SE437834B - SET TO MAKE CYANOACETAMIDE DERIVATIVES OF CEPHALOSPORIN RESPECTIVE PENICILLINES - Google Patents

Description

'780774k-3 agents (as is the case with cephem and penamide derivatives, for example), many side reactions can occur.

In addition, many by-products are formed when using the known mixed anhydrides and one should therefore work at a fairly low temperature. Even in such circumstances, the pure end product can only be recovered by chromatography.

Methods in which water is used as an extractant are quite complicated in industry and only 65% can be recovered. It is difficult to remove the by-products formed, namely H-acyl ureas.

The above disadvantages are eliminated by the method of the present invention.

The present invention also relates to a process for the preparation of acid amide derivatives of the general formula S '1 R CO ~ NH - ~ 1 \\\ \ CZ \ ___N' I / 2Û _ (x) 00-0113 ha where R1 is hydrogen, R 2 is hydrogen or phenyl or R 1 and R 2 together form an alkenyl group, which is optionally substituted by phenyl; R 3 is hydrogen or an easily cleavable esterifying group, preferably trialkylsilyl or trichlorethyl; and so. \ _ \ \ / C fi a C112 eller _ ëuz I // ,, A är // IC \\\\ 1 C xc - cn c - cn o ocu “3/2 3 cn3 ii Poef fl- šavgnggl 10 15 20 25 30 35 vsovvah-3 and salts thereof, the method being characterized by acylating an amine of the general formula (II) wherein R3 and A have the meanings given above, in the presence of a tertiary base and in the presence of an aprotic or dipolar solvent reacting the amine of the above-defined general formula II or a salt thereof with an ester of the general formula ala ícoo _ Rz / c \ CN (In) X where R; and R 2 and R 3 have the above values. And X is halogen, preferably chlorine or fluorine, whereupon, if desired, the protecting group R 3 is cleaved from the ester group in position 3 or 4 and / or, if desired, the product is removed from the salt thereof. and / or converts it to salt.

By "alkyl" in the present context is meant a straight or branched, saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.

R 1 and R 2 together form an alkylene group, for example a C 1-4 alkylene group, preferably methylene or ethylene, optionally substituted with phenyl.

The ester group represented by R 3 may be any esterifying group known in penicillin and cephalosporin chemistry as easy to remove, for example trialkylsilyl or trichloroethyl. As the salt of the compounds I may be mentioned alkali metal salt (for example sodium or potassium salt) or salt formed with an organic amine (for example tri-lower alkylamine, such as triethylamine). Since the substituents in the following have the meanings given above, these will not be repeated. As starting material, a narrower group of acylating agent III, cyanoacetic acid pentachlorophenyl ester, G4-cyanophenylacetic acid pentachlorophenyl ester, Q (-cyano-C-phenyl-acrylic acid pentachlorophenyl ester or the corresponding pentafluoro esters can be preferably used.

The compounds II are preferably used in the form of their salts, most preferably in the form of sodium, potassium and lithium salts or in the form of a salt formed with trialkylamine, such as triethylamine.

The reaction is carried out in the presence of an aprotic solvent. Halogenated hydrocarbons such as carbon tetrachloride, dichloromethane, chloroform or dichloroethane can be used.

Dipolar solvents such as acetonitrile or other solvents may also be used.

The reaction is also carried out in the presence of a tertiary base. Suitable bases are trialkylamines, such as triethylamine or heterocyclic amines, such as pyridine or N "methylmorpholine. The active esters used according to the present invention can be prepared by reacting the appropriate" * ~~. .; ___, _ W * nu à "'"' I ~ 10 \ fl 'G1 7807744-3 \, "l cyanoacetic acid chloride with pentahalogenphenol or salts thereof. The acylation generally takes place under mild reaction conditions at a temperature between 0 and 0 ° C. The product is obtained in good yields and chromatographic purification is not required.

The invention will be further elucidated in the following examples, in which the chromatographic tests were carried out on thin layers using silica gel (Merck F-254) and the following solvent mixtures for developer (4). A mixture of benzene and ethyl acetate in the ratio 2 : 1. (2) A mixture of butanol, acetic acid and water in proportions jzlzl. (3) A mixture of butanol, acetic acid, water and pyridine in the ratio 50: 5: 10: 10. Chlorine / toluidine / KI was used as developer.

