CS202015B2 - Process for preparing derivatives of cyanacetamide - Google Patents

Abstract

Acid amide derivatives of the general formula (I> <IMAGE> where R<1> is hydrogen or a C1-6 alkyl group and R<2> is hydrogen or an unsubstituted or substituted aromatic or heteroaromatic ring or an unsubstituted or substituted C1-6 alkyl group, or R<1> and R<2> together denote an unsubstituted or substituted alkylene group, R<3> is hydrogen or a readily cleavable esterifying group, such as trialkylsilyl or trichloroethyl, and <IMAGE> and salts of such derivatives are prepared by acylating an amine of the general formula (II) using an ester (III) (x is halogen). <IMAGE>

Description

The present invention provides a process for the preparation of cyanacetamide derivatives.

It is known that penam-3-carboxylic acids, acylated cyanacetic acid derivatives,

3-melyl-ceph-3-em-4-alioic acid and β-acetoxymizyl-ceph-h-γ-4-carboixylic acid derivatives are valuable antibiotics used in therapy. According to known methods, the amine to be acylated is acylated with a carboxylic acid halide substituted in the α-position by cyano or mixed carboxylic acid anhydrides.

According to another known method, a carboxylic acid substituted at the α-position by a cyano group is reacted in the presence of water of a scavenger such as dicyclohexylcarbodiimide with an amine (Swiss Patent Nos. 480,365, 542,236 and 507,292). The known processes have the drawback that the pure end product can only be obtained by chromatographic methods and other technological disadvantages are also caused. The use of acid chloride is difficult because pure acid chloride can only be produced by distillation associated with losses and must be further processed immediately to avoid the risk of polymerization. When using crude acid chloride, such molecules in which other nucleophilic-sensitive groups are present may also not be acylated - even in the case of cephem and penam derivatives, since many side reactions occur. In the mixed anhydrides known from the literature, many by-products are formed during the acylation, so the reaction must be carried out at a lower temperature. Even in such circumstances, the pure end product can only be obtained by chromatographic methods. Methods using water-withdrawing agents are industrially difficult and yields are only 65%. · By-products N-acylureas are formed which are difficult to remove.

According to the invention. the above drawbacks can be overcome

The present invention provides a process for the preparation of cyanacetamide derivatives of the general formula (I)

(I) where they mean

R ^{1 is} hydrogen, (C 1 -C 6) -alkyl,

R 2 is hydrogen, phenyl, thienyl, furyl or pyridyl, optionally substituted with at least one halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, C 1 -C 6 alkylamino . Or 6

R ¹ and R ² together represent an alkylene group having 1 to 4 carbon atoms, optionally substituted by a furyl or phenyl group,

R ' ^{3 is} hydrogen or an easily cleavable, esterification residue, preferably a trialkylsilyl or trichloroethyl residue;

And it means

OF

CH3 \ Z

C Z \

CH3 or

\ .........

CHz

AND

C — CH3

Z or \

CH2

AND.

C — CH2OCOCH3,

Z or. their. salts by acylation of amines of the general formula II ^Η χ ^Ν ~ Ι — A

or a salt thereof, wherein R 3 and A have. . the aforementioned meaning, the essence of which is that. the acylation is carried out with an ester of formula III

X 1 / p / ^x wherein R ¹ , R 2 have the above-mentioned meanings α

X is halogen, preferably chlorine or fluorine, in the presence of a tertiary base, preferably trialkylamines having 1 to 6 carbon atoms in the alkyl radical, preferably. triethylamine or pyridine, or N-methylmorpholine, and in the presence of an aprotic solvent, preferably carbon tetrachloride, dichloromethane, chloroform, dichloroethane or a dipolar solvent, preferably acetonitrile.

The protecting group R 3 of the ester group at the 3 or 4 position is optionally. cleavage and / or optionally release the product from its salt and / or convert it into a salt.

