DE2830525A1 - PROCESS FOR THE PRODUCTION OF CYANACETAMIDE DERIVATIVES - Google Patents

Description

It is known that penam-3-carboxylic acid acylated with cyanoacetic acid derivatives, 3-methyl-ceph-3-em-4-carboxylic acid and 3-acetoxymethyl-ceph-3-em-4-carboxylic acid derivatives are valuable Antibiotics are those 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 small alpha position by a cyano group or with mixed anhydrides of the carboxylic acids.

According to another known process, the carboxylic acid substituted in the small alpha position by a cyano group is reacted with an amine in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide (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 there are also other problems which are unfavorable from a technological point of view. The use of the acid chloride is difficult because the pure acid chloride can only be produced by distillation associated with loss, and it must be processed further immediately in order to avoid the risk of polymerization. When using the crude acid chloride, such molecules cannot be acylated in which other groups sensitive to nucleophilic reagents are also present - not even in the case of the cephem - and the penam derivative - since many side reactions occur.

In the case of the mixed anhydrides known from the literature, many by-products are also formed during the acylation, so the reaction must be carried out at 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 produced as by-products and are difficult to remove.

According to the invention, the above disadvantages can be eliminated.

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

(I),

wherein

R [high] 1 hydrogen, alkyl with 1 - 6 carbon atoms

R [high] 2 is hydrogen, or an optionally substituted aromatic or heteroaromatic ring, preferably phenyl, thienyl, furyl, pyridyl or an optionally substituted alkyl group with 1-6 carbon atoms, preferably furylalkyl, or phenylalkyl, or

R [high] 1 and R [high] 2 together form an alkylene or alkenyl group which, if desired, can be substituted, preferably furyl- or phenyl-alkylene or -alkenyl-

R [high] 3 is hydrogen or an easily cleavable esterifying radical, preferably trialkylsilyl or trichloroethyl, or <formula> or <formula>

means - and their salts by the acylation of amines of the general formula (II), in which R [high] 3 and A are as indicated above, characterized in that amines of the general formula II or salts thereof - in which R [high] 3 and A are as indicated above - with an ester of the general formula (III),

wherein R [high] 1, R [high] 2 and R [high] 3 are as stated above and X is halogen, preferably a chlorine atom, or a fluorine atom - and optionally the R [high] 3 protective group of the ester group in the Position 3 or 4 splits off and / or, if desired, releases the product from its salt and / or converts it into a salt.

The alkyl group preferably represents straight or branched, saturated aliphatic hydrocarbons with 1 - 6 carbon atoms, such as methyl, ethyl, z-propyl, iso-propyl, z-butyl, iso-butyl, etc.

The term "aromatic group" means mono- or bicyclic aromatic rings (e.g. phenyl, or naphthyl). The "heteroaromatic" group is an aromatic ring or ring containing one or more heteroatoms (nitrogen atom, oxygen atom and / or sulfur atom) (e.g. thienyl, furyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl, etc.). The aromatic and heteroaromatic rings can carry one or more substituents. The substituent can be a halogen atom (e.g. chlorine, bromine or iodine atom), lower alkyl (e.g. methyl, ethyl), lower alkyl (e.g. methyl, ethyl), lower alkoxy (e.g.

Methoxy, ethoxy), haloalkyl (e.g. trifluoromethyl), amino, substituted amino (e.g. methylamino, ethylamino, etc.) or nitro. The "furylalkyl group" can mean, for example, furylmethyl, furylethyl, and the phenylalkyl group preferably means benzyl, beta-phenylethyl, etc.

R [deep] 1 and R [deep] 2 together form an alkenyl or alkylene group (e.g. alkylene with 1 - 4 carbon atoms, preferably methylene or ethylene), which can optionally represent a substituent e.g. phenyl, furyl, thienyl or pyridyl. X can be a chlorine atom, a bromine atom, a fluorine atom or an iodine atom, preferably a chlorine or fluorine atom.

The ester group R [high] 3 can be any easily cleavable esterifying group known in the chemistry of penicillin and cephalosporin derivatives (e.g. tri- (lower) -alkylsilyl, or trichloroethyl). Suitable 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).

