DD142448A5 - METHOD FOR PRODUCING CYANACETAMIDE DERIVATIVES - Google Patents

Description

METHOD FOR PRODUCING CYANACETAMIDE DERIVATIVES

Characteristics of the known technical solutions?

It is known that the cyanoacetic acid-acylated penam-3-carboxylic acid, the 3-methyl-ceph-3-em-4-carboxylic acid derivatives are valuable antibiotics used in therapy. According to known methods, the amine to be acylated is acylated with an acid halide of incC position substituted with cyano group substituted carboxylic acids or with mixed anhydrides of the carboxylic acids.

According to another known method, the cyano-substituted carboxylic acid in the presence of a cyano group is dissolved in the presence of a dehydrating agent, e.g. Dicyclohexylcarbodiimides reacted with an amine (Swiss Patent Nos. 480 3 & 5, 542 236 and 507 292), The known methods have the disadvantage that the pure end product can be obtained only by chromatographic methods and others

From a technological point of view unfavorable problems are caused. The use of the acid chloride is difficult because the pure acid chloride can only be prepared by loss-making distillation and it must be further processed immediately to avoid the risk of polymerization. When using the crude acid chloride, such molecules can not be acylated, in which other nucleophilic reagent-imageable groups are present - not even in the case of the cephem and penam derivative - since many side reactions occur. In the case of the mixed anhydrides known in the literature, many by-products also form during the acylation, so that 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%. As by-products arise N-acyl-ureas, which are difficult to remove ₀

Zi el the invention?

With the invention, the above disadvantages are to be eliminated.

Explaining the nature of the invention;

The present invention is a process for the preparation of acid amides of the general formula I, wherein

R ^{1 is} hydrogen, alkyl of 1-6 carbon atoms

2 R is hydrogen, or an optionally substituted aromatic or heteroaromatic ring, preferably phenyl, thineyl, furyl, pyridyl or an optionally substituted alkyl group having 1-6 carbon atoms preferably eurylalkyl, or phenylalkyl or

1 2

R and R together form an alkylene group which may desirably be substituted by an iso, preferably furylalkylene or phenylalkylene,

R- * denotes hydrogen or a readily cleavable esterifying radical, preferably trialkylsilyl or trichloroethyl,

CH ₀ CHr) CHq

^ ^k ^ -. ₀ or ^ O - CH ₃ or ^. C-CH ₂ OCOCH ₃

CH ₃

and their salts by the acylation of amines of general formula II,

in which R 1 and A are as stated above, characterized in that amines of the general formula II or their salts - where R and A are as stated above - with an ester of the general formula III,

In which R, R and R are as indicated above and X is halogen, preferably a chlorine atom or fluorine atom.

3. indicates - reacts and optionally cleaves off the R - protecting group of the ester group in the position 3 or 4 and / or releases the product, if desired, from its salt and / or converted into salt.

The alkyl group preferably represents straight or branched, saturated aliphatic hydrocarbons having 1-6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.

By the term "aromatic group" is meant mono- or bicyclic aromatic rings (e.g., phenyl or naphthyl). The "heteroaromatic" group is an aromatic one or more heteroatoms consisting of one or more rings (nitrogen, oxygen and / or sulfur).

retaining system _(ζ.Β β thienyl, furyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl, etc.) · The aromatic and heteroaromatic rings may have one or more substituents · The Substituaat may be a halogen atom (ζ · · Β chlorine, bromine, or iodine atom), lower alkyl (eg, methyl, ethyl), lower alkyl (eg, methyl, ethyl), lower alkoxy (eg, methoxy, ethoxy), haloalkyl (eg, trifluoromethyl), amino, substituted amino (eg, methylamino, ethylamino, etc.) or Mean Uitro. The "furylalkyl group" may be ζ · Β ₀ furylraethyl, Furyläthyl and the phenylalkyl group is preferably benzyl, ß-phenylethyl where R ^x and R together form an alkylene group (eg, alkylene having 1-4 carbon atoms, preferably methylene or ethylene) which may optionally be a substituent z _o, phenyl, Puryl, thienyl or pyridyl may represent ·

X may represent a chlorine atom, bromine atom, fluorine atom or iodine atom, preferably Vhlor or fluorine atom.

