ipsr1ziíylk ^and Ebbo lSaiinf ^1] FeO ¹ lses tyj amino] -2-FOF-1-1zstidÍnsul0onfvé acid

A similar procedure as in Example 40 with the IE instead of (D) -i11i- ^[[[4-T1 L-2 Зid ^F oxo-l- ^{p y} i ^p srezir гl) k8bЪfO ¹ l] amine N ² -ti ^k1 of anode Selim uHje ^ ^{1 (R)} -N ^l a- [^^ уГ-г сНохо- ¹ ^ - ^^ Razin) cartons] amino] enzenoctová tyse ^b ^ a. With a compound Zísě them Uve ^ ^ to the title, .mu.Ci of @ roztttáu at 155 and ^{1 57} ° C.

Examples 46 and 49

For pooHtí Ostu ^{p p} in accordance metoty příěadlu ¹¹ 4 ² 'compensation ⁽⁺⁾ -e ^le - ^(1R 1θπιinf ^to oτ ^{b n} l) 1mlnnf-2-acid methyl ester tioaenfdf modes from ICI ^ ^ OVI compounds listed in Column I See the table below to obtain the compounds listed in column II of this table.

Table

Example čído

II (+) - .alpha. - Q (.beta.-amino) amino] -. ^d nselná acid salt Q ^ 1 ^ I ^(+)] - 3- ^{[[£ (i} ^ i ^ i ^ <^ fxof1eSy θπ ^{11 m} Ni] ---: ^- цurr a1eSy ^{O1 11 f} -2-imino fxo- 1 ⁰ -iziM Mdftiwvi kyseUny, melting at 212 215 ° C Al-Asel-salt ^ (♦ ^^ - [[(ΧΟ ιοme-butyl) amino] ethyl okosc] and ^ i ^ i ^ o] - ² - ^ 01 ^ 18 ^ 1 ^ 1] θiloo ^f - ^ - Omoo! -1zstidín8ulfonfvé acid of melting detuning at ¹ 95 and ¹ 97 ° C ⁽⁺⁾ - i 1 i ¹ - £ £ ^[(s 1 and ^the NME ⁾ amino] oxo1Cdyl] 1iinof- ^{- f} -t dnnoctová thou saliva

Table continuation Example number AND II 48 (K) -alpha- [eminooxoacetylamino] benzeneacetic acid (Fraser s ^ ^u l ^{[3S (R R) S)} -3 - ^{[[((aminooooecetyl)} amino] Ιιοι οι ^ ^ Ι] amino] -2 - oo-1-sulfonic acid tzltidOIS5ul, mp 207 DEG 209 ° C. 49 (K) -alla - [(Sminocarbonyl) amino] - benzenoic acid [3S (R *)] - 3 - [[[(ω-nitro-phenyl) -cyclohexyl] amino] -2-oo-1-thiazolidinedulonic acid potassium salt, melting at 225 ° C with decomposition

Example 50

[3S (+)] - 3 - [(2- (methylthio) -1-oxopropyl) amino] -2-oxo-1-azetidine sulfonic acid potassium salt

The method of Example 31 was followed, substituting (+) - 2- (methylthio) p-opanoic acid for (+) - .beta.-8-benzoic acid. The title compound melted from decomposition at 173 ° C.

Example 51

[3S (rO)] - 3 - [[[[E, 2,3-dioxo-4 - [(fer1 / 1-methylene) -amino] -1-piperazityl] carbonyl] amino] phenyl] ethyl] amide 10,000-azetidine sulfonic acid

0.7 g of (R) -alpha - [[[2, -et-oo-4 - ((folylmelylonaamto-1-piperidinyl)] - [alpha] - [alpha] - [alpha] -benzoyl) acetic acid and 0.8 g are dissolved in 20 ml of tert-o-trile. g of (S) -3-tetra-2-oxo-1-azetininsulonic acid tetrotexylammonium salt · While stirring at 0 ° C, 0.4 g of dicyclohexylcarbodimide is added dropwise and stirring is continued for 18 hours After filtration, the solvent was removed (the oily residue was dissolved in acetone and potassium perlluorobutosullooate was added to the solution to precipitate the title compound. After purification by column chromatography on HP-20 additive using water as The title compound melts at 193-194 ° C.

Example 52

Potassium salt of C 3 S (Z)] -3- [[(2-eminoo4 - iazolll) [(2-methoxybenzoyl> oi 2-oxootODoy.iminoJacetil] amino] ^ - oxo-aaelidinsulfonové ester ¹ (3 g, Z) -2-amino-11a - [(2-Inetooyl-2-oxoethoxy) amino] --- thiazoleacetic acid and 2.03 g of the (th) -alkylaminium salt of (S) -3-amino- Of 2-oxo-1-azetidine sulfonic acid was dissolved in 50 ml of acetontril, and 1.03 g of dicyclohexylbenzamide (4-dimide dissolved in 5 ml of acetortitrile) was added dropwise at 0 ° C. The oily residue is dissolved in acetone and an equivalent amount of potassium perluluorobutanesulfooate is added to the solution, and the title compound is isolated and discarded on a column of adsorbent HP-20 using water as eluent. · The product obtained melts at 195 to 198 ° C ·

la 53

[3S (R *)] - 3 - [[[[3 - [[(4-chlorophenyl) methylene] amino] -2-benzyl] amino-4-ynylcetyl] amino] -1-thiazolidinedulonic acid potassium salt

-1-thmidezz0idiOll] ktrb--

A mixture of 1.5 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt in 100 ml of absolute diethylene glycol dimethyl ether, 1.5 g of (R) -alpha - [[[3 - [[(4- chlorophenyl) methylene] amino] -2-oxo-1-imidazolidimyl] carbonyl] amino] benzeneacetic acid, an equivalent amount of dicyclohexylcarbodiimide and 0.5 g of hydroxybenzotriazole is stirred for 12 hours, then the solvent is evaporated in vacuo, the residue is dissolved in 50 ml of acetone and the solution was filtered. The acetone was distilled off, the residue was dissolved in 200 ml of methylene chloride, the solution was washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, the methylene chloride layer was dried over sodium sulfate and evaporated to dryness. The residue crystallized upon addition of ether. The product is recrystallized from a mixture of acetone and ether, the resulting white crystalline powder is dissolved in acetone and an equivalent amount of potassium perfluorobutanesulfonate in acetone is added to the solution. Filtration of the precipitated title compound affords 1.4 g of the desired product, m.p. 217-222 ° C.

Example 54

[3S (R ^x )] - 3- [CELCE ^2- oxo-3-f (phenylaethylene) amino] -1-imidazolidinyl] carbonyl] amino] phenylacetyl] amino] -1-azetidine sulfonic acid potassium salt

A mixture of 2.25 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt in 100 ml of dry dimethylformamide, 2.5 g of (R) -alpha - [[2-oxo-3 - [( Phenylmethylene) amino] -1-imidazolidinyl] carbonyl] amino] benzeneacetic acid and 0.85 g of hydroxybenzotriazole are stirred at room temperature for 12 hours, then the dimethylformamide is evaporated in vacuo and the residue is dissolved in 50 ml of acetone and the precipitated urea is filtered off. The filtrate was treated with an equivalent amount of potassium perfluorobutanesulfonate in 20 mL acetone. After addition of 100 ml of ether, the title compound precipitates, which is filtered off and purified by dissolving it in a mixture of dimethylformamide and acetone and precipitating with water. 1.5 g of product melting at 224 DEG-226 DEG C. are obtained.

Example 55

[3S (R *)] -3 - [[[[[[3- (methylsulfonyl) -2-oxo-1-imidazolidinyl] carbonyl] amino] phenylacetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt

2.25 g of (S) -3-amino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt in 10 ml of dimethylformamide was stirred with 1.9 g of (R) -alpha - [[[3- (methylsulfonyl) - 2-oxo-1-imidazolidinyl] carbonyl] amino] benzeneacetic acid, 0.75 g hydroxybenzotriazole and 2.3 g dicyclohexylcarbodiimide. The solvent was evaporated in vacuo, the residue was dissolved in 20 ml of acetone and the solution was filtered. Potassium perfluorobutanesulfonate (1.87 g) in acetone (20 ml) was added to the filtrate and the title compound was precipitated by addition of ether to give 2.0 g of material which, upon recrystallization from water, melted with decomposition at 240-245 ° C.

Example 56

[3S (R *)] Hydroxyphenylacetyl) amino] -2-oxo-1-azetidine sulfonic acid potassium salt

1.5 g of (S) -3-fimino-2-oxo-1-azetidine sulfonic acid tetrabutylammonium salt in

100 ml of dry dimethylformamide are stirred for about 16 hours with 1.5 g of dicyclohexylcarbodiimide, 0.5 g of hydroxybenzotriazole 00.0 g of R-alpha-hydroxybenzeneacetic acid. The solvent is evaporated off under vacuum, the residue is dissolved in 20 ml of acetone, the precipitated urea is filtered off. An equivalent amount of potassium perfluorobutanesulfonate is added to the filtrate. After addition of ether, the title compound precipitates and is filtered off. 1.3 g of crude product are obtained which, after purification by chromatography on an HP-20 adsorbent using a 9: 1 mixture of water and acetone, melts with decomposition at 145 to 150 ° C.

Example 57

[3S (S *)] - 3 - [(Hydroxyphenyecetyl) amino] -2-oxo-1-azetidinephalfonic acid potassium salt

The procedure was carried out in an analogous manner to Example 56 except that (S1-alpha-hydroxybenzeneacetic acid) was used in place of (R-alpha-hydroxybenzeneacetic acid) to give the title compound, melting at 195-197 ° C.

Example 58

[3S (+)] - 2-oxo-3 - [(trans-oxoacetyl) amino] -1-azetidine-sulfonic acid potassium salt (1: 2).

A mixture of 2.25 g of (S) -3-amino-2-oxo-1-azetidinium-thioic acid tetrabuhyphammonium salt in 100 ml of diethyl ether. 2.4 g of tert-butylamine and 0.3 g of dimethylaminoppyidine are cooled to 0 DEG C. and 1.8 g of (. + -.) - 6 - (chloroform-11) phizeimetisulfonic acid in 20 ml of dimethylformamide are added dropwise. The solvent is removed in vacuo and the residue is dissolved in acetone. The insoluble precipitate was filtered off and an equivalent amount of potassium perfluorobutanesulfonate was added to the filtrate. After addition of ether, the title compound precipitates and is separated off. 1.4 g of crude product are obtained, which after recrystallization from a mixture of water and acetone melts with decomposition at 240-245 ° C.

Example

Potassium salt of [3S (Z) J-3 - [[(2-80 ^^ 4 - ^ 20 ^ 1) ^ [(phietooylphosphine: hDretooy] irinoacetyl ')

-2-oxo-1-tetridirisulfonic acid

To 2.25 g of (S) 434 amino-2-oxool-azetidine-1-enoic acid tetrobutylammonium salt in 100 ml of dry dimethylformamide was added 1.37 g of (Z) -2-amino-4-tert - [[(dieoozylphosphihl) metho]] imino-4- of thiazoleacetic acid, 0.75 g of hydrogen bromide iso-triazole and 2.29 g of dicyclohexylcarbodiimide and the resulting mixture was stirred for 12 hours. The precipitated urea was filtered off and the solvent was evaporated in vacuo. An equivalent amount of potassium perfluorobutanesulfonate in 20 mL of acetone was added to the oily residue. After addition of ether, the title compound precipitates which, after filtration, affords 2.77 g of crude product. From this crude product, after purification by column chromatography on an HP-20 adsorbent with water / acetone (9: 1) as the eluent, the title compound was obtained, decomposing at 155-160 ° C.

Example 1 a d 60

Potassium salt of [3S (Z)] - 3 - [[(24-amino-4-isolyl)] - [ ^, (2- (1,1-firetyletooy) -2-oxo-1-leiyletooy] imino-10-ethanol) emilo-2-o-o- 1-azetidine sulfonic acid

2.25 g of (S) -3-trino-2-oxo-azazididine sulfonic acid tetrobutyl-ammonium salt in 60 ml of dimethylformamide are stirred with 2.4 g of (Z-amino-ede-f-4) (1.1 g) at room temperature for 12 hours. (Ethylethyl) -2-oxo-1-phenylethino-amino-4-thiazole acetic acid and 1.5 g of dicyclohexylcarbodiimide, the solvent is removed in vacuo, the residue is dissolved in 50 ml of acetone, the precipitated urea is filtered off and the filtrate is treated with an equivalent of m.p. Upon addition of the ethoxy ether, the title compound is isolated by filtration and purified by four-column chromatography using an IBP-20 adsorbent column using water / acetone (7: 3) as the solvent. 1 g of a pure product melting with decomposition above 250 ° C is obtained.

