CH635845A5 - METHOD FOR PRODUCING CYANACETAMIDE DERIVATIVES FROM ANTIBIOTICS. - Google Patents

Description

The present invention relates to a process for the preparation of acid amides of the general formula

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j-y)

oJ — k y

©

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CO-OR

wherein

R1 hydrogen,

R2 is hydrogen or a phenyl group or R1 and R2 together form a benzylidene group, R3 is hydrogen or an esterifying radical, preferably trialkylsilyl or trichloroethyl,

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CH, I <

C - CH0 or

I c

.C-CHo0C0CH. / 2 3

means

and their salts by the acylation of amines of the general formula r2 *

s

V

V

CO-OR3

CO

wherein R3 and A are as defined above, characterized in that amines of the general formula II or their salts - ■ wherein R3 and A are as defined above - with an ester of the general formula wherein R1, R2 and R3 as indicated above are defined and X represents a chlorine atom or fluorine atom - is reacted and, if appropriate, the product is released from its salt or converted into a salt.

45 The ester group R3 can be any easily removable esterifying group known in the chemistry of penicillin and cephalosporin derivatives (e.g. tri- (lower) alkyl- (II) silyl, or trichloroethyl). The salts of the compounds of the general formula I are alkali metal salts (sodium or potassium salts) or salts formed with organic amines, e.g. tri (lower) alkylamine (e.g. triethylamine) in question.

The starting materials used can be the 55 cyanoacetic acid pentachlorophenyl ester, a-cyano-phenyl-acetic acid pentachlorophenyl ester or a-cyano-β-phenyl-acrylic acid pentachlorophenyl ester or the corresponding pentafluorophenyl ester, which forms a narrower group of the acylating agents of the general formula III.

The compounds of general formula II are conveniently in the form of carboxylic acid salts - preferably a sodium, potassium, lithium salt or one with a trialkylamine e.g. Triäthylamin formed salt used (III). The reaction is preferably carried out in the presence of an aprotic solvent. Halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane can be used for this purpose. Dipolar solvents, e.g. Acetonitrile and others are suitable.

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The reaction can preferably be carried out in the presence of a tertiary base. Trialkylamine such as triethylamine or a heterocyclic amine such as e.g. Pyridine or N-methyl morpholine can be used.

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

The details of the invention can be found in the following examples.

Examples

Chromatographic analysis was carried out on thin film and silica gel Merck F-254 was used. Eluent no

1. Benzene-ethyl acetate = 2: 1

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

3. Butanol-acetic acid-water pyridine = 30: 3: 12: 10 developer: chlorine / toluidine / KJ.

example 1

6-ß- (a-cyano) acetylamido-penam-carboxylic acid

2.1 g (0.01 mol) of 6-amino-penicillanic acid (6-APS) are dissolved in 30 ml of dichloromethane by the addition of 2.8 ml (0.02 mol) of triethylamine. At 0 ° C, 3.3 g (0.01 mol) of pentachlorophenyl cyanoacetate are added to the solution. The mixture is stirred for 2 hours at 0 ° C and decomposed with a phosphate buffer of pH = '7. The mixture is then acidified with 1: 3 phosphoric acid in ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated. The remaining crystals are triturated with diisopropyl ether. Yield: 2 g (77%), mp: 2 g (77%).

Analysis:

calculated: C 46.64 H 4.62 N 14.83 found: C 46.72 H 4.58 N 14.72 mobile solvent: 3, Rf = 0.64 lactam C = 0 group: = 783 cm-1.

Example 2

7-ß (a-cyano) acetylamido-3-acetoxymethyl-3-cephem-carboxylic acid

2.7 g of 7-amino-3 acetoxymethyl-3-cephem-carboxylic acid (7-ACA) are suspended in 50 ml of dichloromethane, and 3.5 ml of triethylamine are added dropwise. The pure solution obtained is cooled to 0 ° C. and 3.3 g (0.01 mol) of pentachlorophenyl cyanoacetate are added. The mixture is stirred for 2 hours and decomposed with a buffer of pH = 7. The aqueous phase is washed with ethyl acetate and the alkaline solution is acidified to pH = 2 in ethyl acetate with 2N HCl. The ethyl acetate is dried and concentrated. The product is triturated with diisopropyl ether. Yield: 1.9 g (88%), mp: 168-170 ° C. Analysis:

calculated: C 46.02 H 3.86 N 12.38

found: C 46.08 H 3.93 N 12.25 mobile solvent: 3, Rf = 0.637 lactam C = 0 group: 1792 cm-1.