The acylating agent of the formula (III) is preferably a phenylacrylic acid derivative, for example pentachlorophenyl ester of α-cyano- / 3-phenylacrylic acid, or pentachlorophenyl ester of α-cyanophenylacetic acid.

The alkyl group is preferably a straight or branched chain saturated aliphatic hydrocarbon having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.

Aromatic group for R2 is understood to be monocyclic or bicyclic aromatic rings (e.g. phenyl or naphthyl). The heteroaromatic group for R 2 is aromatic from one or more rings consisting of one. or more heteroatoms (nitrogen atom, oxygen atom and / or sulfur atom (for example thlenyl, furyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl etc.). Aromatic or heteroaromatic rings may carry one or more substituents. The substituent may be a halogen atom (e.g. chlorine atom, bromine atom or iodine atom), low alkyl (for example methyl, ethyl), low alkoxy (for example methoxy, ethoxy), haloalkyl (for example trifluoromethyl), amino, substituted amino (for example methylamino, ethylamino, etc.) or nitrite group. Furylalkyl may be, for example, furylmethyl, furylethyl and phenylalkyl is preferably benzyl, β-enylethyl, etc. R 1 and R 2 together form an alkylene group (e.g. C 1 -C 4 alkylene, preferably methylene or ethylene). a group which may optionally have a substituent, for example phenyl, furyl, thienyl or pyridyl can be chlorine, bromine, fluorine or iodine, preferably chlorine or fluorine.

The ester group R 3 may each be in chemistry. penicillin and cephalosporin derivatives are known, easily cleavable. An alkali metal (sodium or potassium) salt, or a salt formed with an organic amine, for example a tri (low) alkylamine (for example, triethylamine), is suitable as a salt of a compound of formula (I). .

Definition of substituents. is always the same in the following sections of the description and will therefore not be repeated. As starting materials, cyanacetic acid pentachlorophenyl ester, α-cyanophenylacetic acid pentachlorophenyl ester or n -cyano-β-phenylacrylic acid pentachlorophenyl ester or pentachlorophenyl ester forming a narrow group of acylating agents of the formula III or the corresponding pentafluorophenyl esters can be used.

The compounds of formula II are preferably used in the form of carboxylic acid salts, preferably sodium, potassium or lithium salts or salts formed with a trialkylamine, for example triethylamine.

The reaction is carried out in the presence of an aprotic solvent. Halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloro, methane can be used for this purpose. Dipolar solvents such as accetoniril and the like are also suitable.

The reaction is carried out in the presence of a tertiary base. A trialkyamine such as triethylamine or a heterocyclic amine such as pyridine or N-methylmorpholine is used.

The active esters used according to the invention are prepared from the corresponding cyanoacetic acid chloride and pentahalophenol or these salts. The acylation reaction generally takes place under mild reaction conditions at 0 to 200 ° C. The product is obtained in good yield, chromatographic purification is not necessary.

The details of the invention can be derived from the following examples:

Chromatographic analysis was performed on a thin layer of silica gel (Gauge F-2.54).

Elution agents:

1. Benzene-ethyl acetate = 2: 1

2. Butanol - acetic acid - water = 3: 1: 1

3. butanol-acetic acid-water-pyridine = 30: 3: 12: 10

Generator: chloro (toluidine) KJ.

Example 1

6--3- (α-cyano) acetylamidopenamarboxylic acid

2.1 g (O011-imol) of 6-aminopenicillanic acid [6-APS] are dissolved by adding 2.8 ml (0.02 mol) of triethylamine in 30 ml of dichloromethane. They are added to the solution at 0 ° C

3.3 g (0.01 mol) of cyanoacetic acid pentachlorophenyl ester. The mixture was stirred at 0 ° C for 2 hours and quenched with pH 7 phosphate buffer. The mixture was then acidified with 1: 3 phosphoric acid in ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The remaining crystals were triturated with diisopropyl ether. Yield: 2 g (77%).

Analysis:

calculated:

% C, 48.64;% H, 4.62;% N, 14.83.