244146 28

Example 61

Potassium salt of [3S (Z)] -3- [[(2--0ml.no-4-thiazolyl) [OH-tetrazol-5-ylmethylamino] iodoacetyl] amino] -2-oxo-1-azetidirsulfonic acid ¹

1.9 g of (S) -3-amino-2-oxo-1-azetide-one sulfonic acid yet-butyl-8-ammonium salt in dimethylformamide (60 ml) were treated with 1.4 g of (Z) 424-amino-1,4-di- [(1 H)] with stirring for 24 hours. Methyliminoiminoph-44-thiazol-acetic acid, 0.7 g of hydroxybenool triazole and 1.4 g of dl-cyclohexylcarbodiimide After evaporation of the solvent in vacuo, the residue is dissolved in acetone and the precipitated urea is separated by filtration. · acetone the title compound is precipitated by adding 200 ml of ether and purified on a column clhιtomitofrθflí prysk1M.ce HP-20 of eluent water ntola ^. s CIS ^{to 1.05 g} prodiktu detuning melting point at 250 ° C.

Example 62

^And potassium salt [зS ^(Z)] - 3- ^{[£ (2} -liioo Уiazflyl-4) ^{e i} fo1y methoxyphthalene ^s) iiinl] lcet ¹ l] liiool-24lXO 14 4θzetidOnsllfonové acid

A mixture of 1.5 g yetrabutylanioniové centerline (S) 4,3-amiof-24fXf 14lzetid0nsul0onfvé-acid, ^{1.23 g of (Z)} 4.2-el-ailno ^l l ^Q (FOI lieУfxy ^yl) iiiool-4-t θzoloctc ^l) in a ¹ tyselin ^0, 57 ^{g of} hydroxylamine-benzotrilzllu dic1klohexylkerbldiiiidl and 1.14 g in 60 ml dimetylftiilmidl stirred for 24 hours at a locally ^. The precipitated urea is filtered off, the solvent is evaporated and the residue is treated with an equivalent of 50% by weight of ethyl acetate. Potassium perlchlorosulfonyl in 10 ml of acetone. After addition of 200 ml of ether, the title compound precipitates, which is filtered off and recovered. The column was washed with water and acetone (9: 1) as eluent. 1 g of the expected product is obtained, melting with decomposition at 200 ° C.

Example 63

Dnseln ^and salt [ЗS ^(Z)) 43- ^{L £ (4} 24liinOl4- ilzo ^l-yl) [(I-oxo-methoxy phen ^^ ^ m ^ ^ acetoxy ojacetyl] lminol-2-oxoo14lzetid0] sulfonlvé acid

In a similar manner as in Example 28 in that instead of the (Z) -2-Amino-e-a-TFZ tHferýrlmetox ^ ^ -l, 4 ^FII · ^y-yl42 fxle LXY ^yl] -4- iiinol ^ya azoloctové tyselin prn ^ ^{1 (Z)} a-4.2-eiioo вl ^l ll £ ⁴ l0xo 2- (fo1ylietlιx ¹⁾ etlx ^1] iiiol] 444 t ^{l l} йlo tyselina -acetic acid methyl ester. ZIS ^to the composite plated title ^ detuning melting at about ¹⁷⁰ ° C.

Example 64

Dnselrá salt of [3S (Z)] - 3 - [[[(2 · i ⁱ fXfe ^no42-yl ox ^{y) iiinf] (2} 4eiinOl4- iazll ^{y 1} l) acetate ¹ l] вiioo0-24 4fχ (L-14lzetidOnsulfonfvé acid

Working analogously as described in Example 28 in that, instead of (Z) 4.2-aiino-alpha- ^[[- - (d ^ -l ^ eiylteetox 1- ^{fi ietyl-2-yl} oxfe ax ^1] Liina] 444 ^ ^l йf) ^f ^ C ^ World tyceKty ou ^{p u} ije (Z) 4.2-amiol-alll- ^((2-4aθminf fXletf ^χ1) -44 IIIO ^{l y y} aezololc FVA tyseMna. ^of the one hundred-Iskate eoíoi the of melting point at ^{20 to 210} ° C.

Example 65

Dnselrá ^£ salt 3S ^(Z)] -3- ^[C (2-4-LiIo У azll ⁱ l ^{1) (1 1} ydroχ IIIO) eceУyl] -2-Liina ^L-oxOf1 can ^yif iosulfonové acid

Solution 0 og 90% ¹ H (fro) ^ψ1enoz, lrilzoll 100 ml diie ^y 1lformamifu stirred for 1 hour with ^{10 g of} sieves ⁽⁴ x 1 ^{0 "101,} the mixture is zftltruje and nitrate with ^a solution of PMDA

(S) -3-amino-24-fluoro-41-lzetide] -muffonic acid in 0.004 mol of tetrabutylaluminum in (S) -3-amino-4-trifluoromethylphosphonic acid.

After the addition of 0.39 g of (Z) -2-emloo-alpha- (4-hydrloyiminol-4-thiazol-acetic acid), 0.91 g of dicyclo-oxylcarbodiimide is added, the resulting mixture is allowed to evaporate under vacuum for about 16 hours. dissolved in 20 ml of acetone and the solution filtered. SlouSenina title is precipitated by adding a solution of potassium perflslrbutaosslfloáts. After cIhOmaooroafi ^P ryskyXici WP ²⁰ detects ^0, 44 ^{g of} product melting over a ² ° 4 ° C.

Example 66

The potassium salt of ^[3S (Z) J-3- ^{[2- (2--ma0uo} αiazxl ^{4-yl) e (b 0} and x ^m mtUo ^{χ)) m 0} LL uoJвceX ^yl aminoj- ² -lxó ^α-L- azetidOnsuHonové acid ^{0.1 g} potassium Sou ^{3S (Z)] - 3 - [[(4aаmiou --- teаl01 ^{yl) 24-U'ouo22f (0} EI ^lm lmeloo ^s) etlo ^χ Jimi] ECET ^yl] 8miool - ^2-1 -loo αzetid nзu ^{0 f0} o] ^l UVE tysel ¹ ^ ^{(see p} Ia of manufacture ^{for d} ^ 6J are extended ears in a mixture of 5 ml ethanol and 5 ml of water) and hydrogenated at mÍ8tnolti in přítomnolti 0 , 2 g of 10 * palladium on charcoal. After 2 hours' oodfltruje catalyst and the remaining solution lxofilizuje ^whose M ^F of te ^ S ^ u ^ Nina Uve ^d Measured HV ^and invite Tej ^ i for detuning at ²³⁵ ° C.

Example 67

^[ 3S (Z)] - 3 - [[(2-Amino-4-thiobz (1-yl)] ^[[ 2- ⁽ 1'-diethylethyl) -O-t-methylthio-4-oxo-acetyl] amino] acryl] potassium salt ^ - ^ ^{oxo-azetidine-0} ™ ^! ^ ^1! ^ ¹ ^ tysel

In a similar manner as in Example 65 with TIA, ie r - ^f -e instead EA-4X / dгoo imioo ^χ) -4-t ^e alolpctové tysel ¹ ^ W ^ pouteje -aminno - ^! -. '^^ 1- ^ ^^ lnel summer: ⁰⁾⁾ - ¹ - (meeyltio) 22oOxoetoo ^χ] imiool ^{4-t-azo 1} acetic acid. Acquire ih, diná in the title, melting with decomposition at ¹ 3 ⁰ ° C.

Example 63

The potassium salt of (S) -3- [[[[(1 ^-ethyl-4 l four-hydooxy34-methyl-1H-the pyrazolo [3,4-bJpyrid ^ -S-Jkarboinrl yl] eminolfe] wXaceeyl] αminoU 2- α-1-α-azetidine-5-oxoic acid

For pouuití procedure described in Example 65, substituting (Z) -2-8mioo-elfα- (4ydrooylmino) -4-tiazlly ^{l l} oc-oic tyseli alfta- [U-ethyl- ^ J ^ tydroo-methyl - ^ - pyrazolo ^[ 3,4-hj ругМ1о-5- ^yl) carbonyl] ajoBo] ^b eozenuctuvus tysolinou ZMA t ^{l No.} eoioa Uve ^d Measured vn-vu Tej ^ i ^ for the extended and ^p ^ u s ² 3 ^{3 and 2} 3 ⁶ ° C.

Example 69

The potassium salt of [3- ^((2)] -3- ^{[[(methoxycarbonyl o yimioo) [2} - [f ^{e t} o ^oχ onyl) ^y вrbbU ^oχ] eaino0u4-til-EO ^Uyχl Eccta ^yχ] 4 ^2-oxo вDinol- -1-αzeti ^d ints ^fUon tyste ¹ ^

To a solution of 0.170 mmol ^s tetгabst αmmuoiuvé centerline (S) -3-αmioo-2-1-OXU αzetid0ш sfUonové tyseli ^ ^ and b ^ ^0.170 mmol sodteho carbonate in ² mL of methylene ylenchlor ^{e ld} u te ^ OTs at ⁰ ° C ^{EXAMPLE 62 LDA} / ul ^p yr nu ^idi and ^0.51 mmol of ^(Z) -e ^f f - ^(χ meloэ im ^{i oo)} - ² - ^[([(l foyylme oз ^{χ г)} k8rtюn lJemioo ^{χ l} - ⁴ After 40 minutes, the reaction mixture was diluted with mseylene chloride and water, and 5.1 ml of 0.1 M tetrabstate ^and sodium phosphate buffered to pH 4 was added thereto, and the organic layer was separated, acidified to pH 2 with water, with water. adjusted to pH 7 with water saturated with sodium chloride, dried over sodium sulfate and filtered in vacuo, and the residue was dried on 10 g of SiO 2 Si SiCAR CC-4 using 10% methanol in 161101114 to elute the product. . *

Tetrabst ^y aamuoiuvé rozpuutí salt in aqueous acetone and passed through a column of AG 5OW iontomlniče - ^ - _X2> (8 mR K ⁺ - cycle). ^{p dy} in the evaporation of the ^{f y} ro te 1 and ² of Vata ka ^ 40 ^- ^ merged ^{mg of} the title taj ^ i of detuning at ^{172 F} and Γ74 ° C.

Amlýza pro ^c 17 ^H 16 ^M 5 ⁰ 8® ^{2C H} 2 ⁰ calculated noLezeno 37.84% C 3.33% H 37.95% C 3.30% H 12.99% N 11.87 »S, 12.73 «N 11.53% S. Case 70

(3S-TreM) -4-methyl-2-oxo-3 - [(phanylecetyl) 6-Bino] -1-ezetide-4-methylsulfonate

To 420 mg of (3S) -3-amino-4-methyl-2-oxo-1-ethoxy-sulfonic acid tetoabutilemmonium salt ee at 0 ° C was added 206 Bg of dicyclohexylcarbodiimide, 153 mg of N-hydroanbenzotriazole and 138 mg of phenylacetic acid. The reaction mixture was stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. The precipitate is filtered off, the filtrate is evaporated in vacuo, the residue is dissolved in 10 ml of acetone and the solution is filtered. To the filtrate was added 25 [mu] l of acetone saturated with potassium iodide and 200 ml of ether. The precipitated solid material, weighing 752.7 mg, consists of a mixture of the anhydrous and tetrabutylammonium salts of the title acid. This solid material was dissolved in 50 ml of a 0.5 M potassium dihydrogen phosphorone solution and applied to a column of HP-20 pirystyres. Combine with water and then a mixture of water and acetone to obtain several fractions, which are combined and evaporated. The crosslinked tetrabutylammonium salt was dissolved in water and the solution was allowed to pass through the Dowex 50W-X2 (K * -cycle) ion exchange column to give the title potassium salt (121.4 mg). The mixture was triturated

acetone and hexane gave 104.6 mg of compound listed in the title, m.p. 211-213 ° C. Axwlyza:] for ^ 2 ^ 3 ^ 0 ^ 1/2 H ₂ O calculated 4177 9 0 4.09% H 8.11 «N 9.28% N 11.32% K; found C, 4.01%; 8.07 * N 9,01% N 11.02% K.

Example 71

Potassium salt. [3S- al t} ^f and ^(Z), 4 ^{b and} ETE] -3- ^{[[(2-amino-4-tioazo ll} l ^((l mrtox imino) ECR ^tl] amino] -4-2-meeyl -JX0-1-szrtidiадufOoϊюvé acids

A solution of 420 mg of (3S) -3-eminol-4-methyl-2-oxolyl-8-acetylsulfonic acid tetrabutylammonium salt in 25 ml of dimethylformamide was stirred under nitrogen with 161 mg of (Z) -fluoro- (quinoxyl) -2-oxo-4-oxo-4-carboxylic acid. The mixture was stirred under nitrogen for about 16 hours, the dimethylformamide was evaporated in vacuo, the gummy residue was dissolved in acetone and the urea was filtered off.

A solution of 272 mg (0.8 mam) of perfluorobutenesulfonic acid potassium salt in 0.8 mL of acetone was added to the filtrate, the resulting suspension was diluted with an equal volume of ether and filtered. 325.5 mg of crude product is obtained, which is in general not 75 mL of resin

HP-20 AG using 400 ml of water first and then 400 ml of a 9: 1 mixture of water and acetone as co-reagents. The 50 ml fractions were removed. Fractions 3 to 10 contain 335 mg of product. 97.3 mg of analytical material were obtained from fractions 3 to 5 after trituration with acetone / hexane. Similar trituration Nos. 6 to 10 gave an additional 90.4 mg of solid product.