The ester group R.sup.1 can be any easily cleavable esterifying group known in the chemical field of penicillin and cephalosporin derivatives (eg, tri- (lower) alkylsilyl or trichloroethyl.) Salts of the compounds of general formula I are alkali metal salts (Sodium or Kalizmsalze) or salts formed with organic amines, for example tri (lower ^ alkylamine (eg _o triethylamine) in question.

The definition of the substituents is always the same in the following parts of the description, therefore it is no longer repeated. The starting materials which may be used are the cyanoesoacetic acid pentachlorophenyl ester, cyano-phenylacetic acid pentachlorophenyl ester, which forms a tighter group of the acylating agents of general formula III. Cyano-.beta.-phenylacrylic acid pentachlorophenyl ester or the corresponding pentafluorophenyl esters are used.

- 5 - -9

The compounds of general formula II are expediently used in the form of ocarboxylic acid salts - preferably a sodium, potassium, lithium salt or a salt formed with a trialkylamine Z ₀ Be triethylamine. The reaction is preferably carried out in the presence of an aprotic solvent. For this purpose, halogenated hydrocarbons as well as carbon tetrachloride, chloroform, dichloromethane can be used. Also dipolar solvents such as acetonitrile u _o a. are suitable.

The reaction may preferably be carried out in the presence of a tertiary base. Trialkylamine such as triethylamine or a heterocyclic amine such as Z ₀ B. 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 pentahalogenphenol or salts thereof. The acylation reaction generally proceeds under mild reaction conditions at 0-200 C. The product is obtained in good yield, a chromatographic purification is not necessary.

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

Examples? , '

Chromatographic analysis was performed on thin layer and Merck F-254 silica gel was used. Eluent j.

1 "benzene-ethyl acetate = 2: 1

2. Butanol-acetic acid-water = 3? IiI

3. Butanol-acetic acid-water-pyridine = 30: 3: 12: 10 Developer: Ohlor / toluidine / KJ. -. ' ...

- 6

Ausführungsbe ispiele:

• Example 1

6β- (mi-CYAMO-acetylamido-peni-carboxylic acid

2.1 g (0.01 mol) of 6-amino-penicillanic acid (6-APS) are dissolved by the addition of 2.8 ml (0.02 mol) of triethylamine in 30 ml of dichloromethane. At O ⁰ G, 3.3 g (0.01 mol) of cyanoacetic acid pentachlorophenyl ester are added to the solution. The mixture is stirred at ⁰ ° C. for 2 hours 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, concentrated. The remaining crystals are triturated with diisopropyl ether.

Yield: 2 g (77 %) , mp ₀ : 2 g (77 %). Analysis: -

Calculated: C 46.64 % H 4.62 % N 14.83 % Found: C 46.72% H 4.58% N 14.72%. Eluent: 3, R _f = 0.64 lactam C = O group: = 783 cm ^-1 .

Example 2 <

7-ß "(o </ - 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 resulting pure solution is cooled to ⁰ ° C. and 3.3 g (0.01 mol) of cyanoacetic acid pentachlorophenyl ester 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 with 2N NOl acidified to pH «2 in ethyl acetate» The ethyl acetate is dried and concentrated. The product comes with

Diisopropyl ether triturates *

Yield: 1.9 g (88%), m.p .: 168-170 ⁰ C.

Analysis: · -

Calculated: C 46.02%. H 3.86% N 12.38% Found: C 46.08% H 3.93% N 12.25%.

Eluent: 3, Rf = 0.637.

Lactam C = O Group: 1792 cm "" ¹ .

Example 3 7-ß (£ cyano) -acetylamido-3-methy1-3-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 / vial 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 cyanoacetic acid pentachlorophenyl ester 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 carbonate.

From the aqueous phase, the product is acidified with 10% hydrochloric acid in 25 ml of ethyl acetate. The organic phase is dried, concentrated and triturated the precipitated substance with petroleum ether.