The definition of the substituents is always the same in the following parts of the description and is therefore not repeated. The starting materials used are the pentachlorophenyl cyanoacetate, small pentachlorophenyl alpha-cyano-phenylacetate or pentachlorophenyl small alpha-cyano-small beta-phenylacrylate or the corresponding pentafluorophenyl ester, which form a narrower group of acylating agents of the general formula III.

The compounds of the general formula II are expediently used in the form of carboxylic acid salts - preferably a sodium, potassium, lithium salt or a salt formed with a trialkylamine, e.g. triethylamine.

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 such as acetonitrile and others are also suitable.

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

The active esters used according to the invention are prepared from the corresponding cyanoacetic acid chloride and pentahalogen phenol 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

The chromatographic analysis was carried out on thin layer, silica gel Merck F-254 was used.

Eluent:

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-small beta (small alpha-cyano) -acetylamido-pnam-carboxylic acid 2.1 g (0.01 mol) 6-amino-penicillanic acid (6-APS) are obtained by adding 2.8 ml (0.02 Mole) tri- ethylamine dissolved in 30 ml of dichloromethane. 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 a 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%), m.p .: 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 phase: 3, R [deep] f = 0.64

Lactam C = 0 group: = 783 cm [high] -1

Example 2

7-small beta (small alpha-cyano) -acetylamido-3-acetoxmethyl-3-cephem-carboxylic acid

2.7 g of 7-amino-3-acetoxymethyl-3-cephenecarboxylic 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 with 2N HCl to pH = 2 in ethyl acetate. The ethyl acetate is dried and concentrated. The product is triturated with diisopropyl ether.

Yield: 1.9 g (88%),

M.p .: 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 phase: 3, R [deep] 2 = 0.637

Lactam C = 0 group 1792 cm [high] -1.

Example 3

7-small beta (small alpha 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.

From the aqueous phase, the product is acidified with 10% hydrochloric acid in 25 ml of ethyl acetate. The organic phase is dried and concentrated and the precipitated 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 phase: 3, R [deep] f = 0.667

Lactam: C = 0 group: 1785 cm [high] -1.

Example 4

7-small beta (small alpha-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 pentachlorophenyl cyanoacetate 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%), m.p .: 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 phase: 1, R [deep] f = 0.587

Lactam C = 0 group: 1795 cm [high] -1.

Example 5

7-small beta (small alpha-cyano) -acetamido-3-methyl-3-cephem-carboxylic acid

3.0 g (0.007 mol) of 7-small beta (small alpha-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 was added, which had previously been activated with 2N hydrochloric acid. The mixture is stirred for 2 hours at room temperature. The zinc is filtered off 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 precipitated product is triturated with diisopropyl ether.

Yield: 2.0 g (98%), m.p .: 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 phase: 3, R [deep] f = 0.667

Lactam: C = 0 group 1765 cm [high] -1.

Example 6

7-small beta (small alpha-cyano) -acetylamido-3-acetoxymethyl-cephem-carboxylic acid triethylamine salt

1.7 g (0.005 mol) of 7-small beta (small alpha-cyano) -acetamido-3-acetoxy-methyl-3-cephem-carboxylic acid are taken up in 10 ml of acetone, 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%), m.p. 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 phase: 3, R [deep] f = 0.694

Lactam C = 0 group: 1790 cm [high] -1.

Example 7

7-small beta (small alpha-cyano) -acetylamido-3-acetoxymethyl-3-cephem-carboxylic acid sodium salt

1.6 g (0.0035 mol) of 7-small beta (small alpha-cyano) -acetylamido-3-acetoxymethyl-3-cephem-carboxylic acid triethylamine are gently warmed in 20 ml of anhydrous ethanol. This loosens the substance. 0.5 g (0.0035 mol) of sodium diethyl acetic acid in 6 ml of anhydrous ethanol are added dropwise. After the addition, the sodium salt is excreted immediately. The mixture is stirred for a further half an hour, the product is filtered off 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 phase: 3, R [deep] f = 0.695

Lactam C = 0 group: 1792 cm [high] -1

Example 8

6-small beta (small alpha 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%), m.p .: 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 phase: 3, R [deep] f = 0.645

Lactam C = 0 group: 1785 cm [high] -1

Example 9

7-small beta (small alpha-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. and 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 with 2N HCl in

Acidified ethyl acetate. The organic phase is dried and evaporated. The precipitated crystals are triturated with diisopropyl ether.