H, 3.97; N, 17.45; N, 15.97; S, 9.74;

found 30.32% C 3.49 »H 15.82« N 13.95% S 10.45 «K.

MIH spectrum 1.57 (3H, d, J = 7 Hz), 3.97 (3H, s), 4.30 (1H, doublet of quartets, J 7.3 Hz), 4.70 (1H, d, J - 7 H «),

6.95 ppm (lH, a).

Example 72

The potassium salt of ^ - [^ e ^^^ eBet] - ⁵ - ^{[[(2-amino-49tiezolyl)} - ^[(1 -difenylmetoχ ^yk arbonyl- -metyietoxy ¹⁾ irπhlo] acetyl] βmiio] -9-methyl-2- oxo-1-azetidine ufonic acid

A solution of 1.17 g of (5S-tris) -9-ethyl-2-oxo-5 - [[((linylaltoxycarbonyl) carbonyl] -amino] -1-phenylthiulphosulphonic acid tetrafluorophosphoric acid salt in 95 ml of dimethylformamide is stirred for about 19 hours with 1.5 g of dimethylformamide. 29 g of (Z) -2-amino-.alpha .- [(1-difluoropyloxycarbonyl-15-methyl-ethyl) -amino] -9-triazole acetic acid, 0.9 g of N-disodium bromo-Oriazole and 580 mg of dicyclohexylcarbodiimide are evaporated in vacuo and the residue evaporated in vacuo. The filtrate, together with 2 ml of the wash liquor, was treated with 898 mg of potassium perfluorobutanesulfonate in 3 ml of acetone, and the mixture was diluted with ether. The precipitated solid material was collected. decantation of the mother liquors, trituration with ether and filtration to give 0.91 g of the title compound A second crop of the title compound of 0.95 g is obtained from the mother liquors by dilution with an additional 100 ml of ether. .

Example 73 Potassium salt of [5S - [[3alpha (Z), 9beta]] -5 - [[(2-phthalio-9-thiazolyl) [(1-carboxy-1-aelylethoxy) imino] 6-acetyl] amino] - 9--methylcarbamate-2-oxo-5 _to Л βtidiiLSUlfoiové acid

To a suspension of 190 mg of potassium salt of [5S- [35ff8 (Z), 9belaa] -5 - [[(2-phainio-18Zolyl) [(1-difluoromethoxycarbonyl-1-aylethoxy) imino] acetyl] phain-9-9 α-ethyl-2-oxo-1-azetidine sulfonic acid in 0.5 ml of anisole was added under stirring under nitrogen at -12 ° C, 2.5 ml of trifluoroacetic acid, cooled to -10 ° C. After 10 minutes, ether (10 ml) and hexane (5 ml) were added, the resulting suspension was stirred at -12 ° C for 5 minutes, then allowed to warm to msinoose temperature. Solid meate ^! was isolated by centrifugation and washed twice with ether. A solution of this solid material in 5 ml of cold water was immediately basified with 0.9N potassium hydroxide to pH 5.5 and applied to a column of 80 ml of HP-20AG adsorbent. Elution with water, 72 mg of the title compound was collected in fractions 7 and 11 (10 ml fractions), which was isolated by evaporation of these fractions by evaporation of the residue with ether three times. The product melts with decomposition at about 250 ° C.

acetonitrile and trituration

Analysis: calculated for ^C 13 ^H 15 W 2 ^K 2

30.51% C

29.63% C

2> 55% H

33.00% H

133,69%

12,96%

12.53% N

11.94% N

15.28% K;

12.78% K.

NMR Spectrum

9H), 1.58 ^(b íeuter luaooiLd): 1.99 (s, quartet, J = 7 Hz, 2.5 ppm (s, 1H).

(1H, d> J = 7Hz), 9.28 (1H, doublet of Hz), 9.97 (1H, d, J = 2Hz), 9.95

1.22 g of potassium salt of [5S- [5alph (Z), 9bltf]] - 5 - [[[2a-aa-thio-9-thiazolyl] [11] phinylalkoxycarbonyl] -1-ethyl-ethoxy] -amino] -acetyl] -phthalio-atyl- -2-oOoi ezetiíiisuffonové-ester was treated as described above (9.2 ml anisole, 16 ml trflUooroctové acid, 13 minutes at -15 ° C _Z). Chromatography on 300 ml of HP-20AG adsorbent (90 ml fraction) yielded 999 mg of the title compound (from fractions 6 to 9 after treatment as described above).

Examples 79 through

103

Using the procedure described in Example 15, substituting (Z) -2-phthaliphenyl- ([[hydroxy- (phenylamino) phenethyl] -ethoxyphenylamino) -tiphiazolylacetic acid for the acids in column I of the table below gives the compounds shown in in column I! of this table.

Table

Example number Even the starting acid II product 74 2-emino-alpha - [[2- (1,1-dimethylethoxy) -1-methyl-2-oxoethoxy] imino] -4-thiazoleacetic acid potassium salt hydrate [3S (Z)] - 3 - [[[(2-amino-4-thiazolyl) [2- (1,1-dimethylethoxy) -1-methyl-2-oxoethoxy] imino] acetyl] amino] - Of 2-oxo-1-azetidine sulfonic acid (1: 1) melting at 280 ° C with decomposition 75 (R) -pha - [[(4-ethyl-2,3-dloxo-1-piperezinyl) carbonyl] enino] -4-hydroxybenzeneacetic acid potassium salt F3S (R *)] - 3J [[[[(4-ethyl-2,3-dioxo-4-piperazinyl) karbonyljamino] ^(4-hydroxy-1 y ^en> acetyl] amino] -2-oxo-1 -azetidine sulfonic acid melting from decomposition at 197 ° C 76 (+) -? - [[(4-Ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] -2-furanacetic acid [3S (+)] - 3 - [(Xt (4-ethyl-2,3-dioxo-4-piperasinyl) carbonyl] amino] (4-hydroxyphenyl) acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt of acid melting at 169-171 ° C 77 (R) -alpha - [[(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] emino] -1,4-cyclohexadiene acetic acid [3S (R *) 1-3 - [] [1,4-cyclohexadien-1-yl] [(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] ethyl] amino] -2- oxo-1-azetidine sulfonic acid melting at 185 ° C with decomposition 78 (R) -alpha - [[([beta], 3-dioxo-4 - [(phenylmethylene) amino] -1-piperazinyl] carbonyl] amino-4-hydroxybenzeneacetic acid potassium salt of [3S (R *)] - 3- (XC [[2,3-dioxo-4- (phenylmethylene) amino] -1-piperazinyl] carbonyl] amino] (4-hydroxyphenyl) acetyl] amino] -2 oxo-1-azetidine sulfonic acid melting from decomposition at 194 to 197 ° C 79 (Z) -2-Amino-alpha - [(1-methylethoxy) imino] -4-thiazoleacetic acid [3S (Z)] - 3 - [] [] (2-Bmino-4-thiazolyl) - [(1-methyl-ethoxy) imino] acetyl] amino] -2-oxo-1-azetidine sulfonic acid melt salt with decomposition at 195 ° C 80 (Z) -2-amino-alpha- (phenoxyimino) -4-thiazole acetic acid [3S (Z)] - 3 - [[(2-amino-4-thiazolyl) (phenoxyimino) acetyl] amino] -2-oxo-1-azetidine sulfonic acid potassium salt melting at 165 ° C with decomposition 81 (R) -alpha - [[-3- [E (4-hydroxyphenyl) methylene] amino] -2-oxo-1-imidazolidinyl] carbonyl] amino] benzeneacetic acid [3S (R *)] - 3 - [[[[[[3- [|] (4-hydroxyphenyl) -4-ethylene] amino] -2-oxo-1-imidazolidinyl] carbonyl] amino] phenylacetyl] amino] - potassium salt - Of 2-oxo-1-azetidine sulfonic acid melting at 236 ° C

24446

Table 1 continued

Treasure number

Even the starting acid

Product II ^(R) -N a- ^f C [^ -oxo-J- ^{[(НугШо 11} methylthiophenyl 3.en ^yl) amino] - ¹ -imids azKdi! ⁰¹ . karbony1] amino] benzeneacetic acid ^^ - amnooBl-phenyl-f 1 ^{-methyl-e-2-yl-2-} LXL (еыщте ^ ху) etnxj imnco - ^ - ^e iezoloctová acid Draa 1NA AUL [3S (R *)] ^- 2 - ³ © XO ^{- 2-oxo-tLLt -} - ^[(4-py RISO-don t en ^yl) amino] - ¹ -im ^ azo ^ d ^{011] 1} -carbonyl] amino] ^ nytecety] and? tert-11aazeidine sulfonic acid melting at 230 ° C with decomposition.

dra ^ LNA ^with Γ3S U1 (Z)] ^- 3- £ _[(β ⁱ in 22- ^l - ⁴ -t EZL ^{i l} y ^{1) [-9 -i} (^ 1 ^ - ^ 0-2- ^(e nly11metlxy ) ethoxy] iminojacetyl] Eminönü! - ² - ^ © - ¹ -azetidinyl ⁿ iMuioonové acid of melting point 110-115 ° C ^{(2) 2-m} and R 0o- ^{AIF alpha] ()} im.nol- 4-taazlloctová acid potassium salt [3S (Z)] - 3- [J (22aaiinl-4-thiazolyl) £ ^{(^} cycl ^entyloty) imLnolacetyljam. 0 ^^ 0 04 ^ -A ^ of ^ dosul new acid m.P. 200 ° C 85 (R) -? H - [[1-oxo-2 - [[(phenylmethyl) carbon 1] amino] ethyl] amino] benzeneacetic acid potassium salt [ЗS (R ^R )] - 2-l ^χ L-3- (pe * ⁰¹ l ^{[[[l ((feyylmeαx s)} kerbltyl] amino] acety1] -amino] acety1] -amino] -1-azeem пацЗ.Топдоё extended ^ ^k1 e ^d in acid melting at

260 [deg.] C

2-FTIR & nooctová kyselina .ísi-and-CTA-Fure ^d ^ i raseloá sůl ety1 ec) aιmnol-2-one-lxo -a zetidinsulfonové that the decomposition acid melting at 110 DEG C. (R) -a · [[(2- ^ O-3- (011101-1-imidazolyl) carbonyl] aminolbenzeneacetic acid potassium salt (3S - ^ - ^ oxo) - [[t. ^[ ( ^2- oxo-3-phenyl-1-imidazolyl)] and · rbonyl] 8 0 ^ ^^ ^^ 1 8101130] amino] -1 -ezetidOsufoonové acid of melting rozklodu ^p s 217 ^and from 222 DEG C. (R) -alpha a- [[[2-oxo-3- (FeO ^y lmee ^y 1) -L-imidazOHdinyl] 1 -carbonyl] amino] benzeneacetic acid potassium salt ^{[З S} (R ^*)] -2-LXL-3СГ CC ^[2-oxo-3- ((Tetylmetyl) -1-imidazolidinyl] carbonyl 1] a1nino ^l - ^f ei ^of lecetyl] am.no] -1 -ezetidOsufonnové acid, mp 195-200 ° C.

alpha - [[β- (2-furanylmethylene) anino] -2-oxo-1-imidazolidinyl] carbonyl] aminoo-4-hydrorybenzeneacetic acid (R) -aafa - [[[3- [| 3- (2 - ^^ 01) -2-propetyllden] amino] ^{-2-oxo-imidazolidin-imidazol-1} cartons -amino] -acetic acid ^b enzeno potassium salt ^(3S) - ^- - ^{- [[[[3} - ^[(2 »·

-phthaloylmethyl-amino-2-oxyl-1-

-tmita sturdy carbonyl 1] ^ amino] ^(4-hydroxrf ETNL) 1 acetyl] amino] -2-oxo-1 -ezetidnsufoonové acid of melting maiden adlu ^p ^ 2 s ⁴⁴ ° C, potassium salt Dsírf *)] -3 ^- [[[[[3 - [[3- (2- ^(U l) -2pplppeo ^ylidene] amino] -2-oxo--irnčazoltoinyl] carbonyl ^1-amino] ^ nylacetyl] amino] -2-½ ^ ¹ 90