Yield: 2.0 g (71%), m.p. *: 182-184 ⁰ C. Analysis:

Calculated: C 46.96 % H 3.94% N 14.94%. - 'Found: · C 46.71% H 3.90% Ή 14.77% o Eluent: 3, Rf = 0.667 ·

Lactam C = O group: 1785 cm ¹ "",

Ex iel 4

7. ~ ß (^ - cyano) -acetylamido-3-methyl-3-cephem-carbonsäuretrichloräthylester

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 (omol) of pyridine and 3.3 g (0.01 mol) of cyanoacetic acid-pentachlorophenyl ester are added. The mixture is stirred for 2 hours at room temperature and, after completion of the reaction, with 2n H (20 ml) and with 15 ml washed saturated sodium chloride solution, dried with dichloromethane and triturated the resulting product with diisopropyl ether. Yield: 4.12 g (90 %) _t. mp: 158-160 ⁰ C.

Analysis: σ - 83 % H 2, - Έ ίο, 18 % Cl 25 77 calculated: C 37, 63 % H 2, 93 % N 9 95%   Cl 25 75 found:- 37, 76 %

running agent: 1, Rp »0.587

-1 lactam C = O group: 1795 cm.

Example 5 7 "-SS (cC -Cy ano) -acet amido 3-methyl-3-cephem-carboxylic acid

3.0 g (0.007 mol) of 7-β- (cyano) -acetamido-3-methyl-3-cephemcarboxylic 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 in advance was activated with 2N hydrochloric acid. The mixture is stirred for 2 hours at room temperature. The zinc is filtered and the formic acid 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 Diisopropylather, yield: 2.0 g (98%) ₉ m.p .: 180-182 ⁰ C. Analysis:. -

Calculated: C 46.96 % H 3.94 % N 14.94 % Found: C 46.52% H 3.44 % N 14.63%. Eluent: 3, Rf: 0.667

Laktamgrup.pe C = O: -1785 cm. ·

Example 6

7-β (O-cyano) -acetylamido-3-acetoxymethyl-cephem-carboxylic acid triethyl salt

1 »7 g (0.005 mol) of 7-.beta .- (-) cyanoacetamido-3-aceto-xy-methyl-3-cephem-carboxylic acid are taken up in 10 ml of acetone and 0.7 ml (0.005 mol) Triethylamine are added dropwise. A pure solution is obtained. The solution is stirred for a further hour and the crystals are filtered. Yield; 2.1 g (89%)> mp _o: l66-L67 ° C. Analyzes -

calculated: C 51,80 % H 6,64 % N 12,72 % found? C 51.72% H 6.46% N 12.42% Eluant: 3, R _f - 0.694 Lactam 0 = 0. Group ι -1790 cm ". * ¹

Example 7

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

1.6 g (0.0035 mol) of 7-.beta. (6-cyano) -acetylamido-3-acetoxy-methyl-3-cephem-carboxylic acid triethylamine are gently warmed in 20 ml of anhydrous ethanol and the substance is thus dissolved. 0.5 g (0.0035 mol) of diethylacetic acid sodium salt in 6 ml of anhydrous ethanol are added dropwise _β after the addition of the sodium salt is excreted the same. The mixture is stirred for a further half hour and the product is filtered and washed on the filter with 10 ml of cold alcohol.

Yields 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 %. Eluent: 3, Rf ~ 0.695 lactam C = O. Group: 1792 cm "" ¹ .

- 10 ~

Example 8 6-ß (to -CyanoJ-acetylamido-penam-carboxylic acid Triäthylaminsalz

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 mole) of cyanoacetic acid pentachlorophenyl ester are added. The mixture is stirred for 2 hours, concentrated and triturated with diisopropyl ether.

Yield: 3.4 g (88 %), mp: 85-9O ⁰ C (with decomposition). Analysis:. -. ,

Calculated: C 53.13 % H 7.34 % Έ 14.58% Found: C 53.33 % H 7.28 % Έ 14.22 %, eluent: 3, R _f = 0.645 lactam C = O group: 1785 cm "* ¹ .

Example 9 7_ß (e6_0yano) -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 mole) of cyanoacetic acid pentafluorophenyl ester 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 precipitated crystals are triturated with diisopropyl ether.