Example 1: 6-3 (d-Cyaro) -acetylamido-penam-carboxylic acid. (51.9 ml) 6-amino-penicillanic acid (G-APA) was dissolved in 50 ml of dichloromethane by adding 0.8 ml (0.0 mol) of triethylamine and at 0 ° C 5.5 g was added. (0.01 mol) of eyanoacetic acid pentachlorophenyl ester. The mixture was stirred for 2 hours, then decomposed with a pH T phosphate buffer. The mixture was then acidified to ethyl acetate by adding 1: 5 t of phosphoric acid. The organic phase was dried over aqueous sulphate and evaporated. The residue obtained in the form of crystals was triturated with diisopropyl ether to give 3 g of the product (77%).

Analysis 7 $ C “fä /» H 'JáN Calculated 46.64 4.6? § 14.3 Found 46.72 ü, 58 lü, 7? The solvent (5) was used as solvent for the developer, Rf = 0.64. Iactam group C = O: 1785 cm -1.

Example 2: 7-3 (α-Cyano) -acetylamino-5-acetoxymethyl-5-cephemcarbogyl acid. 2 ,? α-amino-5-acetoxymethyl-5-cephem-carboxylic acid (7-ACA) was suspended in 50 ml of dichloromethane and š.5 ml of triethylamine was added dropwise. The clear solution thus obtained was cooled to 0 ° C and 5.5 g (0.01 mol) of cyanoacetic acid pentachlorophenyl ester was added. The mixture was stirred in? hours at Û-5 ° C and decomposed with a buffer of pH T. The aqueous phase was washed with ethyl acetate, the basic solution was acidified with EN-H01 to pH 2 to ethyl acetate.

\ Fl u: O w un 7 ~ ¶, ._..__-_-_- ~ - - _------ v-w - V - '7807744-3 The ethyl acetate was dried and evaporated. The product was triturated with diisopropyl ether to give 1.9 g (88%) with a melting point of 168 DEG-170 DEG C., 1N: 1. QSC "fálí" IÉN Calculated 46.0? 5.86 12 Found 46.08 3.95 l2,? 5 The solvent -4 (5), RT = 0.65? Was used as solvent for the developer. The lactam group C = 0: 1793 of Example 5: 7-B (d-Cyano) Ethylamido-5-methyl-5-cell-carboxylic acid 2. 2 g (0,01 mol) of 7-ADCA were dissolved in P5 ml of acetenitrile by adding 1-2 drops of water and 4 ml (0 ml The clear solution was cooled to 0 ° C and 5.3 g of (G, ol nol) cyanoacetic acid pentachlorophenyl ester were added.

The mixture was stirred for 2 hours and the acetonitrile was distilled off. The residue was taken up in 20 ml of ethyl acetate and washed with 20 ml of a saturated sodium bicarbonate solution. The product was acidified to ethyl acetate by adding 10% -18 hydrochloric acid to the aqueous phase. The organic phase was dried, evaporated and the precipitated product was triturated with petroleum ether. Yield 2.0 g (71%), m.p. 182-184 ° C.

An al ys íáíl% N Berïiknat in? , 9G _? -, Q-'l- l / L, 94 l-'Lmrnï- t IPS, 211. j, 'JO l / l-, 7? The system (5), af = e, eø7 was used as solvent for the developer. The lactam group o = o = 1785 cm -1 Example 4: 7-3 (d-Cyano) -acetylamido-5-methyl-5-cephem-carboxylic acid trichloroethyl ester. 5.8 g (0.01 mol) 7 ADCA trichlorethyl ester hydrochloride was dissolved in 50 ml of dichloromethane by adding 1.6 ml (0.0 mol) of pyridine and 29 ml of water, the phases were separated and the dichloromethane was dried over magnesium sulphate, 0.8 ml ( 0.0l mol) of pyridine and š, 5 g (0.0l mol) of cyanoacetic acid pentachlorophenyl ester The mixture was stirred for 2 hours at room temperature and when the reaction was quenched the reaction mixture was washed with 2N-H01 (20 ml) and with 15 ml of a saturated sodium chloride solution and the dichloromethane were dried and the resulting product was triturated with diisopropyl ether.

Yield 4.12 g (90%), m.p. 155-1 ° C. i pooa QUAï-WY 7BÛT7M + ~ 3 Analyze ÅS% I% Cl Ûeräknaï 77.77 10.18? 5, ° 7? unn6t §Û, ߧ É, "5 9.95 ɧ, Ü5 The system was used as a reading tool for the caller. - ~ "i F f“ * “D. Iactam group C = O: 1 ”} 5 cm ~ * / 1 l IÜI.