24 * 146

Table continued

Example number I starting acid II product 90 azulide oxofluoric acid melting at 195 ° C with decomposition 91 (Z) ^-2-m and nooalfa - [[[(etylamiioOlcarboityll oxy] imLn3] -4-tiisoloctová acid [3S (Z) - 3 - [[(2-Amino-thiazol-11)] [[[((R / R) carbooyl] oxy] ethyl] amino] -2-oxo-1 - potassium salt -Oneucoic acid azetide melting at 230 ° C 92 ^(R [[2,3-dioxo-4- ^(- e-methyl-4-l-piperazinyl) carbonyl] a) benzoacetic acid [33 (R)] - 3 - [[[[2,3-dilxo-4- (pheoylmethyl) -1-piperezioyl] carbonyl] amino] amino] -phenyl salt; [Alpha] L-amino-2-oxo-1-azetidol-4-enoonic acid melting at 158-159 ° C with decomposition 93 (R-m-mt [(4- (1 -metyleeyl) -2,3-dioxo-1 - ^^ l ^ once] ^b of KIR DEG ^yl] amio] benzeneacetic to ^^^ <^^ ^^ ^Li and draseloá «i [3S (R *)] --- [[[[[4 - (1-meeylety1) -2 - dioxo-1-oyl piperael from ^{i] to} r ^b o ° ^ l] ^f amiooj [.Alpha.] -. Alpha.-amino] -2- (1-azetide-5-sulfonic acid), m.p. 185 DEG-187 DEG C .; 94 (Z) -alpha- (non-oxylmino) -2-fluoro-acetic acid ^d race ^and salt of ^l [-size ^-] ^ - [[^ - -furan ^{1- (methoxyimino} ^ C ^ -yl] ^ aHno ¹ -azetidOisufoonové oxo acid of melting point ^fp s 160 ° C 95 (R) -1-8 - [[- 3 - ([(Dimethylamino) methyl] amino] -4- (2-oxo-1-imidolidolidoyl) carbonyl] amino] benzeneacetic acid [3S ( ^{r R} )) - 3 - [[[[[[3 - [[(dimethylamino-methyl) dimethylamino] dimethylamino] -2-methyl-1-imidazolidinyl] carbool-1-propyl] amino]] - ^ 2- ^ x ^ o ^ o ^ 1 --zetid0n8Uflonové taaící acid decomposition ^p s 195 ° C 96 (R) -aafa - [(3-Ethyl-2-oxo-1-imidazoloyl) carboml] amino] benzeneacetic acid draseloá-U1 [3S (R ^R)] - 3- ^{[[[[(3-ethyl- 2-LOXL} 1-imidazole iOlL ^d] karbo0l1] amino-e0řlecetyl] ^ 10 / 1-2 LXL-1-acid azetid0n8Uf0onové m.p. 185-190 ° C 97 (R) -alpha - [[[[N-methoxy-eu -methoxy] carbonyl] amino] acetyl] amino] beose acetic acid draseloá salt of [3S ^(RR)) - 3- [[[[[[[(4-eoyl metlχl ▼) metoχl] carbonyl ^b lnyl- amio] ^{acetyl-amino]} eoy ce ^ t ^yl] amino] - ² - oyl-1-zetidone-8-oxoic acid is secretly decomposed at ²⁶⁸ ° C ? 8 ^(R) -N ^f a- ^[[[2 -oxl 3- [. ^[(- eo lmetoχy ^{s) for} R ^b oi ° rl] -amino '] - -imidezoHdioy ^{1]] to} r ^b o ° ^ j ^l] and ^ l.no'] Enzo ^b ^ (^ <^ ^<t b ^s tyseUoa Drahný ^UL [38 ^) 1-2- ^ 0-3-t ^{[| [[2} -lXl- ^- · - ^{[[t fa} oryrlme lэ Иtartoztyljamioo ^yl] - ¹ - ^ ^^ ζοΚάΙο ^karbony1] amio] ^^ ^ Lecat ^amio] -1-azetid0n8Uf0onlvé tyseliny melting point ^P s 175 ° C

Continuation table Example number I starting acid II product 99 (Z) -2-Ino-α-β - [(2- (1-methyl-1,1-methyl-2-oxoethyl) -pyrimato] -thiazoleacetic acid potassium salt of [3 (Z) J-3 - [[[(2-amino-1,1-methyl-2-x-ethoxy) imino] -4-amino-4'-amino] amino] amino] amino] 2-oxo-1-isididenesulfonic acid melting at 210 ° C with decomposition 100 ALIGN! (R) -a - [[[4- (1-methylethyl) -2,3-dicxo- ¹ - Rezina ^^ ^ ^k r ^b o ⁿ l] amino] -4-hydioxybtnzenoctová. acid potassium salt [-SO2] 1--3 (^ 4 - (1-Ethyl-ethyl) -2,3-oxo-1-piperidines;^- Tortooyl] amino] -4-thyroxyphenyl] -ethoxy] -2-oxo-1-thiazolidinic acid, melting at 201 to 203 ° C with decomposition 101 (R) -alpha - [] [|] 3- (1-methyl-ethyl) -2-oxo-1-> imidazolium carbonyl] amino] benzeneacetic acid .. potassium ^UL [3- ((^ ---- [[[[З- - (1 -íetyletyl) -2 - oxo-1-líiíazo ^{iМ.оу] to} r ^b o ° ^ 1] amino ] ^f eoy Lece butyl] i ^ ^m ^ ^ c ^{o -2-oxo-1} -lottid ^and NSU ^{fO alkyl} sulfonic selioy melting at 195 to 200 ° C 102 ^(Z) -2-amino-O- ^al ^ (^ - ^ [[2- ^{(acetoxy d -methylphenyl)} -1-methyl-2-oxottpXlJiíinnl 44tiazoloctová acid fraselró [salt] -ЗББ ^-amino-4-thiol-11 (1) - [[2- (thienyl) lithium] -1-ethyl-2-oxo-thio] -thiomethyl-amino-2-oxo-1-L-thiazolidine-4-sulfonic acid m.p. 145-150 ° C 103 5-Methyl-34-foyl-1,4-oxo-oxo-carboxylic acid Potassium salt of (O-Z-2-oxo-4-S-oxo-10-yl) -carbamino-2-oxo-1-L-sulfonulfonic acid melting at 230 to 232 ° C with decomposition C

Example 104

Q33afa potassium salt (Z), and 4AL ^f] -3- [[(2-amino-4-o ^ t ^ ^t ^ i ^ 3 (^ lj ^ ^l) (metosqrÍDino-acetyl] amino] -4-methyl- 2-oxo-1-azetidirsuioonic acid

A solution of 62 mg of tert-butylammonium salt of (cis-4-methyl-4-oxo-1-thio-1-isethiosulfonic acid) in 5 ml of dimethylamide is stirred for about 16 hours with 31 mg of (Z) -2-amino. of alae- (p-oxyimino) -4-thiazolo-acetic acid, 27 mg of N-hydroxysulphorilole and 31.5 mg of dicyclohexylkerbodiimide, the reaction solution was evaporated in vacuo and the residue was triturated with 3 ml of acetone. 51 mg of potassium perfluorobutanesulfooate were added to the product, after dilution with 5 ml of ether and filtration, a solid product was obtained which was collected in fractions 3 to 5 (20 ml fractions) using H0-20AG adsorbent (40 ml) using water as the eluant. After evaporation of the ether and ethyl acetate, 23% of the title compound was obtained.

Analysis: ^{G R} ioH12 5 ° ^K 6 ^S 2 Calculated started up

29.91% C

29.30% C

-, 01

3.31

11.44% N;

16.66% N.

mg of the product as a hygroscopic solid

NMR (CDCl3): 1.40 (d, 3H, J = 7 Hz), 3.97 (a, 3H), 4.46 (apparent foaming, 1H, m.p.

J 7 Hz, 5.37 (d, 1H, J 7 Hz), 6.97 ppa (a, 1H).

Example 105

[3S- [3A] - [alpha] -alpha-4-a-2-Amino-N-thiazol-2-oxo-1-yl-acetyl] -methyl-2-oxo-1-azetidine sulfonic acid dibasic salt

To a solution of 201 mg of (Z) -2-aainioalpha- (aetozoline) -44-thiazoleacetic acid and 153 mg of N-hydro-sorbeniotriazlomonohydrate in 3 µl of diethylphthalide was added 206 mg of dicycloylcarbodiamide. The mixture was stirred under nitrogen at room temperature for 20 minutes, then a solution of 180 mg of (3S-cis) -3-aainz-44a-ethyl-2-oxo-1-azetidine sulfonic acid and 0.14 ml of trielylmin in 2 ml was added. Dimethylformamide (1 ml of dimethyiormiamide is used to flush this solution) and the resulting mixture is stirred for about 16 hours. The suspension is evaporated. in vacuo, the residue is triturated with 12 ml of acetone, the mixture is centrifuged and 338 mg of potassium p-trifluorobutinate is added to the liquid portion. Dilution with 10 ml of ether and lithiation yielded a solid product which was clarified on 200 mL of H 2 -20 adsorbent using water as eluent to give 274 mg of the title compound as a hygroscopic solid. The product was isolated from the combined 18 ei 30 fractions (20 ml fractions) by fractionation.

Analysis: C0 ^H 12 ^N 5 ^{O 6! K} 2 ^S Calculated 29.91. % C 3.01 «H 17.44% N found 30.03% C 3.11« Н 17.06 «X.

NMR (CDCl 3): 1.40 (d, 3H, J and 6.5%), 3.98 (s, 3H, 4.48 (dMe, triplets), 1H,

J = 6.4, 5.5 Hz), 5.36 (d, 1H, J = 5.5 Hz), 6.97 (s, 1H).

Examples 106 and 109

The procedure was carried out in an analogous manner to that of Example 105 except that (3S-trans) -3-8ainz-4-methyl-24zxz was used in place of (3S-trans) -3-amino-3,4-ethynyl-2-oxo-4-azetidine-phosphonic acid. -1-azetidine sulfonic acid and substitute for (Z) -24-amino-4-yl- (acetyl) amino-4-acetic acid

acid, the corresponding acid listed in column Z of the following overview. They obtain the compounds listed in paragraph II of this review. Table Example number I starting material II product 106 (Η) 4101ι4 [[[3 - [(24'-rlnylaeeylene) 4 amino] 424oχ-1- [ΙύΙύΙύζϋύϋύϋύ] carbonyl] aminoo benzeneacetic acid, Potassium salt of [3S [3alpha (R *)] - belaU * - 3 - [[[[[3 - [(24LUlronylaotylon) aail] 424zχz-1- [ΙύΙύζζϋύϋύΐΐcarbonyl]] η-mercuryl] amino] -4 ^ 0171-a- oxo-L. azetidiisuffonic acid, melting at 200 ° C . 107 (R) -aafe - {[(4-ethyl-2,3-disoxz41-). (piperazinyl) carbonyl] amino] benzeneacetic acid bS- [beta] 1-[alpha] -3-Methoxy-3 - [[[P (44-ethyl-2,3-dioxo-1,414-piperidinylcarbityl] amino] fetylecetyl] amino] 444-ethyl-424oxz-1-α with thidiisullzinic acid, melting at 177 ° C 108 (Z) 424aainis4af and- (hydroimino) -4, -thiazoleacetic acid potassium salt [M- ^ allBCZhAtate]] - 434 [[(2-вai! Ю444tiesoly)] ((hydlzχl- ‘

Continuation table

Example number

I starting material

II product

108

109 (+) - alpha - [(aminooxoacetyl) aminoo -2-thiopheneacetyl imino) acetyl] amino] -4-methyl-2-oxo-1-azetidirulonic acid, m.p. 230 DEG C. [3S- [3aalO8] potassium salt (iMbetafl-3 - [[[(eminoooooacphyl) amino] -2-thienylacetyl-anino-4-methyl-2-ooo-1-azetide] Muffon acid, melting at 135 ° C with decomposition

Example 110

Potassium salt of [3S-O3alpha (Z), 4beta]] -3-f [(2-eminoo-4-tazolyl) [[1,1-dimethylamino] - ((4-nitroOenpl) methoxy] -2-oofetooy [imnf] lcetyl] amine] -4-methyl-2-ooo-1-azetidine sulfonic acid

K. a suspension of 0.36 g of [3S-trans-3-amino-4-methyl-2-oxo-1-azetidine sulfonic acid saliva in 30 ml of dry dimethylformamide is added under nitrogen at 26 ° C with 309.yUL of tristyaamine. In this reaction, the mixture becomes a clear solution, to which is added first 0.816 g of (Z - [(4-nitrophenyl) methyl] - [1,1-dimethyl-2 - [(4-nitrophenyl) methyl]. 2-oxoethyl-imino] -4-thiasoleacetic acid, then 0.334 g of N-1-dihydroxyphenylbenzoylzole and 0.453 g of dicyclorphenyloyl chloride, stirred at 26 ° C for 12 hours, the solvent was then removed in vacuo and the residue triturated with 30 ml. After rinsing for five minutes, the solids were collected and 3.680 g of potassium perluorobutulonate in 5 ml of acetone were added to the frostbite, after which about 40 ml precipitate was collected and filtered and dried in vacuo to give 1.073 g of product in the second. 0.066 g of product was obtained, thus a total yield of 1.14 g.

Analysis; for ^{K <H} 2 ° calculated. % H, 13.41;% N, 10.23;% K;

found 38.30% C 3.63% H 13.41% »N 9.88% S 5.98% K.