Yield: 2.9 g (85%), m.p ,: 168-170 ⁰ C. Analysis: -

Calculated: C 46.02 % H 3.86 % N 12.38 %, Found: C 46.09 % H 3.85 % Ή 11.98 %. Eluent: 3, R _f << 0.637 lactam C = O group J-1792 cm ·

- η - g

Example 10 7-.beta .- (- / - Cyano) -acetamido-3-methyl-1-cephemic 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 pentano-5-cyanoacetate are added. Das.Gemisch is stirred for 2 hours at ^{0 0} C and the acetonitrile distilled off. The residue is taken up in 20 ml of ethyl acetate and washed with 20 ml of saturated sodium carbonate solution. From the aqueous phase, the product is acidified 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 g), m.p. 183-185 ⁰ C. Analysis: -

calculated? C 46.96 % H 3.94 % Ή 14.94% C found 46.95 % H 4.12 % Ή 15.08%. Eluent: 3, Rf «0.667

Lactam C = O-group: 1785 cm "* ¹ .

, '. · Example. 11 6β (06-cyano) β-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 in 30 ml of dichloromethane. After the solution ⁰ C 2.1 g (0.005 mol) ^ be in O - Gyánó-ß-phenyl-acrylic acid-pentachlorophenyl ester are added. The mixture is stirred for a further 2 hours at ⁰ ° C. 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 precipitated matter is triturated with diisopropyl ether

Yield: 1.35 g (72.5%), mp: 147-15O ⁰ C Analysis:

- 12 -

calculated: 0 58,20 % H 4,6l% N 11,32%

found! C 58.17% H 5.03% N 11.14% Eluent: 2, IL * 0.685

Lactam C = O Group: 1795 cm.

Example "12

7-ß (e ^ -Cyano) ß-phenylakrylamido-3-acetoxymethy1-3-cephem- carboxylic acid.

1.4 g (0.005 mol) of 7-ACA are dissolved in 30 ml of dichloromethane with 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 mole) of o-cyano-.beta.-phenyl-pentachlorophenyl acrylate are added. After stirring for 1 hour, the solution is decomposed with a phosphate of pH = 7 and the aqueous phase is acidified with ethyl acetate of phosphoric acid. The ethyl acetate is dried, concentrated and the precipitated substance is triturated with diisopropyl ether. Yield: 1.6 g (72.5 g %) Analysis:

Calculated: C 56.20 % H 4.01% N 0.83 % Found: C 56.44 % H 4.20 % N 10.03 %. Ö'aufmittel: 3, E »« 0,578 lactam C = O group: 1785 cm.

Example 13 7-β (o (/ -cyano) -β-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 oC-cyano-.beta.-pheny1-acyl-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 dissolved in ethyl

- 13

ft

taken up 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 precipitated substance is triturated with ether. Yield: 3.0 g (80%), m.p .: 178-180 ⁰ G. analysis: -;

calculated: C 58 , 52 % H 4, 09 % Έ 11 38 % found: C 58 , 76 % H 4, 43 % N 11 27 % Eluent: 2, R _f = 0, , 687 Lactara C = O Group: 1790 cm ^-1 O 14 example

7-ß ~ (^ - cyano) -beta-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. 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 extracted from the basic phase in .mu.l of .alpha.-butylphenyl-pentafluorophenyl ester ethyl acetate acidified the organic phase is dried, concentrated, and the precipitated material with ether triturated yield:.. 3.5 g (86%), mp _0: 179-180 ⁰ C. analysis: ..-- ..

Calculated: C 58.52 % H 4.09 % U 11.38 % Found: C 58.67 % H 4.25 % Έ 11.56 %, eluent: 2, R _f = 0.687 Lactam C = O Group: -1790 cm " ¹ .

7-.beta. ("</ - cyano) -β-phenylacryloamido-3-methyl-3-cephem ~ carboxylic acid trichloroethyl ester

- 14 -

1 »7 g (0.005 mol) of 7-ADCA-Trichloräthylester hydrochloride are dissolved with the addition of 1.4 ml (0.01 mol) of triethylamine in 30 ml of dichloromethane. 2.1 g (0.005 mol) of $ 0-cyano-β-phenyl-pentachlorophenyl acrylate 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 2 N 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 $), Schmp.i 125-130 ⁰ 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 % _t Eluent: 1, R _f = 0,71o Lactam C = O Group: 1785 cm " ¹ .