Example 3

7-β- (a-cyano) -acetylamido-3-methyl-3-cephem-carboxylic acid

2.2 g (0.01 mol) of 7-ADCA are dissolved in 25 ml of acetonitrile with the addition of 1-2 drops of water and 4.2 ml (0.03 mol) of triethylamine. The pure solution is cooled to 0 ° C. and 3.3 g (0.01 mol) of pentachlorophenyl cyanoacetate are added. The mixture is mixed for 2 hours and the acetonitrile is distilled off. The residue is taken up in 20 ml of ethyl acetate and washed with 20 ml of saturated sodium bicarbonate.

The product is acidified from the aqueous phase with 10% hydrochloric acid in 25 ml of ethyl acetate. The organic phase is dried, concentrated and the excreted substance is 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 found: C 46.71 H 3.90 N 14.77 mobile solvent: 3, Rf = 0.667 lactam C = 0 group: 1785 cm "1.

Example 4

7-ß (a-cyano) acetylamido-3-methyl-3-cephem-carboxylic acid - trichloroethyl ester

3.8 g (0.01 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 dichloromethane. 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 pentachloro-phenyl cyanoacetic acid are added. The mixture is stirred at room temperature for 2 hours and, after the reaction has ended, washed with 2N HCl (20 ml) and with 15 ml of saturated sodium chloride solution, dried with dichloromethane and the product obtained is triturated with diisopropyl ether. Yield: 4.12 g (90%), mp: 158-160 ° C. Analysis:

calculated: C 37.83 H 2.93 N 10.18 Cl 25.77 found: C 37.63 H 2.76 N 9.95 Cl 25.75 mobile solvent: 1, Rf = 0.587 lactam C = 0 group: 1795 cm-1.

Example 5

7-ß (a-cyano) -acetamido-3-methyl-3-cephem-carboxylic acid

3.0 g (0.007 mol) of 7β (a-cyano) acetamido-3-methyl-3 - cephem-carboxylic 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 2N hydrochloric acid. The mixture is stirred for 2 hours at room temperature. The zinc is filtered and the formic acid is distilled off. The remaining oil is taken up in water and shaken in ethyl acetate. The organic phase is dried with magnesium sulfate and distilled off. The excreted product is triturated with diisopropyl ether. Yield: 2.0 g (98%), mp: 180-182 ° C. Analysis:

calculated: C 46.96 H 3.94 N 14.94 found: C 46.52 H 3.44 N 14.63 mobile solvent: 3, Rf: 0.667 lactam group C = 0: 1785 cm-1.

Example 6

7-ß (a-cyano) -acetyIamido-3-acetoxymethyl-cephem-

-carboxylic acid triethylamine salt 1.7 g (0.005 mol) 7-ß (a-cyano) -acetamido-3-acetoxy - methyl-3-cephem-carboxylic acid in 10 ml of acetone

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taken and 0.7 ml (0.005 mol) of triethylamine are added dropwise. A pure solution is obtained. The solution is stirred for a further 1 hour and the crystals are filtered. Yield: 2.1 g (89%), mp: 166-167 ° C.

Analysis:

calculated: C 51.80 H 6.64 N 12.72 found: C 51.72 H 6.46 N 12.42 mobile solvent: 3, Rf = 0.694 lactam C = 0 group: 1790 cm "1.

Example 7

7-ß (a-cyano) acetylamido-3-acetoxymethyl-3 cephem - carboxylic acid sodium salt

1.6 g (0.0035 mol) of 7-β (a-cyano) -acetylamido-3-acetoxy-methyl-3-cephem-carboxylic acid triethylamine salt are warmed gently in 20 ml of anhydrous ethanol and the substance is thus dissolved. 0.5 g (0.0035 mol) of diethyl acetic acid sodium salt in 6 ml of anhydrous ethanol are added dropwise. After the addition, the sodium salt is immediately excreted. The mixture is stirred for a further half an hour and the product is filtered and washed on the filter with 10 ml of cold alcohol. Yield: 1.2 g (95%).

Analysis:

calculated: C 43.22 H 3.98 N 11.63 found: C 43.12 H 3.52 N 11.47 mobile solvent: 3, Rr = 0.695 lactam C = 0 group: 1792 cm "1.

Example 8

6-ß (a-cyano) acetylamido-penam-carboxylic acid triethylamine salt

2.2 g of 6-APS (0.01 mol) are dissolved in 50 ml of dichloromethane with the addition of 2.8 ml (0.02 mol) of triethylamine. The solution is filtered until a clear solution is obtained. The solution is cooled to 0 ° C., 3.4 g (0.01 mol) of pentachlorophenyl cyanoacetate are added. The mixture is stirred for 2 hours, concentrated and triturated with diisopropyl ether. Yield: 3.4 g (88%), mp: 85-90 ° C (with decomposition).