C, 46.72; H, 4.58; N, 14.72. Eluent: 3, Rf = 0.64. Lactam C = O group: 783 cm @ ^-1 .

Example 2

7-fi- (acyano) acetylamido-3-acetomethyl-3-cephemarboxylic acid

2.7 g of 7-amino-3-acetoxymethyl-3-cephemarboxylic acid (7 ACA) was suspended in 50 ml of dichloromethane and added dropwise with 3.5 ml of triethylamine. The resulting clear solution was cooled to 0 ° C and 3.3 g (0.01 mol) of cyanotrolic acid cyanoacetic acid was added. The mixture was stirred for 2 hours and quenched with pH-7 buffer. The aqueous phase was washed with ethyl acetate and the alkaline solution was acidified to pH = 2 with 2 N hydrochloric acid in ethyl acetate. The ethyl acetate phase was dried and concentrated. The product was triturated with diisopropyl ether. Yield: 1.9 g (88%). Melting point: 168-170 ° C.

Analysis:

calculated:

46.02% · C, 3.86% Ή, 12.38 ·% N found:

% H, 3.93;% N, 12.25

Eluent: 3, Rf = 0.637 Lactam C = O group: 1792 cm ^{@ 4} .

Example 1 a d 3

7-β- (α-cyano) acetylamido-3-methyl-3-cephemicarboxylic acid

2.2-g (0.01 mole) of 7-ADCA are dissolved in 25 ml of acetonitrile with the addition of 1 to 2 flaps of water and 4.2 ml (0.03 mole) of triethylamine. The clear solution was cooled to 0 ° C and 3.3 g (0.01 mol) of cyanoacetic acid pentachlorophenyl ester were added. The mixture was stirred for 2 hours and acetonitrile was distilled off. The residue is taken up in 20 ml of ethyl acetate and washed with 20 ml of saturated sodium hydrogen carbonate solution.

The product was precipitated from the aqueous phase by acidification with 10% hydrochloric acid in 25 ml of ethyl acetate. The organic phase was dried, concentrated and triturated with petroleum ether. . .

Yield: 2.0 g (71%), m.p. 182-184 ° C.

Analysis:

calculated:

% C, 46.96;% H, 3.94;% N, 14.94.

46.71% C, 3.00% H, 14.77% N eluent: 3, Rf = 0.667

Lactam C = O group: 1785 c-im ⁴

Example 4

7-β- (α-Cyano) -acetamido-3-methyl-3-cephemarboxylic acid trichloroethyl ester

3.8 g (0.011 mol) of 7-ADCA-trichloroethyl hydrochloride are dissolved in 1.6 ml (0.02 mol) of pyridine and 20 ml of water in 50 ml of dichloroethane. The phases are separated and dried over magnesium sulfate. 0.8 ml (0.01 mol) of pyridine and 3.3 g (0.01 mol) of pentachlorophenyl cyanoacetic acid ester are added. After stirring at room temperature for 2 hours, the reaction was washed with 2N hydrochloric acid (20 ml) and saturated sodium chloride solution (15 ml), dried with dichloromethane and triturated with diisopropyl ether. Yield: 4.12 g (90%).

M.p .: 158-160 ° C.

Analysis:

calculated:

% C, 37.83;% H, 2.93;% N, 10.18;% Cl, 25.77.

37.63% C, 2.76% H, 9.95% N, 25.75% Cl, eluent: 1, _Rf - 0.587

Lactam C-O group: 1795 cm ^-1 .

Example 5

7-β- (α-cyano) -acetamido-3-methyl-3-cephemicarboxylic acid

3.0 g (0.007 mol) of 7β- (α-cyano) acetamido-3-methyl-3-cephemarboxylic acid trichloroethyl ester are dissolved in 25 ml of formic acid and the solution is cooled to 0 ° C and 1 g of zinc is added, which was previously activated with 2 N hydrochloric acid. The mixture was stirred at room temperature for 2 hours. The zinc is filtered off and the formic acid is distilled off. The residual oil was taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and distilled off. The precipitated product was triturated with diisopropyl ether.