H h ..

Eyemnel 7: "~ i« fs-Cj¶no) ~ acet9 do-j-methyl-§-cefem-carboxyl- sïre. J, ¿D ¿9, CfT mal) 72- (u ~ Cyeno) ~ fl cetanido-E Methyl-α-ceilin-carbexylic acid trichlorethyl ester was read in 25 ml of formic acid or 10 times simultaneously with TN-H01, the slurry was stirred and cooled to 0 DEG C., then the mixture was added for ten hours, the mixture was heated to room temperature for 10 hours. The remaining oily Puhntünnen was absorbed in water and was now shaken in ethyl acetate.

The organic phase was also dried over magnesium sulphate and evaporated. The precipitated substance was triturated with di-propyl ether. Yield 2.0 g (98%), m.p. 130 DEG-13 DEG. 1 .: \ _ "1 Lz: a lya íóC íåïí 3013 'eeršaïflqnz, z 11.6, 9: a -s, 91: - 14, 91» vunnet -16,5?, N¿Fl l%, ßš? “Sem solution flour may be used from the developer system ._ _, _ w - 'I ¿,), R? = 0, 6a. Iaetnmgruppsn C = O: 1/85 en et0xlmethyl-5-ceFem- Exennel 62 7-¿(1 ~ ÛFen0) ~ acetylamido ~ ï “arbomjlsïre-tristylaminesalt. 1," 3 (f, fñ? Ful; "L ~ (1-C7anø) ~ efætani fl o« 5 ~ acßtcwlmetYl-5 ~ cefem-karbøïflw "“ W n_eton, varpå 0, "ml (0.005 ml) of triethylene drop * -1 was added. He obtained a clear solution. The mixture was stirred at room temperature. The triethylamine salt was removed in about 33 minutes. The mixture was stirred for one hour and the crystals were filtered off.

Utä te T l Q fïq fi) melts unkt lâq-lE °° C. 3 a \ 1 1 30 .Analys% C íâí f fl í Calculated 51.80 C, 6ï l?, 7? linnet El, T? 6.4C 12.42 The solvent used in the developer is the system .. w T. . 4 ~ l (;), Rf = O, n; fl. inxtam group C = O: JJÖU en. Example 7: "J" (: - Cyano) -acetylanido-E-acetoylmethyl-1-cephem-E; carboxylic acid sodium salt. lfß 3 (0, ÖO ¥ 5 moi 7ß ~ (> ~ Cyano) - «@ ethylemidn ~ 3 ~ acct fi ximethyl-š ~ ceïem ~ carboxy2acid-triethylamine salt was gently heated with 29 ml of anhydrous ethanol, whereby the solution was dissolved in a solution. of 0.5 g (0.00? mol) of Poof in uUAl- "Y 'POÛR QtALITY" low-density diethyl acetic acid sodium salt dissolved in G ml of dry ethanol was added dropwise. After the addition was complete, the sodium salt precipitated immediately. The mixture was stirred for a further 50 minutes and cooled to 0 DEG-5 DEG C., after which the substance was filtered off. During the filtration, the substance was washed with 10 ml of cold alcohol. Exhalation (95%) - Annlys XC% H% N Vrrïtnet 45, ?? 3.93 11.63 Found 45.1? 5 5? Ll, 47 10 As a solvent for the developer, the system in (3), W? = 0.623 was used. In the gruppen ktam group C = C: 1TÛ? Cn "q.

Example 8: 6β- (α-Cyano) -acetylamido-penam-carboxylic acid triethylamine "lamine salt. 6 g of AP-APA (0,01 mol) were dissolved in 50 ml of dichloromethane by adding 2.8 ml of (0.0? Mol) of triethylamine, the solution was filtered to clear, then cooled to G ° C and added with 5.4 g of cyanoacetic acid pentachlorophenyl ester (U, Ol flour), the mixture was stirred for 1 hour at C, evaporation and the evaporation residue were triturated with diisopropyl ether. Replacement j, ï Q (in fl å, melting point 35-OO “C (decomposition). '-23 in axl jrs IÉC' @ 14.58 / '/ å * Lf-I m Sunnet 5}, š§ f,? 8 l4, ?? The system (Z), Kf = Û, Gü5 was used as solvent for Framksllsron. Iektsmgrupp fi n C = O: 1735 cm_ fi Example 9: TJ- (α-Gyano) -acetamido-β-acetoxymethyl-acetyl carboxylic acid .g? (0.01 mol) 7-AGA was suspended in dichloromethane and 2.8 ml ( 0.0? Mol) of triethylamine was added to give a solution, the mixture was cooled to 0 ° C and? 5l W (D, Ol flour) cyanoacetic acid-pentafluorophenyl ester added to f) MN C) sat thesis. the landing was stirred in? hours at room temperature and decomposed with a saturated solution of sodium hydrogen carbonate.