Analysis:

calculated: C 53.13 H 7.34 N 14.58

found: C 53.33 H 7.28 N 14.22 mobile solvent: 3, Rt = 0.645 lactam C = 0 group: 1785 cm "1.

Example 9

7-ß (a-cyano) acetamido-3-acetoxymethyl-3-cephem-carboxylic acid

2.7 g (0.01 mol) of 7-ACA are suspended in dichloromethane and dissolved with 2.8 ml (0.02 mol) of triethylamine. The solution is cooled to 0 ° C., 2.51 g (0.01 mol) of pentafluorophenyl cyanoacetate are added. The mixture is stirred for 2 hours and decomposed with saturated sodium carbonate solution. The product is acidified with 2N HCl in ethyl acetate. The organic phase is dried and evaporated. The separated crystals are triturated with diisopropyl ether. Yield: 2.9 g (85%), mp: 168-170 ° C.

Analysis:

calculated: C 46.02 H 3.86 N 12.38 found: C 46.09 H 3.85 N 11.98 mobile solvent: 3, R, = 0.637 lactam C = 0 group: 1792 cm "1.

Example 10

7-ß (a-cyano) acetamido-3-methyl-3-cephem-carboxylic acid

2.2 g (0.01 mol) of 7-ADCA are dissolved in 25 ml of acetonitrile with the addition of 1-2 drops of water and 4.2 ml (0.03 mol) of triethylamine in 25 ml of acetonitrile. The pure solution is cooled to 0 ° C. and 2.51 g (0.01 mol) of pentafluorophenyl cyanoacetate are added. The mixture is stirred at 0 ° C. for 2 hours and the acetonitrile is 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 is acidified from the aqueous phase with 20% HCl in 25 ml of ethyl acetate. The organic phase is dried and the excreted product is triturated with petroleum ether. Yield: 2.3 g (81.5 g), mp: 183-185 ° C.

Analysis:

calculated: C 46.96 H 3.94 N 14.94

found: C 46.95 H 4.12 N 15.08 eluent: 3, R, = 0.667 lactam C = 0 group: 1785 cm "1.

Example 11

6β (a-cyano) -ß-phenylacrylamido-penam-carboxylic acid

1.1 g (0.005 mol) of 6-APS are dissolved in 30 ml of dichloromethane with the addition of 1.4 ml (0.01 mol) of triethylamine in 30 ml of dichloromethane. After the solution, 2.1 g (0.005 mol) of a-cyano-β-phenyl-acrylic acid - pentachlorophenyl ester are added at 0 ° C. The mixture is stirred at 0 ° C. for a further 2 hours. The solution is washed with saturated sodium bicarbonate solution and acidified with 1: 3 phosphoric acid in ethyl acetate. The ethyl acetate is dried and the excreted substance is triturated with diisopropyl ether. Yield: 1.35 g (72.5%), mp: 147-150 ° C. Analysis:

calculated: C 58.20 H 4.61 N 11.32

found: C 58.17 H 5.03 N 11.14 mobile phase: 2, R, = 0.685 lactam C = 0 group: 1795 cm "1.

Example 12

7-ß (a-cyano) ß-phenylacrylamido-3acetoxymethyl-3-cephem - carboxylic acid

1.4 g (0.005 mol) of 7-ACA are dissolved in 30 ml of dichloromethane with the addition of 1.4 ml (0.01 mol) of triethylamine. The solution is filtered and cooled to 0 ° C., and 2.2 g (0.05 mol) of pentachlorophenyl a-cyano-β-phenylacrylic acid are added. After stirring for 1 hour, the solution is decomposed with a phosphate of pH = 7 and the aqueous phase is acidified with 1: 3 phosphoric acid in ethyl acetate. The ethyl acetate is dried, concentrated, and the excreted substance is triturated with diisopropyl ether. Yield: 1.6 g (72.5%).

Analysis:

calculated: C 56.20 H 4.01 N 9.83

found: C 56.44 H 4.20 N 10.03 mobile solvent: 3, Rf = 0.578 lactam C = 0 group: 1785 cm "1.

Example 13

7-ß (a-cyano) ß-phenylacrylamido-3-methyl-3-cephem - carboxylic acid

2.2 g (0.01 mol) of 7-ADCA are dissolved in 25 ml of acetonitrile with the addition of 2 drops of water and 4.2 ml of triethylamine. 4.1 g (0.01 mol) of a-cyano-ß-phenyl-acrylic acid-penta-

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chloro or fluorophenyl esters are added at room temperature. The mixture is stirred at room temperature for 2 hours and the solvent is distilled off. The residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The product is acidified from the aqueous phase in ethyl acetate. The organic phase is dried and the excreted substance is triturated with ether. Yield: 3.0 g (80%), mp: 178-180 ° C.