Peak tuned

Potassium salt (4-oxo), 4a10a] -3 - [[(2-amino-4-thiaolyl) [(1-carboxy-1-methyl-ethoxy) -ranea] acetyl] -amino-methyl-2-oxo-8-thiophenesulfonic acid (1) : 2)

A) Potassium salt of [3a10a (Z), 4a10a] -3 - [[(Zeemino-a-thiazolyl) [[1-dipheryl-4-ethoxycarbonyl-imino] acetyl] amino] -4-methyl-2-methyl-2 -fxo-1-azethanesulfonate acid

A solution of > 50 mg of tetrabutylammonium salt (s) of 4-methyl-2-oxo-3-phenoxy-118-pyridinophenoic acid in 5 ml of 4-methylphosphoric acid was mixed with 146 mg of (Z-4-aranoalpha) - for about 16 hours. 11-Diphenylmethylcarbonyl-1-methyl-methyl-imino-4-trifluoromethyl-acid, 73-ng of dicyclohexyl-cyclobenzamide, and 51 mg of N-methyl-benzoimidazole were evaporated in vacuo and the residue was slurried with 4 ml of acetone. The solid product is washed twice with 2 ml of acetone each time, the filtrate is combined with the anti-swelling fluids, and 113 mg of potassium perluorobutane sulphonate are added, and diluting with 24 ml of ether gives a solid oil which yields 186 mg of the title compound.

B) Draaal salt [3,10Oa (Z), 4alpha] -3 - ['((2-amino-4-thioootyl) [1-benzoyl-11-methyl-oxo] amino] acetyl] -1'-oxo-2-methyl-4-oxo-4-oxo 1-azethionine sulfonate acid (1: 2)

Suspension 186 mg of potassium salt of [3alpha (Z), 4alpha-3- [r (2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo The -1-azetidine sulfonic acid in 0.6 ml of distilled anisole was cooled to -12 ° C and 3.0 ml of distilled trifluoroacetic acid was added thereto at -10 ° C. The solution was stirred for 10 minutes, then ether (12 ml) was added followed by hexane (6 ml). After stirring for 5 minutes at -10 ° C and stirring for 15 minutes at room temperature, the solid is collected by centrifugation and washed four times with ether. This gives 141 mg of material which is dried under vacuum, sprayed, dissolved in 5 ml of water and immediately treated with 0.4N sodium hydroxide nc pH 5.6. The resulting solution is applied to an HP-20 AQ adsorbent column and eluted with water, collecting 10 ml fractions. Fractions 8-12 are combined and evaporated in vacuo. acetonitrile is added to the residue and the mixture is evaporated. This process is repeated three times. The residue, after trituration with ether, provides 101.7 mg of the desired product as a hygroscopic solid.

% H, 13.69;% N, 12.53;% K, 15.28;

found 30.11% C 3.26% H 13.35% N 12.12% S 15.02% K.

Examples 112 to 114

The procedure is analogous to that of Example 105 except that the corresponding compound of column I of the following table is used instead of (Z) -2-amino-alpha- (methoxyimino) -4-thiazoleacetic acid. The compounds listed in column II of this table are obtained.

Table

Example Silo I starting material II product 112 (R) - .alpha .- [[[2,3-dioxo-4 - [[(phenylmethoxycarbonyl] amino] -1-piperazinyl] carbonyl] amino] benzeneacetic acid [3S- [3elfe (B *), 4elfe] - [4 - [([2 - [(4-methyl-3-oxo-1-sulfo-3-a-zetidinyl) amino] -2-oxo-2-oxo] -] 1-Phenylethyl] amino] carbonyl] -2,3-dioxo-1-piperazinyl-1] carbanic acid, melting with decomposition at 191 ° C 113 (R) - [alpha] - [[[(2-Furanylmethylene) amino] -2-oxoimidazolidinyl] carbonyl] amino] benzeneacetic acid [3S- [3alpha (R *), 4alpha]] -3 - [[[[[[3 - [(2-furanylmethylene) amino] -2-oxo-1-imidazolidinyl] carbonyl] amino] phenylacetyl] potassium salt amino] -4-methyl-2-oxo-1-azetldine sulfonic acid 114 (R) -alpha - [[(4-ethyl-2,3-dioxo-1-piperazines Dcarbonyl) amino] benzeneacetic acid potassium salt (3S- [3alpha (R *), 4alpha)] -3-[[[[[(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylmethyl] amino] - 4-methyl-2-oxo-1-azetidine-sulfonic acid

Example 115

[3S- [3alpha (Z), 4alpha]] -3- [f (2-amino-4-thiaeolyl) [(1-carboxymethylmethoxy) imino] acetyl] amino] -4-methyl-2-oxo potassium salt -1-azetidinaulfonové acid (1: 2) ^A) potassium salt of S- ^ ^ al ^ CO 4β1ι].] - ³ - [^ -. ^ ^ carbo eyylmeto -1 - ^ 'γ1β! ^ ί Umino] Acetyl] amino] -4-methyl-2-oxo-1-azylthiophonic acid

To a solution of 440 mg of (Z) -2-erino-61ft- [11-carbonyl-1-methyl-ethyl-4-amino-4-thiazole acetic acid and 153 mg of N-thiophonic acid thionyl ester monopolyate in 3 ml of di-phenylphosphoramide is added 206 mg of dicyclohexylbutyric acid. The mixture was stirred at room temperature for 30 minutes under nitrogen, then a solution of 160 mg of (9S-cit) -9-arino- ^4- methyl-2-xo-2-oxo-2-ol was added. 1-azetine sulfonic acid and 0.14 ml of triethylamine in 2 ml of dihydroforide (another 1 ml of ethylmethylamide is used to flush the above solution) and the resulting mixture is stirred for about 16 hours. The mixture was evaporated in vacuo, the residue was triturated with 12 ml of acetone, the suspension swallowed and solid malerted. 3 times of acetone. The filtrate was mixed with the washings and 338 mg of potassium perfluorobutan sulphate was added. Dilution with 30 ml of ether gives a gummy solid which is slowly solidified. This hard has! is removed and washed with ether. This afforded 656 g of the title compound.

B) jersey salt [3S- 3θl ¹ t ^{(Z) 4elfe]]} 9 - [[(4-MMIO ^e t ^e l zooУ ^{i) 1-} (1-keг ^{- y} of R-1-i ^ íttyleto ^χy rl ^ amino] ^ECET] 1mlnó] - ⁴ -methyl l- ^{tt 2} --xo- ¹ -ezetidirs ufonové tyseliny

A suspension of ⁶ 5 ⁶ mg .'sel 'Soh [3S- [93lfa (Z) .41 ^) - ³ ^ ((2e8íinoo44tiezo ^{0ly) [(1-eitenylrtt} xykarbornУ-1-r®tylet () xy] lrino] acetyl ] imino] -4-retyl 2 - x - 1 2 -azttedinsu1fonové acid ³ ml was .eetHovaného ochla.í nt - ¹² ° C. and the ¹ к ^1, 5 mL of t ^ ^ oooo OVE tyseHi ^ ^- pře.em ochlazť nt -1 ⁰ ° C. Výslé.ný soln ^ ¹ MIC 5 minutes' nt ^ i was added was 46 ml of ether and then 23 ml of hexane. After five minutes of reaction at - ¹⁰ ° ^{C Patna} ctirinu ^- Verify stirring at temperatures locally! solid ma ^ elšl odentruje and graduating with ether. There were obtained 457 mg of a very hygroscopic ^ ic resin which rozpuutí in 6 ml of cold water. the solution was o ^ i ^ i ^ ^II ^ S adjusted 0.4N KOH nt pH 5.6, applied e nt sifupec prystyřice 200 ml of HP-20 and tifuptc vysývá with water, adding an played fractions of 50 ml are obtained 239 mg of

Fraction 7 was collected and combined. in the form of a solid.

in title, ve

Arnalysis: calculated for C ₁₃ H ₁₅ O ₈ 1 ^ S ₂ K ₂ .L / 2H ₂ O 29.99% C found 29.94% C

3.10% H

3.30% H

13.45% N,

13.30% N

12.32% S;

11.93% S.

NMR ^^^ ΓΐυίοΌ:

= 75 Hz), 1.46 (s, 6H), 4.48 (doublet of triplets, 1H,

1.44 (d, 3H,

J = 75, 5.5 Hz), 5.34 (d, 1H, J = 5.5), 6.96 ppm (s, 1H)

Example 1 116

Potassium salt (3S-TREN) -3- [[(2-Arino-aj-4-yl) oxotcttyl] 1minn] - ^4-oxo -metyУi2 -'- azetieinsulfonové acid

To a solution of 1.85 g of diphenyl HosHnyl. chloride in 15 ml of dry diretylfomIaridu cooled in a cooling bath composed of methanol in dem ^ No - ¹ 5 ° C T ^≥ - ²⁰ ° C, ^{2.14 g} ρΗ.ά SOH ^(2-thiazol-4 atino- yl) ^ gУy After stirring for half an hour, a solution of 1.08 g of (3 - (-) - 1 -) - 3-8 - (-) - 4-ethyl-4-oxo-1-azttedil-3-nitrile is added to a cold solution of mixed t-tyridide. Kyseliny) Acetic acid (1.92 ml) in triplicate in 5 ml of dry dimethylformamide and the reaction mixture was stirred at 5 ° C for ² hours. Evaporate in vacuo, dark-colored residue is r-swollen in water and mixed with nt column with 200 ml of Dowex 50 X 2 - ДО (K ⁺ - cycle). ^ oupec in m ^ ^{y <weighing} water ^and the PRICE odďrají fractions of 15 ml · ei Fractions 13 to 27 gave 3.37 g of crude product which was chroιmto ge1iuíe-nt column prystyřice 200 ml H? -20, using water as its reagent.

Fractions of 15 AD were removed. Each product is contained in fractions 18 and 26.

Evaporation of water in vacuo afforded the title compound as an aroffic powder.

Analysis for (372.42) calculated 29.02% C 2.44 ·% H 15.04 »K 17.22% S 10.50% K;

found: 28.87% C 2.62% H 14.85% N 15.09% S 10.8% -1% K.

Example 1 ad 117

[3 ^S (R *)] -3-f [[(Eminoacetyl) phenylacetyl] -eino] -2-oxo-1-azetidirwulfonic acid trifluoroacetate salt (1: 1)

Removal of the temple groups from potassium aol [3S (R)] - 3 - [[[[C 1 H ((4-oxo-phenyl) -methoxy] -carbonyl]] amino] -ethyl] -amino] -phenyl] -amino] -22-oxo-azetidine sulfonic acid acid (see Example 97) using trifluoroacetic acid and enol to give the title compound, melting at 165 ° C.

Example 118

Potassium Hall [3S- [3Fa (Z), 4beta]] - [[4-Amino-4-azzolyrl-4-yloxy] -2-oxo] tooylamino} ethyl] amino] --- mlyl-4-oxo 1-Ethylsulfonic acid

The procedure is analogous to that in Example 105 except that the (Z) -2-amino-.alpha.-4-thiazoleacetic acid is (Z-2-emino-4-anael) -1- [[2] (3-Difluoromethoxy) -2-oxoethoxy] imino] -4-thiazoleacetic acid (3S-cif) -3-fluoro-4-lefyl-2-oxo-1-asethylsulfonic acid ee first treated with triethylamine to give the title compound , melting at 155 ei to 160 ° C,

Example 119

Dvojdrese ^ and salt ^[3S [3el ^f e ^(z) 4Ье ^]] - ³ - ^{[[[(kertooyyetoujrHiiinon]} 22afiюu0-tiaez0yl) ^acetyl] jDiiюO --- * lltyl-2-oxo-1-acid azetiSiuellfouové

Removal of the temple groups from the potassium salt of [3S- [3alpha] [beta]] -3 - [[(2R, 4R) -zo-4-thiazolyl) (22-diphenylmethoxy) -2-methoxysoylmino] ethyl] emiLlo] --2lt ^yl - 40xoo1 - sefiSiusifonové acid (see example 118) of trifluoroacetic acid pouHtí fH ^ ^^ ^^ i ^ ee emotional SOU gave the title compound, rozkláddjící at a temperature above 250 ° C.

Example 120

(S) -3 · - [[(2,6-Sichloro-4-pyrazinyl) tic] ethyl] amino] -2-oxo-1-iodophenoic acid, potassium salt

Acylation of the tetrabutylemmonium salt of (S) -3-fluoro-2-oxo-1-8-azinesulfonic acid 4-nitro-tert-butylphenyl [(2,6-Sichloro-4-pyridine) thio] acetic acid a. following potassium p-chlorobutane sulphate treatment afforded the title compound, m.p. 212-214 ° C.

Example 121

[[1-carbonyl-1-uphthylphtooyl] amino] acetyl] amino] -2-oxo-1-iodophenylcarbonic acid sodium salt (1: 2)

From tetrj -but ^y jθloniové salt of [3S (3)) J-3 - ([(2-jmLn --- ttaeo0yУ) l [[2- (SlfeIylftoχ> Silefyl -1,1-2-oooftoχy] Ilino] 8cet ^yl] jmiiu] - 2oxoo1-jzftisinsulfonové acid with pouHtí 'trifuuoroctové of 8 · fuisoll odětěpí.chránncí group. after conversion works! · aqueous sodium hydroxide solution and after dvojeodnou salt vypištění chrómeeoogaaií on a column of HP-20 yield compound EE · In the title, melting from decomposition at 185 ° C.