Example 16 6-.beta .- (f.epsilon.-cyano) -phenylacetajnido-penam-carbohydric 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) _; Ε-Cyano-phenylacetic acid pentachlorophenyl ester 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, dried and concentrated. The precipitated crystals are triturated with ether. Yield; 3.1 g (85 %) analysis:

Calculated: C 5 ^, 81 % H 4.76% N 11.69 Si Found: - C 56.70 % H 4.65 % N 11.60 % Eluent: 2, R _f = 0.580 Lactam C = O Group: 1788 cm "" ¹ .

- 15 -

Example 17 cyano) -phenyl tajnido ^ -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 (0.3 mol) of triethylamine in 40 ml of acetonitrile. 4.0 g (0.01 mol) of 6-cyano-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 dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution and the material is acidified from the basic phase (sodium bicarbonate) with 10N phosphoric acid in ethyl acetate. The fabric is dried, concentrated and the precipitated substance triturated with ether. Yield? 2.9 g (85%), m.p .: 178-180 ⁰ C. Analysis; -

calculated; Q 57.14% H 4.23% N 11.76% Found: 0 56.91% H 4.27% N 11.41%. Eluent: 2 _$ IL, = 0.678 Lactam C = O Group: 1790 cm.

Example 18 7 ~ ß (o £. "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 o-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, concentrated and the precipitated crystals 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 concentrated, dried and the precipitated crystals are triturated with ethyl ether.

- 16 -

Yield: 3.2 g (92%), mp: 178-180 ⁰ C ₀

Analysis: - -

Calculated: G 57.14% H 4.23% H 11.76% Found: C 57.20% H 4.45%. N 11.92% »Eluent: 2, R _f = 0.678

lactam 0 = 0 group: 1790 cm " ¹ .

Example · 19

7-ß (c ^ -cyano) ~ acetylamido-3-acetoxy-methyl-3-cephem-carboxylic acid Triäthylaminsalz

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

Analysis: ·

Calculated: C 51.80% H 6.46% N 12.72% Found: C 51.40% H 6.23% N 12.50%.

- 17 -

CO-NH-

(I)

CO-OR ⁹

H ₁ N

(Π)

CO-OR ³

TN ^ γ "Χ X

(Ffl)

Claims (5)

Process for the preparation of acid amide derivatives of general formula I, wherein R 1 is hydrogen, alkyl of 1-6 carbon atoms, R 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 1 ' C - CH ₃ or C - CH ₂ OCOCH ₃ C .. or C - CH ₀ or and their salts by the acylation of amines of general formula II, in which Ro and A are as indicated above, characterized in that amines of the general formula II or their salts - in which R and A are as stated above - are reacted with an ester of the general formula III, 12 3 wherein R, R and R- are as indicated above and X is halogen, preferably a chlorine atom, or fluorine atom. means - reacts and optionally cleaves off the R ^ protecting group of the ester group in the position 3 or 4 and / or releases the product, if desired, from its salt and / or converted into the salt - 18 - Method according to. Item 1, characterized in that compounds of the general formula II or a sodium, potassium, lithium or trialkylamine, preferably triethylamine salt thereof with £ -Gyano-ß-phenyl-akrylsäurepentachlorphenylester.jC-cyano-phenylessigsäurepentachlorphenylester or cyanoacetic acid converts pentachlorophenyl ester. 1 2 R and R together form an alkylene group which may be desirably substituted, preferably furylalkylene or phenylalkylene, R- ⁵ . Is hydrogen or a readily cleavable esterifying radical, preferably trialkylsilyl or trichloroethyl, CH 1 CH ₀ CH ₃ 3. Process according to item 1 and 2, characterized in that the reaction is carried out in the presence of a tertiary base. « 4. The method according to item 1 to 3, characterized in that the reaction is carried out in the presence of an aprotic solvent, preferably of carbon tetrachloride, dichloromethane, chloroform, dichloroethane or dipolar solvent, preferably acetonitrile. 5 «method according to item 3, characterized in that the reaction in the presence of trialkylamines, preferably of triethylamine or pyridine or N-methyl-morpholine is performed. For this iSeite formulas