Yield: 2.9 g (85%), m.p .: 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 phase: 3, R [deep] f = 0.637

Lactam C = 0 group: 1792 cm [high] -1.

Example 10

7-small beta (small alpha-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 precipitated product is triturated with petroleum ether. Yield: 2.3 g (81.5%) m.p .: 185-185 ° C.

Analysis:

calculated: C 46.96% H 3.94% N 14.94%

Found: C 46.95%, H 4.12%, N 15.08%.

Mobile phase: 3, R [deep] f = 0.667

Lactam C = 0 group: 1785 cm [high] -1

Example 11

6-small beta (small alpha-cyano) -small beta-phenylacrylamide-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 dissolved in 30 ml of dichloromethane. After the solution is dissolved, 2.1 g (0.005 mol) of small alpha-cyanmo-small beta-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 acethyl acetate. The ethyl acetate is dried and the precipitated substance is triturated with diisopropyl ether.

Yield: 1.35 g (72.5%), m.p .: 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 [deep] f = 0.685

Lactam C = 0 group: 1795 cm [high] -1.

Example 12

7-small beta (small alpha cyano) -small beta-phenylacrylamido-3-acetoxy-methyl-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 small alpha-cyano-small beta-phenyl-acrylic acid-pentachlorophenyl ester are added, after stirring for 1 hour the solution is made with a phosphate of pH = 7 decomposed and the aqueous phase acidified with 1: 3 phosphoric acid in ethyl acetate. The ethyl acetate is dried and concentrated, and the precipitated 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 phase: 3 R [deep] f = 0.378

Lactam C = 0 group: 1785 cm [high] -1

Example 13

7-small beta-8 small alpha-cyano) -small beta-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 small alpha-cyano-small beta-phenylacrylic acid-pentahalogen-phenyl ester 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 with 1: 3 phosphoric acid in ethyl acetate. The organic phase is dried and the precipitated substance is triturated with ether.

Yield: 3.0 g (80%), m.p .: 178-180 ° C.

Analysis:

calculated: C 58.52% H 4.09% N 11.38%

Found: C 58.76% H 4.43% N 11.27%.

Mobile phase: 2, R [deep] f = 0.687

Lactam C = 0 group: 1790 cm [high] -1.

Example 14

7-small beta (small alpha cyano) -small beta-phenylacetamido-3-methyl-3-dephem-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)

Triethylamine added. 3.4 g (0.01 mol) of small alpha-cyano-small beta-phenylacrylic acid-pentafluorophenyl ester are also added at room temperature. 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 with 1: 3 phosphoric acid in ethyl acetate. The organic phase is dried and concentrated and the precipitated substance is triturated with ether.

Yield: 3.5 g (86%), m.p .: 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 phase: 2 R [deep] f = 0.687

Lactam C = 0 group: 1790 cm [high] -1.

Example 15

7-small beta (small alpha-cyano) -small beta-phenylacrylamido-3-methyl-3-cephem-carboxylic acid trichloroethyl ester 1.7 g (0.005 mol) of 7-ADCA trichloroethyl ester hydrochloride are added with the addition of 1.4 ml (0.01 mol) of triethylamine dissolved in 30 ml of dichloromethane. 2.1 g (0.005 mol) of small alpha-cyano-small beta-phenylacrylic acid-pentachlorophenyl ester 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 with saturated sodium bicarbonate solution, washed with 2N HCl and with saturated sodium chloride solution. The solution is dried and concentrated. The precipitated substance is triturated with anhydrous ethanol.

Yield: 2.0 g (80%), m.p .: 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 phase: C = 0 group: 1785 cm [high] -1.

Lactam C = 0 group: 1785 cm [high] -1.

Example 16

6-small beta (small alpha-cyano) -phenylacetamido-penam-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 small alpha-cyano-phenylacetic acid pentachlorophenyl ester 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%.

Mobile phase: 2 R [deep] f = 0.580

Lactam C = 0 group: 1788 cm [high] -1.