Severography, n. P., MOST

Price 2,40 Kčs'

Example 122 to 125

Works with analfrickým manner as in Example 15 by oamísto (Z) -2-aninf-alpha- ^[[ee dfο: ^{y ((e} ols líetfοy ^{L) l l} ftf ^{O xy]] íetfοe.]} 14 titzol ^{ρ e k} -acetic y8el ^and the ^EP ouUžja ai ^y přísluSoá kyselioa shall cause the column I ^ i ^ s <^ (^ u ^ Ujica table. Získaaí uvaeané the products in column II of the table.

Table

Example number

I starting material

II product

122

2,6-Diluted o] o-Benzoic acid and Dyaselium salt (S) -3 - [(2,1-edimatphenoyeofeLamino] ‘- 20fOo1-α2-diethylsulfooic acid, melting at 180 ° C

123 draseHá ^UL -3 ((Ζ)] - 2- [[^ artooM (Z) -2-aíinOf1afa- [[4 · ^! ^^ !! · íetfзοe) -4-oοfeuto: χe] iíinOf1-1tiazol- N-azoles 1) [[4-difluoro-lithoyl] -41-phosphonoacetic acid and butoxy] amino-4-oxo] acetyl] amino] -2-oxo-1-azetide-4-fluorophosphoric acid, melting with decomposition at 125 to 130 ° C

² 124 - - - ^{(FAO s} Leah fχy ^t ^ ^^ Arto amio] methyl] benzoic acid ^and tyselioa

125 alpha ^{- [} [5 ^{- (-) - [} 2- ⁽⁴ -iodo-1- ( ¹ -piperidinyl) pyrido [2,3-eepyimidin-6-yl] carbooyl] amino) benzeneacetic acid and erataloate salt (S), 12-fX0f1 - [[22 [[[(1 ^^^ feoylmetoxy] amino] methyl] · e nzofe] amino] - ¹ -azetidinyl su ^ ^ ^ OOC Icyeehoy ^melting of extended and ^{kl d} u at 2? 5 ° C ^d гatelo ^and salt ^(3S) -3- ^{[[[[[1 H} H ^ED УfO ^y - ² - (1-y 4-1frí -piperazin ziorl) -pyrido 2,3-d] pyrimidio ^ ^-yl] oo r ^{b y 1]} ^ e Loo] feitylece ^t ^ y ^{l l]} aIaino] -2-1fxοo ¹ -azatid ^O n8U ^{1f r} kyselioy -ones of melting. dec 265-270 ° C

See Example 126

DVO ^ ^ a peat salt ^(traos, Z) -3- [t ^{(2-aíioOf4-thiazolyl] yl) [(l s} -kвeboο - ^- -íaty e ^{and f i} oзχ iπLiΩo] acetyl] amio] -4-θtyl- 2-oo-11 · azetideO8u1foΩovr kyselioy

A) Dvojdyaseloá salt (traoSjZ) -3- [[(4--aaíiof tazfoeyl (11d-1-daOenílaeOοeykarefneL íeayeetf ^{χe) and} íiof] acetyl] amaoo] 4 - ethyl ² -oοo- ¹ -azat ^e d ^About n8U ^1f ones by ^é tyseiaoy

0.55 g of (trans) -3-alio-4-atel-2fOOf-1-azetedotoluene acid and 335 mg of aria were dissolved in 50 ml of dry ooramic amine and initially 450 mg was added to the solution at 0 ° C. íydroзχbeaozOriazolu and then 0.69 g eicekloheχelkarbfdiiíidu ♦ game ^{Z b} and ^p o ^r Settn ctíhod ester a ^O! Chen in the temperature 0 ° C and evacuated tank к pevoiému residue was added 25 ml of dry acetone. The mixture was filtered and to the filtrate was first added 0.94 g of potassium parfluorosulfonate and then 100 ml of ether. After jednohodlnovém stáoí at 0 ° C, the product pevoý] ^d e1ltruja, prornyje with ether and under vacuum.

1.58 g of the indicated compound are obtained.

B) DvojdyM ^ Oe salt (traos, Z) -3 - [[(2-eíioOf1 ^{also] -yl)} ^ - ^ ^1-methyl rtoix- tonnes) ^and líloofaae y ^el amino J4 ^and e-yl-2-oxo- 1-Al ^and edulphonic acid

244146. 42

To a suspension of 1.31 g of the (tran8, Z) -3 - [[(2-amino-4-thesolyl)] - (1-diphenylmethoxycarbiol-1-ethyl-ethyl) amino] acatyl] azino-4-ethyl-1-oxo-oxalate salt. azetidiosulfooic acid in 10 µl znisol is added at 10 ° C to -15 ° C during 10 µm of 5 µl Orifluoroacylic acid. After a two hour rinsing at -10 ° C, a clear roolok is obtained, to which 80 µl of dry ether is added at -30 ° C. The precipitate formed is stirred, stirred with 5 µl of water, the pH is adjusted to 5.5 with 1 N potassium hydroxide at a temperature of 0 ° C, and the mixture is filtered to remove unreacted starting naaleial. The filtrate was purified on ad80iben HP-40 using water as the eluent. thioflisation yielded 185 ng of the title compound melting at about 160 ° C.

Example 127

CCS (Z) Potassium Salt - [([(24zminol-4-isol-1-yl)] ((44-cydrooy-4-oo: obuooy Н 1 о] о] о]] о о о о))

Removal of the potassium group with [3 S (Z)] - 3 - [[(24-zino-4-thiazolyl) [[4- (di-4-phenylmethyl) -4,4-benzo [b] oxo] anino]] thiol-1-carboxylic acid (vio) EXAMPLE 12310 Using a difluoroacetic acid and anisole, the title compound is obtained, which is above 200 ° C.

EXAMPLE 128 (S) -3 - [[4- (8-Methoxy-ethoxy) -benzyl] -4-p-4-azetidiosulfonic acid in the form of the external salt

Removal of the potassium salt group (n) 44t · oo: α3- [42 - [[[((III-methylpoly) kaquinol] erano] neyl] benzoyl] ara] n 4] Theodiophosphoric acid acidified the use of hydrogen gas, palladium on the union and hydrochloric acid, to give the title compound, mp 162-165 ° C.

Example 129

Potassium salt of (S) 43 - [[] (24 (4-piperidin-1-yl-4-hydrooylpyrido [2,3-d] pyridin-6-yl) -carbonyl-isoquinoline-4-oxo-isoelidiol) Sulfonic acid

The tert-butylanonium salt (S) 43t-Ethyl-2-oxo-14-azolidiosulphonic acid is reacted with 2- (4-chloro-14β-piperidinol) -5-thioyl-6-f (4-nitro-pyrrolo) kequinoline pyridine (2,3-dlpyrrolidine). the product is then treated with potassium perfluorobenzenesulfate in methylene chloride to give the title compound melting at 290 ° C.

Example 1 a d 130

Potassium potassium □ S-threo-4-alpha-K-44-nely4-4o0l01lsluf0lzaz-aeetiOnye) eno] kigbolll] beozenoic acid (3S-Oians) t-3-amino-4-neolol-2-oxo · azetLdinsulfonic acid -keirbooz ^ 1) was zoecoAlllchlorid a. The resulting prodlet is treated with potassium bisulfate and potassium difluorobenzene sulphonate. The title compound is obtained, melting and flashing at 147 ° C.

, Example 1 a.d · 131. Potassium salt [3 (- [3alpha (Z), 4bela]] - 3 [[[((4aa-4'-4-methyl)] (ello:] Linill) ace0ll] amioo] -44Clclokezorl-240oo-14azoidiouulonic acids

0.45 g of (3S-Oiana) 434-amino-4-cycloloholyl-2-oxo-18-zetyl-diphenyl cone was rotated in 30 ml of dry dimethylformamide and 0.12 g of triellamine. Once the mixture becomes a clear solution with stirring, 0.2 g of (Z) -thio-11- (isthoylino) -4-thiazoloethic acid, 0.16 g of hanczphthiisole and 0.42 g of dihydrochloride are added. 1 ^ 0012 ^^. The reaction mixture was stirred at room temperature for 48 hours, then the precipitated urea was removed and the solvent was removed in vacuo. Dissolve the residue in 10 ml of acetone and add 0.41 g of potassium perllufrbutaosullonate to the solution. After addition of 50 ml of ether, the title compound is dried, which is decanted and subjected to an elution with the HP-20 idsorbent column using a 9: 1 mixture of water and acetone as eluent. To afford (after lyophilization) 0.36 g of product ^f T ^ ai lftě mp 200 205 ° C.

P peak) and 11 32 ^D VOF ^and гaselo ^A 'salt [3S- PAWIA ^^ BST ¹ 3- ^[(2- and Ln ^ ^m ^^ ^- ^^ i ^ ⁱ ^ ez L ^ ^l ^ l ^l) ^ ^ ox ^ -kix -meSylsto: ⁰¹⁾ iminf] 1eetyl] 1iioo] -4-e1k1fhsDorl --- FOF-1-1ZstidÍn8U1fonové acid

A) The potassium salt of ^[3c - ^[3 Al ¹ 1 ^(Z). 4 ^b ete ^1] - ³ - ^χ [ ^'(- 1aπliíf-4-t ¹ azolyl ^{y1 (d} L1 ^s0 1n ^and latfoз ¹ k1r ^b o ⁿ 1-1-metylstfoy) iminof1eetyl] ^1iioof-4-yl e1klohso --- ooo 1-izstidnnsulfonové acid

0.2 g (3ič-tr1ot) ^-3-1miof-4-r eyklfheзo 11 ---- Exo 1-1zstidnn8Ulfonové acid under stirring in 30 ml rozpuutí dimethylamide and 0.09 g treel-ethylamine. 0.30 g of (Z-t-biphenyl-alfta [(((1-dSbiphenyl-1-methylphenylcyclobenzoyl-1-methylstfol)) iminoph-4-18Zoloetic acid) and 0.33 g of dicyclohexylcarbodiimide are added and stirring is continued at room temperature for 12 hours. . Vysráiená oddlUzuje urea and the mother liquor is odppří to dryness. the oily residue was rfzpustí in 5 ml of acetone, to the solution was added 0.3 g of potassium peгlluorbut1otullfnátu under stirring poured ^d ^ f ¹⁰⁰ mL of ether. Vyssáži.se potassium salt [^ - [. ^ ^^ Ahe LFL ^ ^1] - 3- [[^ ^-iminn-f-011 Uoiol -) Ιι ^ ^Η-1-enyl ..metfo Arhon ¹ -L ¹ -melylsto HMI n ^ ^f] Г acet ^y ^^ ^ ооЦ -e1k1ohs: ιofl --- oof-1-1zstidnnвй1fínoVé acid which oddllt ^ her. Výtěiek amounts to 0.61 g.

B) ^ Dvofdrissl salt [3S- [3alli ^(Z) ^ ^ Bete -3- ^{[((4-2-1iinOf i1zolyl)} ^ -n-card-MES-ethoxyethyl ^0! · I ^ MINFO] e <^ 1-Amino-4-cyclohexyl-2-oxo-1-sulfonyl sulfonic acid

0.61 g of potassium sofi 1 ^(d -lSfeiylmetfoy) ^ιγ6οπ ο 1- -ieSylsto ^{1: oyy} Loo ^m i] with no ¢ ^{m f} etylIs ^-4-yl klohβJ c ^of r ¹ - ^- -ooo-! -1zatid ⁿ nзu ^1f sulfonic tyselin ¹ was sus-Nuclease Buffer in 6 ml miso! ^ Suspension was cooled to-5 ° C and stirring was moats ^thereto 5 ml trliufOfoetové acid. Shon said Jeet udriujs temperature for 1 hour, to a NACA ° .žl -3 to ⁰ ° ^{C and} the mixture was coarsely ground ^{to 100} ml dry ether tic r ^{1 t} chlofS ^to tsplfti -I did not exceed ⁰ ° C. The precipitated compound is filtered and the chromium is effected on the HP-20 piriethyl ether. of water and acetone (9: 1) as eluent. Obtained is ^{0, 1} 3 ^g s.oučenin uva title Christians ^d (f ^p ^ tyffilizaci rozěěu melting at ¹¹⁰ and ¹²⁰ ° C.