Analysis:

calculated: C 58.52 H 4.09 N 11.39

found: C 58.76 H 4.43 N 11.27 mobile solvent: 2, Rt = 0.687 lactam C = 0 group: 1790 cm-1.

Example 14

7-ß («- cyano) -ß-phenylacetamido-3-methyl-3-cephem - carboxylic 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 mol) of triethylamine are added. At room temperature, 3.4 g (0.01 mol) of pentafluorophenyl a-cyano-β-phenyl-acrylic acid are added. The mixture is stirred for 2 hours and the solvent is distilled off. The residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The product is acidified from the basic phase in ethyl acetate. The organic phase is dried, concentrated and the excreted substance is triturated with ether. Yield: 3.5 g (86%), mp. 179-180 ° C.

Analysis:

calculated: C 58.52 H 4.09 N 11.38

found: C 58.67 H 4.25 N 11.56 mobile solvent: 2, Rf = 0.687 lactam C = 6 group: 1790 cm-1.

Example 15

7-ß (a-cyano) -ß-phenyIacrylamido-3-methyl-3-cephem - carboxylic acid trichloroethyl ester

1.7 g (0.005 mol) of 7-ADCA-trichloroethyl ester hydrochloride are dissolved in 30 ml of dichloromethane with the addition of 1.4 ml (0.01 mol) of triethylamine. 2.1 g (0.005 mol) of pentachlorophenyl a-cyano-β-phenyl-acrylic acid are added. The mixture is mixed for 3 hours at room temperature and the dichloromethane is distilled off. The residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, with 2N HCl and with saturated sodium chloride solution. The solution is dried and concentrated. The excreted substance is triturated with anhydrous ethanol. Yield: 2.0 g (80%), mp: 125-130 ° C.

Analysis:

calculated: C 47.95 H 3.22 N 8.39 Cl 21.24

found: C 48.12 H 3.30 N 8.50 Cl 21.26 mobile solvent: 1, Rf = 0.710 lactam C = 0 group: 1785 cm-1

Example 16

6-ß (a-cyano) phenylacetamidopenam carboxylic acid

2.1 g (0.01 mol) of 6-APS are dissolved in 50 ml of dichloromethane with the addition of 4.2 ml (0.03 mol) of triethylamine.

After the solution, 4.0 g (0.01 mol) of pentachlorophenyl a-cyano-phenyl-acetic acid are added. The solution is stirred for a further hour at room temperature, decomposed with sodium bicarbonate and acidified with 1: 3 phosphoric acid in ethyl acetate. The solution is dried over magnesium sulfate and concentrated. The separated crystals are triturated with ether. Yield: 3.1 g (85%).

Analysis:

calculated: C 56.81 H 4.76 N 11.69

found: C 56.70 H 4.65 N 11.60 eluent: 2, Rf = 0.580 lactam C = 0 group: 1788 cm-1.

Example 17

7-ß (a-cyano) phenylacetamido-3-methyl-3-cephem-carboxylic acid

2.2 g (0.01 mol) of 7-ADCA are taken up with 2 drops of water and 4.2 ml (0.3 mol) of triethylamine in 40 ml of acetonitrile. 4.0 g (0.01 mol) of pentachlorophenyl a-cyano-phenylacetic acid are added at 0.degree. The mixture is stirred at 0 ° C. for 2 hours and the solvent is distilled off. The residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and the substance is acidified from the basic phase (sodium bicarbonate) with 1: 3 phosphoric acid in ethyl acetate. The substance is dried, concentrated and the excreted substance is triturated with ether. Yield: 2.9 g (85%), mp: 178-180 ° C. Analysis:

calculated: C 57.14 H 4.23 N 11.76 found: C 56.91 H 4.27 N 11.41 mobile solvent: 2, Rf = 0.678 lactam C = 0 group: 1790 cm-1.