Example 17

7-small beta (small alpha cyamo) -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 small alpha-cyamo-phenylacetic acid pentachlorophenyl ester are added at 0 ° C. The mixture is stirred for 2 hours at 0 ° C. and the solvent is distilled off. The residue is in

Dissolved ethyl acetate is 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 material is dried and concentrated, and the precipitated material is triturated with ether.

Yield: 2.9 g (85%), m.p .: 170-180 ° C.

Analysis:

calculated: C 57.14% H 4.23% N 11.75%

Found: C 56.91%, H 4.27%, N 11.41%.

Mobile phase: 2 R [deep] f = 0.678

Lactam C = 0 group: 1790 cm [high] -1.

Example 18

7-small beta (small alpha-cyano) -phenylacetamido-3-methyl-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. At 0 ° C., 3.3 g (0.01 mol) of small alpha-cyano-phenylacetic acid pentafluorophenyl ester are added. 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 and concentrated, and the crystals which have separated out are taken up with 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 and concentrated, and the crystals which have separated out 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: C 57.20% H 4.45% N 11.92%.

Mobile phase: 2, R [deep] f = 0.678

Lactam C = 0 group: 1790 cm [high] -1.

Example 19

7-small beta (small alpha cyamo) acetylamido-3-acetoxy-methyl-3-cephem-carboxylic acid triethylamine salt

5.4 g (0.02 mol) of 7-ACA are dissolved in 50 ml, 5.6 ml (0.04 mol) of dichloromethane containing triethylamine. The solution is cooled to 0 ° C. and at this temperature 6.6 g (0.02 mol) of penta-chlorophenyl cyanoacetate are added, the mixture is stirred for 30 minutes and the solvent is removed by distillation in vacuo and the residue is extracted from 25 ml Recrystallized acetone, cooled and filtered.

Yield: 7.5 g (85%), m.p .: 128-130 ° C.

Analysis:

calculated: C 51.80% H 6.45% N 12.72%

Found: C 51.40%, H 6.23%, N 12.50%.

Claims (5)

1. Process for the preparation of acid amide derivatives of the general formula: (I), wherein R [high] 1 hydrogen, alkyl with 1 to 6 carbon atoms, R [high] 2 is hydrogen or an optionally substituted aromatic or heteroaromatic ring, preferably phenyl, thienyl, furyl, pyridyl or an optionally substituted alkyl group with 1 to 6 carbon atoms, preferably furylalkyl or phenylalkyl, or R [high] 1 and R [high] 2 together form an alkylene or alkenyl group which, if desired, can be substituted, preferably furyl or phenylalkylene or alkenyl, R [high] 3 is hydrogen or an easily cleavable, esterifying radical, preferably trialkylsilyl or trichloroethyl, (I) means - and their salts by the acylation of amines of the general formula: (II) in which R [high] 3 and A have the meaning given above, characterized in that amines of the general formula II or salts thereof, in which R [high] 3 and A are as stated above, with an ester of the general formula: (III), wherein R [high] 1, R [high] 2 and R [high] 3 have the meaning given above and X denotes halogen, preferably a chlorine atom or fluorine atom, and optionally converts the R [high] 3 protective group of the ester group in the Position 3 or 4 splits off and / or, if desired, releases the product from its salt and / or converts it into the salt. 2. The method according to claim 1, characterized in that compounds of the general formula II or a sodium, potassium, lithium or trialkylamine, preferably triethylamine salt thereof with small alpha-cyano-small beta-phenyl-acrylic acid-pentachlor phenyl ester, alpha-cyano-phenylacetic acid pentachlorophenyl ester or cyanoacetic acid pentachlorophenyl ester. 3. Process according to Claims 1 or 2, characterized in that the reaction is carried out in the presence of a tertiary base. 4. The method according to claims 1 to 3, characterized in that the reaction is carried out in the presence of an aprotic solvent, preferably carbon tetrachloride, dichloromethane, chloroform, dichloroethane, or a dipolar solvent, preferably acetonitrile. 5. The method according to claim 3, characterized in that the reaction is carried out in the presence of trialkylamines, preferably triethylamine, pyridine or N-methyl-morpholine.