Example 133

Potassium Siula ^ -UoI ^{14 4beta)]} -4-e ^ lfhen ^01-3 ^ ^[[[[3- -tti ^ ^ ^ triphenylmethyl amino] -З-ooo- -imii1zfli ^{d 1} from ¹ l] ¹ rb ^{f) 1} i] amino] ^ nyliest ^11] imino ^j - ^ Ooh-izstidtasuKonové tyselin ¹

0.1 g of (3S-tr 10 -4 -3- 100-4-1) 1-oxo-1- (2-phenoxy) -isulfonic acid is mixed with 30 ml of dry filmic acid and 0.05 g of trSel with stirring. -lamine. Added 0 ¹⁴ g ^([[[(1 pellet, ^y --1Uιг80 ^1SO) 1minof- ^- -fxo- ^{m 1} -i. ^{I i} 1zoli ^oyl] keг ooyly ^{b] fl} enyloctfvé imino acid, 0.06 g H1 ^d The solution was stirred at room temperature for 5 days, the solvent was removed in vacuo, the residue dissolved in 10 ml of acetone, and the precipitated urea was separated by stirring 0.1 g of the mother liquor. The potassium bromide isoborosulphosulphate was diluted with 50 ml of ether and the mixture was separated by filtration and purified on a HP-20 mixture of water and acetone (9: 1) as eluent to give 0.1 g of the product. of decomposition at 195 to 200 ° C.

AND

Example 134

[3S- [3alpha (R *), 4beta]] - 4-Cyclohexyl-3 - [[3- (4-ethyl-2,3-dioxo-1-piperazinyl) -1,3-dioxo-2-] potassium salt phenylpropyl] amino] -2-oxo-1-azetidine sulfonic acid

OJ g of (3S-trene) -3-amino-4-cyclohexyl-2-oxo-1-azetidine sulfonic acid is dissolved in 30 ml of dimethylformamide and 0.5 g of triethylamine under stirring, and (R) -alpha- [f ( 4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] benzeneacetic acid, 0.06 g of hydroxybeniotriaBOl and 0.17 g of dicyclohexylkerbodiimide, were stirred at room temperature for about 16 hours. The solvent is distilled off in vacuo and the oily residue is dissolved in 10 ml of acetone. The precipitated urea is filtered off, the mother liquor is stirred with 0.15 g of potassium perfluorobutane sulphonate and diluted with 50 ml of ether. elution with water / acetone (9: 1) as the eluent. lyophilization gave 0.15 g of the title compound, m.p. 175-180 ° C.

Example 135

(Trans, Z) -3 - [[(2-Amino-4-tlazolyl) (methoxyimino) acetyl] amind] -4-ethyl-2-oxo-1-azetidine sulfonic acid potassium salt

The procedure is analogous to that described in Part A) of Example 126 except that ee (Z) -2-amino-alpha- (methoxyimino) -4-thiazole acetic acid is used as the starting material instead of (Z) -2-amino- alpha - [(1-Diphenylmethoxycarbonyl-1-methylethoxy} imino) -4-thiazoleacetic acid. The title compound melted with decomposition at 190 ° C.

Example 36

(+) - (trans) -2-oxo-4-phenyl-3 - [(phenylacetyl) amino] -1-azetidine sulfonic acid potassium salt

A) (♦) - (trans) -2-oxo-4-phenyl-3 - [(phenylacetylamino) -1-azetidine sulfonic acid tetrabutylammonium salt

To a solution of 52 mg of N-hydroxybenzotriazole monohydrate and 46 mg of phenylacetic acid in 0.3 ml of dimethylformamide under argon at 0 ° C was added 70 mg of solid dicyclohexylcarbodiimide. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 hour. Dilution with an additional 0.3 ml of dimethylformamide is first added with 75 mg of solid (*) - (trans) -3-amino-2-oxo-4-phenyl-1-azetidine sulfonic acid and then dropwise with 0.05 ml of triethylamine. After stirring at room temperature for 23 hours, it was filtered and the filter cake was washed with dimethylformamide. The filtrate was added to 20 ml of 0.5 M potassium dihydrogen phosphate solution (pH 4.5), washed three times with 8 ml of ethyl acetate each time (the extract was discarded) and thereto was added 105 mg (0.31 mmol) of tetrabutylammonium hydrogen sulfate. The resulting mixture is extracted three times with 15 ml of dichloromethane each time, the extracts are washed twice with 15 ml each of 10% sodium chloride solution and 10 ml of saturated sodium chloride solution, and dried over sodium sulfate after filtration, concentration under vacuum and heating under high vacuum to 32 °. C, 165 mg of oily material was obtained, containing about 40% of the desired compound and 60% of dimethylformamide.

B) Potassium salt of 1 (+) - (trans) -2-oxo-4-phenyl-3 - [(phenylacetyl) amino] -1-azetidine sulfonic acid

To a solution of tetrebutylammonium salt of (+) - (trans-2-oxo-4-phenyl-3 - [(phenylacetyl) amino] -1-azetidine sulfonic acid in 1.5 ml of acetone was added 41 mg (0.121 mmol) of potassium perfluorobutone sulfonate. Dilution with 12 ml of ether yields a glassy material which, after trituration with ether, gives 43 mg of a solid containing about 20% impurity containing tetrabutylammonium residue. This solid is dissolved in 50 $ aqueous acetone and passed through a 1 ml column of Dowex 50W-X2 ion exchanger. (K * - cycle).

After evaporation of the solvent, a solid is obtained which is washed with acetone and hexane, ° C and dried under high vacuum at ⁶⁰ 15 mg.

The yield of the title compound is

Analysis calculated for C ^ XH ^^NgO ^S: C, 23 ° C

50.44% C

3.80% H

4.20% H

7,03%

7,01 Draw

8.05% N

7.59% S

9.81% K;

9.40% K.

He said d 137

^And potassium salt of (+) - (trans, Z) -3- [[^ -amino-E- ^ tlazolyl) (rneoo imd.nojacetyljaminoo ^ ^ -oxo-feny1-1 -azetidnnsufoonové acid

To a solution of 52 mg of N-tydrooylbenzole zole hydrate and 69 ml of Z1-2-amino-tert- (methoxthiool-4-thiozoacetic acid in 0.3 ml of dimethyfoomiamide at 70 DEG C. under argon was added 70 mg of solid ethoxyclohexyltriodiimine. The mixture was stirred for 1 hour, then 75 mg of solid + 1-thionyl-2-oxo-2-oxo-4-phenyl-1-8-phenylthio-tufonic acid was added, followed by the dropwise addition of 0.05 ml of triethylamine. . The reaction mixture was ^stirred 23 hours at místnooU ^s, pa ^as from it in a high vacuum ^p s at ³⁰ ° ^C odppří tometylfoirapmid residue was triuuruje and 2 mL of acetone and filtered. Filter cake twice with 3 ml of acetone each and 86 mg of aerofluoromethyl sulfoate are added to the filtrate. Dilution with 10 ml of ether precipitates a patty-like material which, after trituration with n-hexane and drying, yields mg of the title compound.

is washed with potassium. Proim acetoAnalysis: for C5 ^I ^ 1 ^^ 5 ^O 6 ^S ^ 2 ' ^K calculated found

40.26 X.C 38.60XC

316 X H

319 XH

15.65 X N

15107 X N

14.33 XS 8.74% K;

13.87 X S 7.5% K.

He said d 138

(+) - (cis, Z) -3 - [[(2-Amino-4-thiazolyl) mmetotylamino] acetyl] amino] -2-oxo-4- (2-fentyl-ethoxy) -1H-azetidine-sulfonic acid potassium salt

To a solution of 68 mg of 2-amino-β-alpha - ((methoxyl) -4-thiazoleacetic acid and 51 mg of N, N, N, N, N, N, N, N, N, N, N 69 mg of dicycloheztylcarbodiimide was added in 2 ml of dimethyl amide, and the resulting mixture was stirred under stirring at room temperature for 30 minutes and 90 mg of cis-2-carboxylic acid were added. r- (2-Esterolentyl) -1-oetidenesulfonic acid and 34 mg of triethylamine, and the mixture was stirred under nitrogen for 20 hours, the resulting suspension was evaporated in vacuo, the residue triturated with 10 ml of acetone, filtered and the filtrate added. 113 mg of potassium perfluorobutanesulfonate After dilution with 30 ml of ether and filtration, 169 kg of solid product are obtained, which is dissolved in a small volume of about 10X acetone in water.

a. Apply 34 ml of HP-20 resin to the column. The column is eluted with 150 ml of water and then with acetone in water 10X while odeeííraí et al ^ i ⁸ odppří solvent, as a solid.

fractions of 15 m. Fractions 16 to 19 of 110 mg of the title compound to yield

Analysis: calculated for C, ₇ h, ₍ ? ₆ n ₅ s ₂ kh ₂ o)

40.23 X C

40.03 X C

3.50 X H

3.05 X H

13.80 X N 13.61 X N.

12.6 * 3XS

12,31 X S

7.7? 0 X K;

7,56 X K.

PHkl ad 139

Potassium salt of (C 15) -3 - [[(2-amino-44-isolyl) -1 [[1- (diphenylmethoxycarbonyl ^, t) -1-methylethyl] iminooacetyl] aminoo-4- (methoxycarbooyl) -2-oxo-1-azetidenesulfonic acid

To a solution of 34 mg of N-lldгoml®eiziгiLlzol lydrátu and 101 mg of Z-eadni-o-le-fflL ^ difenrl ^1eel Xlkar ^{0 O)} N ^{I) -1} · ^m etlle t ¹ xy] ίιΐη] - ⁴ - ^ ' ^La zl ^L1 ^ C ^ Шé tyselio ¹ in ^0.5 ml iaθt ^{d l} l ss ¹ omlαaidu added - 45 mg of solid dicykllleχllkerbldiiaids, ss mixture under argon for 45 min p ^ i aístnooSi temperature whereupon ss Oi added was 45 mg 0.03 ml of ereely18aios was added dropwise thereto, and the mixture was stirred at room temperature for about 16 hours, then the diatytyllalaid was evaporated in a high vacuum. at 30 DEG C., the solution is trduurated with acetone and 67 mg of potassium perfluorobutyl sulphate are added to the liquid oid to form a solid malesral which, after ether and drying in vacuo, yields 93 mg of the title compound.

Example - 140

DVO jcdraselrá salt ^(о1у) - ³ - ^{[((2-a and} .nOl ^- 4 ^- i8zo ^{0ll) [(1-carboxy!} -Ae the year: ¹⁾ L ^ ^ CLI] | l acetate ^i] em. ^amino] -4- [i ^{l e} Ooy ksbolo ^nl J ^- -010 ^- -eze ^t id ⁱ neufonové tysel ¹ ^ ^{K -} toisetaé reindeer suspension of ^(cis) -3 - [[(2-m ^{i no-4-one} t COO ^l1 l) ^{l [(DLD e} 0ln ^and lee0o: ^{L n} k1r011 ^II-j-1 aetýletox iainoj acetyl] αιΐο ^ -4- ^{(aeeoo χl} kαbo ¹ R) -2-oxo-> 1-1zetidinsslOon (> Vé tyselio ¹ in ^0.4 ml mlsotu Zi ss aíchfaí under dinitrogen ^p s TEPO -Ί2 C ^0.9 al ^РМГ г eгffUlrlocOové acids ^{1 -} ochlizeo ^Star ni - ¹⁰ ° C. ^1.5 TODI ^{P 1} s ^p s ^d Aji 4 ml ETAR and 2 ml of hexane Equals ^{SUS p} Enzo is ^{Aichi 15} min s ^ P ^ ^{1 to 10} ° C, and ^P and ^{for 15} minutes s TEPO lístnoS) NICs ^SS solid oddtředí and graduating DC e4erea. This aeltetál The suspension is suspended in 0.5 ml of cold water, the pH of the suspension is adjusted to pH 6 with 1 H potassium hydroxide, and the mixture of DC oeoese 01 Column 30 al of HP-20AO resin is eluted with water. iceeeliterl mixture was added 1 ss odpplř again. This procedure is repeated twice es. 30 mg of the title compound are obtained.

Anal. Calcd. For R ₄ R ₅ ^{1 1} ½ ° ⁹ ¾ 31, 1 5 96 0 2.81% H 12.98% N;

found 29.08% C 3.03% H 12.19% N ..

Example 141 '

Driselo ^and salt (3S- [331 ^f i (Z) ^ eti]) -3- ([^ ^ -iainoo- ti.azol.yl) ^(x aeto3 Riain) acetyl] 181 ^) - 4-etirlfl 21χxo- 1iθzetddisuul0incwé acids'

To a flask of 10 ml were weighed 100 mg of (Z) -2-1aino-> elF1A-metoзχlmini) - ⁴ 4-i1zoloctové acid, 85 mg of N-aonotylrátu lldro2χboeiolei1Zlls 1113 mg diclkL.lleχylker01diiaids. The flask was purged with nitrogen, cooled in ice-water, added 0.6 ml of diastyl to the eye, stirred for 10 minutes, then added an additional 0.6 ml of water to the eye. After the addition of 95 mg of solid (S) -tenzenes-3-eaio-4-ethyl-210xl-1-zetidine-diolulic acid together with 1.0 µl of dimethylflamlamide 15 µl of toluene, the cooling bath was removed with stirring for 22 hours. After addition of 3 ml of acetone, the solids were filtered off with a further 4 ml of acetone. The solvents were evaporated under vacuum, the remainder span in 5 ml of methanol 1 in this solution was sparged with 162 mg of potassium pyrosulphosulfloate. Upon standing, a solid product precipitates from the resulting solution which is isolated by centrifugation. There were obtained 68 mg of compound ¹ shall cause melting Razvi ^ oid ² 30 ° C.