Yield: 2.0 g (98%). Melting point: 180-182 ° C.

Analysis:

calculated:

% H, 3.94%, N 14.94% found ·

46.52% C, 3.44% H, 14.63% N, eluent: 3, _Rf = 0,66'7 lactam C = O: 1785 cm ^-1 ·.

Example 6

7-R - (4-cyano) -acetylamido-3-acetoxymethyl-3-cephemarboxylic acid triethylamine salt

1.7 g (0.005 mol) of 7- [3- (α-, cyano) -acetamido-3-acetoxyimeityl-3-cephemarboxylic acid are taken up in 10 ml of acetone and 0.7 ml (0.0015 mol) of triethylamine are added dropwise. A clear solution is obtained. The solution was stirred for 1 hour and the crystals were filtered off.

Yield: 2.1 g (89%). Melting point: 166-167 ° C.

Analysis:

calculated:

% C, 51.60;% H, 6.64;% N, 12.72.

51.72% C, 6.46% H, 12.42% N, eluent: 3, _Rf = 0.694 lactam C = O group 1790 om ^-1.

Example 7

7- [- (N-Cyano) -acetamido-3-acetoxymethyl-3-cephemarboxylic acid sodium salt

1.6 g (0.0035 mol) of triethylamine 7- N - (? -Cyano) acetylamido-5-acetoxymethyl-5-cephemarboxylic acid are gently heated in 20 µl of anhydrous ethanol to dissolve the substance. 0.5 g (0.0035 mol) of sodium diethyl acetic acid in 6 ml of anhydrous ethanol is added dropwise. Upon addition, the sodium salt precipitated immediately. The mixture was stirred for half an hour and the product was filtered and washed with 10 ml of cold alcohol on the filter.

Yield: 1.2 g (95%).

Analysis:

calculated:

% C, 43.22;% H, 3.98;% N, 11.63.

43.12% C, 3.52% H, 11.47% N eluent: 3. _Rf = 0.669. Lactam C-O group: 1792 cm @ ^-1 .

Example 8

6- / 3- (α-Cyano) -acetylamidopenamarboxylic acid triethylamine salt

2.2 g of 6-APS (0.01 mol) were added with addition

2.8 ml (0.02 mol) of triethylamine are dissolved in ml of dichloromethane. The solution is filtered until a clear solution is obtained. The solution was cooled to RT, 3.4 g (0.01 mol) of cyanoacetic acid pentachlorophenyl ester was added. The mixture was stirred for 2 hours, concentrated and triturated with diisopropyl ether.

Yield: 3.4 g (88%), m.p. 85-90 ° C (dec.).

Analysis:

calculated:

53,13% C, 7.34% H, 14.58 O / o N; found: 53,33% C, 7.28 o / o H, 14.22 O / o N. Eluent: 3, R _f = 0.645. Lactam C = O group: 1785 cm ^-1 . Example 9

7-β- (α-Cyano) -acetamido-3 acetoxymethyl-3-cphphemcarboxylic acid

2.7 g (0.01 mol) of 7-ACA is suspended in dichloromethane and dissolved in 2.8 ml (0.02 mol) of triethylamine. The solution is cooled to 0 [deg.] C., and 2.51 g (.mu.mol) of cyanacetic acid pentafluorophenyl ester are added. The mixture was stirred for 2 hours and quenched with saturated sodium carbonate solution. The product was acidified with 2N hydrochloric acid in ethyl acetate. The organic phase was dried and evaporated. The precipitated crystals are triturated with diisopropyl ether.

Yield: 2.9 g (85%), m.p. 168-170 ° C.