Example 18

7-ß (a-cyano) -phenylacetamido-3methyl-cephem - carboxylic acid

2.2 g (0.01 mol) of 7-ADCA are taken up with 2 drops of water and 4.2 ml (0.03 mol) of triethylamine in 40 ml of acetonitrile. 3.3 g (0.01 mol) of pentafluorophenyl a-cyano-phenylacetate are added at 0 ° C. The mixture is stirred for one hour, concentrated and taken up in ethyl acetate. The mixture is washed with saturated sodium bicarbonate solution and acidified with 1: 3 phosphoric acid in ethyl acetate. The solution is dried, concentrated and the crystals which have separated out are taken up in ethyl acetate. The mixture is washed with saturated sodium bicarbonate solution and acidified with 1: 3 phosphoric acid in ethyl acetate. The solution is dried, concentrated and the crystals which have separated out are triturated with ethyl ether. Yield: 3.2 g (92%), mp: 178-180 ° C. Analysis:

calculated: C 57.14 H 4.23 N 11.76 found: C 57.20 H 4.45 N 11.92 mobile solvent: 2, Rf = 0.678 lactam C = 0 group: 1790 cm "1.

Example 19

7-ß (a-cyano) acetylamido-3-acetoxy-methyl-3-cephem-carboxylic acid triethylamine salt

5.4 g (0.02 mol) of 7-ACA are dissolved in dichloromethane containing 50 ml, 5.6 ml (0.04 mol) of triethylamine. The

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The solution is cooled to 0 ° C. and 6.6 g (0.002 mol) of pentachlorophenyl cyanoacetate 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. cooled and filtered. Yield:

130 ° C.

Analysis:

calculated: C 51.80 5 found: C 51.40

635845

7.5 g (85%), mp .: 128 to

H 6.46 N 12.72 H 6.23 N 12.50

v

Claims (3)

635845 2. The method according to claim 1, characterized in that compounds of the general formula II or a sodium, potassium, lithium or trialkylamine salt, preferably the triethylamine salt, the same with a-cyano-ß-phe-nyl-acrylic acid pentachlorophenyl ester, a-cyanophenylacetic acid pentachlorophenyl ester or cyanoacetic acid pentachlorophenyl ester. It is known that the penam-3-carboxylic acid 45 acylated with cyanoacetic acid derivatives, the 3-methyl-ceph-3-em-4-carboxylic acid and the 3-acetoxymethyl-ceph-3-em-4 carboxylic acid- Derivatives are valuable antibiotics that are used in therapy. According to the known processes, the amine to be acylated is acylated with an acid halide of carboxylic acids substituted in the a-position with cyano group or with mixed anhydrides of the carboxylic acids. According to another known method, the carboxylic acid substituted with a cyano group in the presence of a dehydrating agent is e.g. Dicyclo-55 hexylcarbodiimide reacted with an amine (Swiss Patent Nos. 480 365, 542 236 and 507 292). The known processes have the disadvantage that the pure end product can only be obtained by chromatographic methods and that other problems from a technological standpoint are also caused. The use of acid chloride is difficult because the pure acid chloride can only be produced by lossy distillation, and it must be processed immediately to avoid the risk of polymerisation. When using the crude acid chloride, such molecules cannot be acylated in which other groups according to the invention for nucleophilic reagents are also present - not even in the case of the cephem and 2nd PATENT CLAIMS 1. Process for the preparation of acid amide derivatives of the general formula ti1 -v. . CC - NH j f \ « "c ^ l -) - ^ y - * - « CN. ", CO-OR3 10 wherein R1 hydrogen, R2 represents hydrogen or a phenyl group, or 15 R1 and R2 together form a benzylidene group, R3 represents hydrogen or an esterifying radical, or CH> C-CHnQCÖCH " means and their salts by the acylation of amines of the general formula (II) CO-OR ' wherein R3 and A are as defined above, characterized in that amines of the general formula II or their salts - wherein R3 and A are as defined above - with an ester of the general formula 3. Process according to claims 1 and 2, characterized in that the reaction in the presence of a tertiary 30 base is carried out. 4. The method according to any one of claims 1 to 3, characterized in that the reaction in the presence of an aprotic solvent, preferably carbon tetrachloride, dichloromethane, chloroform, dichloroethane, or 35 a dipolar solvent, preferably aceto-nitrile, is carried out. 5. The method according to claim 3, characterized in that the reaction in the presence of trialkylamines, preferably triethylamine, pyridine or N-methyl-mor- 40 pholine. (III) wherein R1, R2 and R3 are defined as indicated above and X represents a chlorine atom or fluorine atom - and optionally releases the product from its salt or converts it to a salt. 3rd 635845 Penam Derivates - since many side reactions occur. In the case of the mixed anhydrides known from the literature, many by-products also form during the acylation, so the reaction must be carried out at a low temperature. Even under such circumstances, the pure end product can only be obtained by chromatographic methods. The processes using dehydrating agents are difficult for industrial reasons, and the yields are only 65%. N-acyl ureas are by-products that are difficult to remove. Thanks to our invention, the above disadvantages can be eliminated.