Example 142

DrisSLná salt of (S) -3 - ((. ^{((2,5-dlclLorfeoyl) EIO] icetyl]} IAIO] ^-2-one lXl- -1zetld ^and nsul ¹ onivé acid

100 mg of 3-1ainO12-α1-l-zetidine sulfonic acid is dissolved in 2 [mu] l of dry diethyl ether. To the solution was added 123 mg of 2,5-riclllrfeiylt01oclové acid (0.602 mmHg, 81 mg of N-lldгoэχrlosizlгr0Zol glycols (LRRT 1124 mg riclkllle: χ ^ ker01ditaMu 1 aoěs ss AICT therein tearing ^{p 1 p} 2 TODI Rd splashing «s tnuta 1? ^1k 2 ^{г щ} wallpaper at ⁵ ° C.

Rozpcujšё ^d lo st evaporated in vacuo, the residue taken up in water, the solution zliltiujt st through křemeeinu and the filtrate ttyltcttátem rubs. The aqueous layer was treated with dichloromethane, and 612 mg of t-butylbutyl-d-hp (drug) was added, the pH of the solution was raised to pH 3 with a 1N potassium hydroxide solution, and the mixture was extracted three times with dichloromethane. The oily residue was dissolved in acetone and added with a solution of 612 mg of potassium trifluorobutyrate succinate in acetone, precipitating the solid material. After addition of a small amount of ether, the solid material was filtered and filtered. The mixture was washed with acetone and dried to give 206 mg of a powdered product.

Anal. Calcd for C 11 H 8 N 8 O 5 S 9 ClCl K 31.32 * found. 27.90 * C

H, 6.62; N, 2.14

2.11 * H 5.84 * N

16.75% 01;

18.04% CL.

Example 143

(35-trans) -3 - ([[(2,5-Dichloroltol) eia] acetyl] amino] -4-methyl-4-Oko-J-azetidine diphosphonic acid potassium salt

250 mg of 33S-trans-3-amino-4-methyl-2-axo-1-tetridine sulfonic acid are dissolved in 2 m of dimethylfamiamide containing 193 .mu.l of tree-phytamine and 285 mg of 2,5-dichloro-phenoxyacetic acid, 213 mg of N hydrate are added. -UydroaχУetnoOtitzol and 287 mg Ut: ιqrlУαrbuditmidu. The mixture was stirred at room temperature for about 16 hours, then filtered and the solvent was evaporated in vacuo. The residue is taken up in water, the solution is filtered, the filtrate is washed with CH 2 Cl 2, overlaid with dichloromethane and 4.2 mmol of etherabutyl mono-tetrahydrate are added. The mixture is extracted three times with dichloromethane. the combined extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. The oily residue (920 mg) was dissolved in acetone, and 946 mg of potassium perlluoroantiluununate dissolved in acetone was added. A precipitate slowly formed which was collected, washed twice with ether, and dried over a precipitate. 306 mg of powdered powder are obtained, which is chromatographed on a column of 100 m HP-20 resin, using 20% acetic acid and 80% water as the reagent, to give the desired product which crystallizes from aqueous methanol by evaporation. Trituration of the residue with acetone gave 233 mg of a powdery product melting at ²⁰ ° to 213 ° C.

Aralysis: for C,95 gH ^ ^N ^O ^ClgSgK calculated 33.95 5 0 2.54% H6.1.1C * N 16.21 * 0.11 14.6b% S;

found 32.91% C 2.60% H 6.42% N 16.50% Cl 13.77% S.

Peaks 144 to 145

Using the procedure described in Example 105, substituting (3S-cit) -3-amino-4-acetyl-2-oxo-1'-trifluoromethyl-3-amino-3-amino-4-ethyl-2-oxo-2-carboxylic acid. 1-tert-C18-ufonic acid and (Z) -2-olefinine-1-methyl-4-indole-4-induculoic acid by the acid listed in column I of the following overview give the compounds in column II of this overview.

Example #

II ^(R) - ^{[(taioccuιx>} utce ^cl) -θm ⁱ n ^u] <4- ^Uyd ro ^χř: tnyl ^l ^ CI ^ tyseHca Dra LNA ^UL [зS- [3θll ^(R *) ⁷ 4betaa] -3 ~

- ^{[([(E m} .noooxute ^EEY.) Α ^m .oo.] U-tytooxy-phenyl-acetyl] amino] -methyl ^ ^ ^ -cxo -tzetidCnsufocnové acid

144 i

145 (R) -C (Aminooxoxyl) erinoOfelnr1-potassium salt of [3S- [3,111i (R *), Abeta] acetic acid -3 - [[[(ωmixxxxθcettl) amLOxχfetetacetyl] - amino] -4- [1- (2-methyl) -butyl] -4- (2,4-dimethoxy) -4- [eta] &lt; 4 &gt;

m.p. 187 DEG C. decomposes at 187 DEG C. with decomposition

Example 146 /

Draeelná centuries [ЗS (R ^*)) -34ϊ [(E ((ioxxxoacetyl) lmioo] (4-tydroз ^of fУle ⁿ t) θcet ^yl] вmOno] ^ -ONO L-lzetidiI'½blOonxaé acid

The procedure was carried out in a small-scale manner as in Example 28, with the difference that it was. (Z) -2-pyrrolidine-11a - [[2χ (longlinethoxy) -1,1-dimethyl-2-oxoxetoyl] irino-4-thiolsyl] oxoacetic acid will give the indicated (R) - ['(amino) oxooxyl] lm.LloX (4-Hydroxyphenyl) acetic acid to give the title compound, melting with decomposition at 128 ° C.

lad 147

Potassium salt of [3S (rO)] - 3 - [((2-chloro-4'-xyl)) [[[Z-P-bromoyl-ethyl] -one] -2-xox-1-imidazolidinyl] ketone 1] sriox] lcattl] lminine]

The procedure is analogous to that in Example 10 except that the ene is replaced by (R) -2-amino-amino [[[3 - [(2-fluorinomethyl-amino) -2-oxo-1-imidazol-1-yl] carbonyl]] amino] - 4-1 (isoxexyxic acid) to give the title compound, melting above 250 ° C.

Claims (1)

Process for the preparation of beta-acetic antibiotics of the formula R _R NH-CH C-R-j N-SOjM * in which R ₁ is hydrogen or an acyl radical selected from the group consisting of (a) aliphatic radicals of formula ⁰ R5-C in which R 8 represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkenyl group, a cycloalkenyl group, a cyclohexyl group or an alkyl or alkenyl group having from one to five substituents selected from the group consisting of halogen, amino, mercapto, amino, mercapto, alkyl, alkenyl, cycloalkenyl, cycloalkenyl, cycloalkenyl. (b) aromatic residues of the formula or wherein n ^{Η 8} (c) has a value of 0> 2 or 3, independently of one another; modes of hydrogen, halogen, hydroxy, nitro, amino, cyano, trifUoomlntyOovos, alkyl having 1 i 4 alkyl, alУoxχtУupiou 1 EI-C4alkoxy or аminumeny ^χ uvuu group and an amino group, hydruxyluvou group Уarboxyluvos group in forms of SOD, carboxyl nstnrifУUvvenus farms for logically přijatenncu ctaránicí ester group fuΣmχloxytkupiou, sulfo in the form of SOD in the form tulfoaminotkupins SOD αzldotkupios, halogen, tydrazlootУupiou, αlkχl4ydrezinotkspios, ny ^ ^^ r ^ imskupinu or [tedylUo) ^t loxomeny ^χj thiol ^k with ^{p 10} , heteroatomic radicals of the formula II. ° ° - ⁽ β ^) _n -C1 Я, _O -CH-C ¹⁰ ] 9 9 C Rq = O-CR-CO II R ₀ -S-CR-C0 and R ₀ - <- -. or n is 1, 2 or 3, represents an amine group, a hydroxyl group, a kerbuxyl group in the form of soH, a carboxyl group esterified with an ester-anakologically ingested group, -OR 4 -oxy, a sulfo group in the form of soH, flfoanioo Kfpinf in the form of soH, ezidoscopic, atom. halogeno, hydrazino group, &quot; alkyltydrazino &quot;, phenylaminohydrazino or [(allyl (1) thioxlienyl) cycloalkyl] and a five-, six-, or seven-membered heterocyclic aromatic ring containing one, two, three or four nitrogen atoms, d) substituted with 1 to 5 substituents selected from the group consisting of halogen atoms, hydroxyl, oitro, cyano, C1-4 alkyl, C1-C4 alkyl and C1-C4 alkoxy groups; either of the groups ^Rg , Ra ^and _{Q are each} independently hydrogen or halogen, hydroxylvof, nitro, amino, cyanopheria, C1-4alkyl, C1-4alkyl, C1-4alkyloxy carbon or am (0-oenylooof group). oebo. zoameoá p ^ ETB - ěeeti- oebo membered heterocyclic ring lЪ8S-hfící one, two, three, four oebo nitrogen, oxygen and sulfur, optionally substituted as indicated in the remainder of q, and 'l ^R ₂ represents a group -N-CH- R1, -NH-] - R1, alkylcarbooylamino, alkyl, or L-alkyl substituted by one to five substituents selected from the group consisting of halogen atoms, cyano, oitro, amino, and ercapto, (e) radicals of the formula —OR j Where> 11 represents a group of the formula wherein Rg, Ry and Rq are each independently hydrogen or halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy or aminomethyl, or represents * five - or six membered heterocyclic ring containing one, two, three or four nitrogen atoms, oxygen and sulfur, optionally substituted as described above for the radical R _10, and "13 represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkylaminocarbonyl group, a group of the formula -NH-Rp or an alkyl group substituted with one to five substituents selected from the group consisting of halogen atoms, cyano, nitro, amino, mercapto, alkylthio, radicals; R 1> carboxyl, carboxy in salt, amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkylphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl and dialkoxyphosphinyl, (F) remnants of the formula? ? -C-CH-NH-CR ₁₄ in which «11 11 represents a group of the formula wherein Rg, R? and R 8 are each independently hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or aminomethyl, or is five a six- or seven-membered heterocyclic ring containing one, two, three or four nitrogen, oxygen and sulfur atoms, optionally substituted as indicated for the radical Rq, and tolerates a group of the formula wherein n is 0, 1, 2 or 3, furthermore is amino, alkylamino, (cyanalkyl) amino, anidoacupine, alkylanido, (cyanaltylenidene), formula and (g) residues in which R 1 represents a group in the formula where R 8, R 8 and R 8 are each independently hydrogen, halogen, hydroxyl, nitro, nitro, eaino, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or aminomethyl, or represents a five-, six-, or seven-membered heterocyclic ring containing one, two, three or four atoms of nitrogen, oxygen, sulfur and optionally substituted as indicated for the residue Rq; and H ₁₅ represents a hydrogen atom, an alkylsulfonyl group, an -NaCH-R 6 group, a group -R ₆ , wherein R 8 is hydrogen, alkyl or haloalkyl, or an unsaturated radical R 6, alkyl or alkyl substituted by one to five substituents on one another selected from the group consisting of halogen atoms, cyano, nitro, amino and mercapto; n, 53 244146 wherein, unless stated otherwise, all of the above-mentioned alkyl and alkoxy radicals denote straight-chain or branched radicals having from 1 to 10 carbon atoms, cycloalkyl groups and cycloalkenyl groups of the respective C3-7 carbon atoms and straight or branched chain alkenyl groups groups of 2 to 10 carbon atoms, R and Kd, which may be the same or different, are in each case hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl or phenyl, optionally substituted by one, two or three sub-nitrites n ^ 2 ^ i ^ Each of them is selected from the group consisting of amino, halogen, hydroxy, tri-methyl, C1-C4alkyl and C1-C4alkoxy, or one of R's. and R 1 is hydrogen and the other is C 1 -C 10 alkoxycarbonyl, 1-alkenyl of up to 10 carbon atoms, 1- (1-up) of up to 10 carbon atoms, 2-phenylethenyl or 2-phenylethyl group a M ⁺ represents a hydrogen or a cation salt ^to zbyttu siphon Sehne ^ ^ ^ profess UJC! A compound according to any one of claims 1 to 4, wherein: ^and R 8 R 4 V it has the same meaning as R @ 1 or is an amino functional group, as defined above. and represents a cleavage group such as a minifluorone, a benzermulfonyl or a trifluoromethyl group, chlorine, bromine or iodine, by sulfonation and cyclization, wherein the sulfonation is carried out by reacting the starting material with a sulfur trioxide complex or an equivalent reagent in an organic solvent such as pyridine or a mixture of organic solvents, preferably a mixture of a polar solvent such as dimethyl amide and a halogenated hydrocarbon such as dichloromethane and cyclization is carried out by treatment with a base such as potassium carbonate, whereupon optionally the present amine function cleavage group is cleaved and the resulting product in which Rf is hydrogen is converted to the corresponding prodrug in acylation. the acyl group as defined above, and optionally converting the obtained compound into its salt in a mild fashion of tubercle M.