The substance was acidified to ethyl acetate by adding? N> HCl.

The organic phase was dried and evaporated. The precipitated crystals were triturated with diisopropyl ether. Yield?, 9 g (155), mp 168-170 ° C. "Analysis ï '% H Calculated 46.02 5.86 Found ü6.09 5.85 As solvent for the developer, the system k» "Jl v, S TS å? _. _. \ _-.') KN CU Co s was used , slmsesß fi w 10 15? O U.) \ J '| 50 9 7807744-3 (5), Kf = 0,657. Iaktamgruppen c = o = 1792 cm "“.

Example 10: -S (1- "Yano) -acetamido-5-methyl-5-cephem-carboxylic acid. 3. g (0.01 mol) of 7-ADCA were dissolved in 25 ml of acetonitrile by the addition of 1 drop of water and 4.1 ml (0.05 mol) of triethylamine The pure solution was cooled to 0 DEG C. and 2.51 g (0.01 mol) of cyanoacetic acid pentafluorophenyl ester were added.

The mixture was stirred for 2 hours, then the acetonitrile was distilled off. The residue was taken up in 20 ml of ethyl acetate and washed with 20 ml of a saturated sodium bicarbonate solution. The substance in the aqueous phase was acidified with a 20% solution of HCl in TE ml of ethyl acetate. The organic phase was dried, evaporated and the precipitate was triturated with petroleum ether.

Yield 2.5 g (81.5%), m.p. 185-185 ° C.

Analysis% C% H% N Calculated 46.96 5.94 14.94 Found 46.95 4.1? 15.08 The solvent (3) was used as the solvent for the developer, Rf = 0.6G ?. Iactam group C = O: 1785 cm_4.

Example 11: 6-β (m-Cyano) β-phenylacrylamido-penam-carboxylic acid. 1 g (0.005 mol) of 6-APA was dissolved in 50 ml of dichloromethane by adding 1.4 ml (0.0l mol) of triethylamine. After the substance was completely dissolved, 2.1 g (0.005 ml) of m-cyano-β-phenyl-acrylic acid pentachlorophenyl ester were added at 0 ° C, and the mixture was stirred for 7 hours at 0 ° C. The mixture was washed with a saturated sodium bicarbonate solution and acidified to ethyl acetate with 1: 5 phosphoric acid, the ethyl acetate was dried, evaporated and the precipitated product was triturated with diisopropyl ether. Yield 1.55 g (72.5%), melting point 147 ~ 150 ° C.

In: '11 ys' Iz / JC "IÉII" ONE Calculated 58.20 4.61 11.3? Found 53.17 5.05 11.14 The solvent (2) was used as the solvent for the developer, Kf = 0, se5. Iaktamgruppen e = o = 1795 øm ““.

Example 1 = = 7-β (β-Cyano) -phenylacrylamido-2-acetoxymethyl-β-cephem-carbogyl 1.4 g (0.005 mol) of 7-ACA were dissolved in 50 ml of dichloromethane by adding 1.4 ml (0.01 mol) of triethylamine. the solution was filtered, whereby it became clear, cooled to 0 ° C and added with 9,? g (0.05 mol) of α-cyano-β-phenyl-acrylic acid pentachlorophenyl ester. After stirring for 1 hour, it was partitioned with a pH 7 buffer and the aqueous phase was acidified to ethyl acetate with 1: 3 phosphoric acid. The ethyl acetate was dried, evaporated and the precipitated product was triturated with diisopropyl ether. Yield 1.6 S <72.5%).

Analysis 'åáC% H' IÅN Calculated 56.20 # .0l 0.83 Found 56.44 4.30 10.05 The solvent (5) was used as the solvent for the developer, Hr = 0.5? S. Iactam group C = O: 1785 cmfq.