Analysis:

calculated:

46.02% C, 3.86% H, 12.38% N found:

46.09% C, 3.85% H, 11.98% N, eluent: 3, _Rf = 0,6'37 lactam C = O group: 1792 cm ^4th

Example 10

7-β- (ols-cyano) -acetamido-3-matyl-3-cephemarboxylic acid

2.2 g (0.0 ₍ 1 mol) of 7-ADCA in 26 ml of acetonitrile are added with 1 to 2 drops of water and

4.2 ml (0.0-3 mol) of triethylamine are dissolved in 25 ml of acetonitrile. The clear solution was cooled to 0 ° C and 2.51 was added. g (0.01 imol) of cyanacetic acid pentafluorophenyl ester. The mixture was stirred at 0 ° C for 2 hours and the acetonitrile was distilled off. The residue is taken up in 20 ml of ethyl acetate and washed with 20 ml of saturated sodium carbonate solution. The product was precipitated from the aqueous phase by acidification with 20% hydrochloric acid in 25 ml of ethyl acetate. The organic phase is dried and the precipitated product is triturated with petroleum ether. Yield: 2.3 g (81.5%), mp 183-185 ° C.

Analysis:

calculated:

% C, 46.96;% H, 3.94;% N, 14.94.

46.95% C, 4.12% H, 15.08% N, eluent: 3, R _f = 0.667 lactam group: 1785 cm ^-1.

Example 11

6- /? - (анкуапо ·) -β-t-enylacrylamidopenamcarboxylic acid

Dissolve 1.1 g (0.005 mol) of 6-APS in 30 ml of dichloromethane with the addition of 1.4 ml [0.01 imol] of triethylamine in 30 ml of dichloromethane. After dissolution, 2.1 g (0.005 mol) of .alpha.-capro-.beta.-phenylacrylic acid pentachlorophenyl ester is added at 0 ° C. The mixture was stirred for 2 hours at 0 DEG C. The solution ^Q was washed with saturated sodium carbonate solution and acidified with phosphoric acid in ethyl acetate in the ratio 1: 3rd The ethyl acetate phase was dried and the precipitate was triturated with diisopropyl ether.

Yield: 1.35 g (72.5%), m.p. 147-150 ° C.

Analysis:

calculated:

% H, 4.01;% N, 11.32

ΤΊ A1 P 7 P *

58.17% C, 5.03% H, 11.14% N, eluent: 2, _Rf = 0.685 lactam C = O group 1795 om ^-1.

Example 12

7- (4-cyano) -4-phenylacrylamido-3-acetoxymethyl-3-cephemarboxylic acid

1.4 g (0.005 mol) of 7-ACA were dissolved in 30 ml of dichloro methane with the addition of 1.4 µl (0.01 mol) of triethylamine. The solution was filtered and cooled to 0 [deg.] C. and 2.2 g (0.05 mol) of [alpha] -cyano-4-phenylacrylic acid pentachlorophenyl ester were added. After stirring for 1 hour, the solution is quenched with pH = 7 phosphate and the aqueous phase is acidified with 1: 3 phosphoric acid in ethyl acetate. The ethyl acetate phase was dried, concentrated and triturated with diisopropyl ether.

Yield: 1.6 g (72.5%)

Analysis:

calculated:

H, 4.01; N, 9.83. Found:

56.44% С, Η 4.20%, 10.03% N, eluent: 3, _Rf = 0.578 Laktamoivá C = 0 group: 1785 cm ^-1.

Annex 1 a d 13

7-β- (α-Cyano) -β-phenylacrylamido-3-methyl-3-C-epanedioic acid

2.2 g (0.01 mol) of 7-ADCA are dissolved in 25 ml of acetonitrile by addition of 2 drops of water and 4.2 ml of triethylamine. 4.1 g (0.01 mol) of .alpha.-cyano- [beta] -phenylacrylic acid pentahalophenyl ester are added at room temperature. The mixture was stirred at room temperature for 2 hours and the solvent was distilled off. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The product is obtained from the aqueous phase by acidification in ethyl acetate. The organic phase was dried and the precipitate was triturated with ether.