Example 15: N-β (d-Cyano) -3-phenylacrylamido-E-methyl-5-cephem-carbogilic acid. 9 ,? g (0.01 mol) of 7-ADCA was dissolved in 95 ml of acetonitrile by adding 2 drops of water and M, 2 ml (0.05 ml) of triethylamine. At room temperature, ,1 g (G, mel1 ml) of cyano-β-phenyl-acrylic acid pentachlorophenyl ester were added and the mixture was stirred for 3 hours at room temperature, then the solvent was distilled off. The remaining product was taken up in ethyl acetate and washed with a saturated solution of sodium bicarbonate. The product was acidified from the aqueous phase into ethyl acetate. The organic phase was dried, evaporated and the precipitated product was triturated with ether. Yield 5.0 g (80%), m.p. 178-180 ° C.

Ana lys E60 “iáíl f / 'áN Calculated §8, §? 4.09 11.58 Found 58.76 4.45 11.2? The solvent (?), Ef = 0.68? Was used as solvent for the developer. Iactam group C = O: 1790 cm -1.

Example 14: T-C (i-Cyano) -3-phenylacrylamido-5-methyl-β-cephem-curboxylic acid. 7 ,? g (0.01 mol)? -ADCA was dissolved in 25 ml of acetonitrile by the addition of? drops of water and 4 ,? ml (0.05 nol) of triethylamine. At room temperature, 5.4 g (0.01 mol) of α-cyano-S-phenyl-acrylic acid pentafluorophenyl ester were added and the mixture was stirred for 2 hours at room temperature, after which the solvent was distilled off. The residue was taken up in ethyl acetate and washed with a saturated sodium bicarbonate solution. The substance was acidified from the basic phase into ethyl acetate. The organic phase was dried, evaporated and the precipitated solid triturated with ether. Yield 5.5 g (25%), m.p. 179-180 ° C.

FOR QUALITY vw 15? 0 50 \ .WJ \ “. '1 7807744-3 ll Anal ys íïâC' ïáH% N -Calculated 58.5? 4.09 11.58 Found 58.67 4.25 11.56 The solvent (3), no = 0.607 was used as solvent for the developer. Iaktamgruppen 0 = 0 = 1790 @m "“.

Example 15: 7-3 (m-Cyano) -β-phenylacrylamido-3-methyl-5-cephemcarboxylic acid trichloromethyl ester. 1 ,? (0.005 mol) of 7-ADCA trichlorethyl ester hydrochloride was dissolved in 50 ml of dichloromethane by the addition of 1.1 ml (0.01 mol) of triethylamine. To the solution was added ?.1 g (0.005 mol) of m-cyano-β-phenyl-acrylic acid-penta-chlorophenyl ester. The mixture was stirred for 5 hours at room temperature and the dichloromethane was distilled off. The residue was dissolved in ethyl acetate and the solution was washed with a saturated solution of sodium bicarbonate, 2NHCl and with a saturated solution of sodium chloride, then dried and evaporated.

The precipitated solid was triturated with dry ethanol.

Yield 3.0 ((80%), melting point 1.5 ~ 130 ° C.

Ana iLys 3% 9611 fi álï 9130 1 Calculated 47.95 §,? 2 8.35? L, 24 Found & 8, l? 5.50 8.50? 1, š6 The system (1), RS, was used as solvent for the developer. = 0.710. Iektamgruppen c = o = 17115 <¶.1 '“'.

Example 16: 6-β- (α-Cyano) -phenylacetamidopenam carboxylic acid. 1.5 (0.01 mol) of 6-APA was dissolved in 50 nd of dichloromethane by the addition of 4.2 ml (0.05 mol) of triethylamine. When the substance is dissolved runscï fi ndigl; 11.0 g (0.01 ml) of ct-eyano-phenyl-acetic acid-pentachlorophenyl ester were added and the mixture was stirred for 1 hour at room temperature, then decomposed with sodium bicarbonate and acidified in ethyl acetate with 1: 5 phosphoric acid.

The mixture was dried over magnesium sulfate and evaporated. The precipitated crystals were triturated with ether. Yield 5.1 5 (S593).

Analysis 960 ïálï åáll Calculated 56.81 4.76 11.60 Found 56.70 4.65 11.60 The solvent A 0 ~ ¶ '(), R? = 0.590. Iactam group C = O: 1/88 cm.

Example 17: 7- (α-Cyano) -phenylacetamido-5-methyl-~-cephem-enrbogilic acid. 3 ,? 3 (0,01 ml) 7-ADCA was taken up in 1 H0 ml of aceto- .c MP 9913 HEM * u.) (0.05 ml) triethylamine. At 0 ° C, 4.0 g (Q, Ol mol) of α-cyanophenylacetic acid pentachlorophenyl ester were added and the mixture was stirred for 3 hours, after which the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with a saturated solution of sodium bicarbonate and the product was acidified from the bicarbonate phase in ethyl acetate by adding 1: 5 phosphoric acid. The solution was dried, evaporated and the precipitated solid was triturated with ether. Yield?, 9 g (35%), melting point 17 ° - 'rf »f * JJ in \,' ~ J c Analysis 'íáC íáH' iáI-T Calculated 57.14 #,? 5 11.76 ëunnet 56.91 4.77 11.41 As solvent for the developer, the system (7) was used, Ef = 0, C Iactam group C = 0: 1? 9O cm_ ?.

Example 13: β-β- (x-Cyano) -phenylacetamido-5-methyl-Cephem-carbogilic acid. 9.2 5 (0.01 ml) 7-ADCA was taken up in # 0 ml acetonitrile by addition of? drops of water and @ ,? ml (0.0 ml) triethylamine. At 0 ° C, š, 6 g (U, Ol flour) of α-cyanophenylacetic acid pentafluorophenyl ester were added and the mixture was stirred for 1 hour, evaporated and the residue taken up in ethyl acetate.

The mixture was washed with a saturated solution of sodium micronate and acidified with 1: 5 phosphoric acid in ethyl acetate. The precipitate was dried, evaporated and the precipitated crystals were triturated with ethyl ether. Yield 5,? g (99%), mp 178-180 ° C.

Anal ys 760 751%% N Calculated 57.14 4.25 ll, 76 Found Û?,? O &, H5 ll, 92 The solvent (ä),: av =: Lffï-æ was used as solvent for the developer. Inkt fl mgruppen c = o = if- * qe om ".

Example 19: 7-2- (K-Cyano) -acetylamido-5-acetoxymethyl-5-cephemcarboxylic acid triethylamine salt. 5.4 g (Ü, O 2 mol) of 7-AGA were dissolved at room temperature in 5.6 ml (0.04 mol) of triethylamine containing 50 ml of dichloromethane. The mixture was cooled to 0 ° C and at this temperature 6.6 g (0.0 mol) of cyanoacetic acid pentachlorophenyl ester were added and the mixture was stirred for 50 minutes, then the solvent was distilled off in vacuo. The residues were recrystallized from 25 ml of acetone and the precipitated whites of the crystals were washed in acetone, cooled and filtered off.

Yield 7.5 g (85%), melting point 228-150 ° C.

Analysis% C% H% N 51.80 6.46 12.72 5], äO 6.25 19.50 Calculated Found POQR ~ ~ ¶ f W QÜÄLfTífåmwv

Claims (4)

'7807744-3 PATENT REQUIREMENTS A process for preparing acid amide derivatives of the general formula (I) wherein R 1 is hydrogen, R 2 is hydrogen or phenyl or R 1 and R 2 together form an alkenyl group, which is optionally substituted by phenyl; R 3 is hydrogen or a readily cleavable esterifying group, preferably trialkylsilyl or trichloroethyl and \ \ \ / GHz cnz or meadow 1, A is C 11 I / \ le - C 11 a - 3 i and salts thereof, characterized in that an amine of the general formula ß- “(II) CO-OR 3 O / where R3 and A have the meanings given above, in the presence of a tertiary base and in the presence of an aprotic or dipolar solvent react the amine of the above-defined general formula II or a salt thereof with an ester of the general formula - '----_ U -, -, -. --- ..._. (III) where R 1 and R 2 and R 3 have the meanings given above and X is halogen, preferably chlorine or fluorine, then, if desired, the protecting group R 3 is cleaved from the ester group in position 3 or 4 and / or releases the product, if desired from the salt thereof and / or converts it to salt. 2. A process according to claim 1, characterized in that compounds of the general formula II or a sodium, potassium, lithium or trialkylamine, preferably a triethylamine salt thereof, are reacted with d-cyano-β-phenylacrylic acid penta chlorophenyl ester or α-cyano-phenylacetic acid-pentachlorophenyl ester or cyanoacetic acid-pentachlorophenyl ester. 3. A process according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of carbon tetrachloride, dichloromethane, chloroform or dichloroethane as aprotic solvent or in acetonitrile as dipolar solvent. 4. A process according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of trialkylamine, triethylamine, pyridine or N-methylmorpholine, as tertiary base.