Yield: 3.0 g (80%), m.p. 178-180 ° C.

Analysis:

calculated:

% H, 4.09;% N, 11.38

Пд] п7ОГ | А ·

58.76% C, 4.43% H, 11.27% N, eluent: 2, _Rf = 0.687 lactam C = O group: 1700 cm ^'1.

Example 14

7-β- (κ-Chloro) -4-phenylacetamido-3-methyl-3-cephemicarboxylic acid

2.2 g (0.01 mol) of 7-ADCA are dissolved in 25 ml of acetonitrile and 2 drops of water and 4.2 ml (0.03 imol) of triethylamine are added. 3.4 g (0.01 mol) of .alpha.-cyano-15-phenylacrylic acid pentafluorophenyl ester are added at room temperature. The mixture was stirred for 2 hours and the solvent was distilled off. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The product is precipitated from the basic phase by acidification in ethyl acetate. The organic phase was dried, concentrated and triturated with ether. Yield: 3.5 g (86%). Melting point: 179-180 ° C.

Analysis:

calculated:

% H, 4.09;% N, 11.38

Π-Я 107ОП A *

58.87 ° C, 4.25% H, 11.56% N eluent: 2, R _f = 0.687 Lactam C = O group: 1790 cm ^-1 .

Example 1 a d 15

7-β- (α-Cyano) -β-phenylacrylamido-3-methyl-3-cephemarboxylic acid triohloroethyl ester

1.7 g (0.005 mol) of trichloroethyl ester hydrochloride 7-ADCA are dissolved by addition of 1.4 ml (0.01 mol) of triethylamine in 30 ml of dichloromethane. 2.1 g (0.005 mol) of α-cyano-4-phenylacrylic acid pentachlorophenyl ester are added. The mixture was stirred at room temperature for 3 hours and the dichloromethane was distilled off. The residue was dissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate solution, 2 N hydrochloric acid and saturated sodium chloride solution. The solution is dried and concentrated. The precipitate was triturated with anhydrous ptanol. Yield: 2.0 g (80%), m.p. 125-130 ° C.

Analysis:

calculated:

% C, 47.95;% H, 3.22;% N, 8.39;

% C, 48.12;% H, 3.30;% N, 8.50.% Cl, 21.26%. _Rf = 0.710

Lactam C = O group: 1785 cm ^-1 .

Example 1 a d 16

Q-β- (α-cyano) -phenylacetamidopenamarboxylic acid

Dissolve 2.1 g (0.01 mol) of 6-APS in 50 ml of dichloromethane with the addition of 4.2 ml (0.03 mol) of triethylamine. After dissolution, 4.0 g (0.01 mol) of α-cyanophenylacetic acid pentadhlorophenyl ester are added. The solution was stirred for an additional hour at room temperature, quenched with sodium bicarbonate and acidified with 1: 3 phosphoric acid in ethyl acetate. The solution was dried (MgSO4) and concentrated. The separated crystals were triturated with ether.

Yield: 3.1 g. (85%)

Analysis:

calculated:

% C, 56.81;% H, 4.76;% N, 11.69;

56.70% C, 4.65% H, 11.60% N, eluent: 2, R _f - 0.580

Lactam C = O group: 1788 cm ^-1 .

Example · 17

7-β <(α-cyano-phenylacetamido-3-methyl-3-cephemarboxylic acid

2.2 g [0.01 imol] of 7-ADCA are taken up in 40 ml of acetoniiril with 2 drops of water and 4.2 ml (0.3 mol) of triethylamine. 4.0 g (0.01 mol) of pentachlorophenyl ester of α-cyanophenylacetic acid are added at 0 ° C. The mixture was stirred at 0 ° C for 2 hours and the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with a saturated sodium hydrogen carbonate solution, and the material was precipitated from the basic phase (sodium hydrogen carbonate) by acidification with 1: 3 phosphoric acid in ethyl acetate. The material was dried, concentrated and triturated with ether.

Yield: 2.9 g [85%], m.p. 178-180 ° C.

Analysis:

calculated:

H, 4.23; N, 11.76. found:

56.91% C, 4.27% H, 11.41% N eluent: 2, _Rf = 0.678

Lactam C-O group: 1790 cm ^-1 .

Example 18

7-β- (aceto-phenylacetamido-3-methyl-3-cephemarboxylic acid)

2.2 (0.01 mol) of 7-ADCA is taken up in 40 ml of acetonitrile with 2 drops of water and 4.2 ml (0.03 mol) of triethylamine. Add at 0 ° C

3.3 g [0.01 mol] of α-cyanophenylacetic acid pentafluorophenyl ester. The mixture was stirred for 1 hour, concentrated and taken up in ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution and acidified with 1: 3 phosphoric acid in ethyl acetate.

The solution was dried, concentrated and the precipitated crystals were taken up in ethyl acetate. The solution is dried, concentrated and the precipitated crystals are triturated with ethyl ether.

Yield: 3.2 g (92%), m.p. 178-180 ° C.

Analysis:

calculated:

% C, 57.14;% H, 4.23;% N, 11.76; found:

57.20% C, 4.45% H, 11.92% N. Eluent: 2, R _f - 0.678 lactam C = O group: 1790 cm ^4th

Example 19

Triethyl amine salt of N - [(a-ccaao) acetylamido-3-acetoxymethyl-3-cephemarboxylic acid]

5.4 g (0.02 mol) of 7-ACA are dissolved in 50 ml of dichloromethane containing 5.6 ml (0.04 mol). triethylamine. The solution is cooled to 0 ° C and 6.6 g (0.02 mol) of cyanoacetic pentachlorophenyl ester are added at this temperature, the mixture is stirred for 30 minutes and the solvent is removed in vacuo by distillation and the residue is recrystallized from 25 ml of acetone. filters. Yield: 7.5 g (85%). Melting point: 128-130 ° C.

Analysis:

calculated:

% C, 51.80;% H, 6.46;% N, 12.72;

found:

% C, 51.40;% H, 6.23;% N, 12.50.

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of cyanacetamide derivatives of the general formula I R * .CO-NH C ' R ^x CN ^ϋ CO-OR ^{3 (1)} . where they mean R ^{1 is} hydrogen, (C 1 -C 6) -alkyl, R ^{2 is} hydrogen, phenyl, thienyl, furyl or pyridyl, optionally substituted with at least one halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, amino, C 1 alkylamino up to 6 carbon atoms or nitro; R ¹ and R 2 together represent an alkylene group having 1 to 4 carbon atoms, optionally substituted by a furyl or phenyl group, R ³ is hydrogen or a readily cleavable esterification residue, preferably a trialkylsilyl or trichloroethyl radical, \ And it means СНз \ Z с / \ СНз or \ CH2 AND С — СНз Z or \ CH2 AND C — CH2OCOCH3 Z or salts thereof by acylating amines of formula ^{II-1-AZ-N-A-0} CO-OR * (ID or a salt thereof, wherein R3 and A are as defined above, wherein the acylation is an ester. Formula III where R 1, R ² have the abovementioned meaning and X represents a halogen, preferably a chlorine or fluorine atom, in the presence of a tertiary base, preferably a trialkylamine of 1 to 6 carbon atoms in the alkyl radical, p. preferably triethylamine or pyridine or N-methylmorpholine and in the presence of aprotic. solvents, p. preferably carbon tetrachloride, dichloromethane, chloroform, dichloroethane or a dipolar solvent, preferably acetonitrile. 2.. 2. The process of claim 1, wherein the acylating agent of the formula (III) is a phenylacrylic acid derivative, for example pentachlorophenyl ester of .alpha.-cyano-.alpha.-phenylacrylic acid, or pentachlorophenyl .alpha.-cyanophenylacetic acid ester.