SU511011A3 - The method of obtaining derivatives of penicillin - Google Patents

Description

(54) METHOD FOR OBTAINING PENICILLIN DERIVATIVES where R and R are as defined above, reacts with an amine of the general formula, where R and R have the above values, and the resulting amidine derivatives of penidyllines of general formula I are then isolated as acids or their salts by known methods. TClj, PC1z, POC1e, SOC (COCO3 ILISOC12, mainly PCIs) are used as chlorinating agents for the preparation of imidochlorides. Pensions are interacting with chlorinating agents at a temperature of from -50 to + 20 ° C, preferably from -30 to 0 ° C. methylene chloride, ethylene chloride, benzene, toluene, distillate ether, chloroform, ethyl acetate are used as anhydrous organic solvents immiscible with water. Pyridine, quinoline, isoquinoline, N g alkyl piperidine, N - alkyl morphine are used as tertiary amines. Common amines of general formula IV use common alkylamines, predominantly methylamine, ztilamine, propylamine, butylamine, hexylamine, as well as aceticlic amines, mainly cyclomethylamine, cyclohexylamine, or aromatic amines, mainly aniline, toluidine, or aralkylamines, preferentially amines. Formulas IV use dimethylamine, diethylamin) n, diaganolamine, ethylisopropylamine, as well as cyclic amines, preferably N-methylcyclopentamine, N-methylocylohexyxylamine, substituted;, or ne substituted pyrrolidane, morpholine, piperidine, hexamethylenimine, heptamethylenimine; or aralkylamines, preferably N-methylbenzylamine. Ammonosis of Imidochlorides of the general formula III is carried out at a temperature of from -50 to + 50 ° C, mostly from-30 to + 10 ° C. The compound of general formula 4 is substituted in the form of salts with inorganic or organic acids, mainly hydrochloric, phosphoric, and - toluenesulfonic, citric, sorrel, tartaric acids. Example. To a solution of 7.5 g (0.02 mol of the potassium salt of 6 - (phenylacetamido) penicillanic acid in 70 ml of dry methylene chloride, was added 2.4 ml (0.03 mol) of pyridine and 3.5 ml (0.028 mol) of trimethylchlorosilane and move for 1.5 hours. The reaction mixture is cooled to -20 ° C, 4.3 ml (0.053 mol) of pyridine is added, then dropwise pour into a solution of 4.6 g (0.022 mol) of PCIs in 90 ml of chloride methylene and stirred for 30 minutes at 0 ° C. Then it is cooled to -40 ° C and 8.7 ml (0.08 mol) of benzylamine is added dropwise and the stirring is continued for 0.5 hour. The reaction mixture is washed with water and concentrated to a dry mass. The crude product is purified by chromatography to obtain 3.86 g of pure 6 - (N - benzylphenylacetamidino) - penicillanic acid, i.e. 45.5% of the theoretical yield. Found: N: 10.08. CjsHjsNsSOs. Calculated,%: N, 9.92. EXAMPLE 2 According to the procedure described in Example 1, 6 - (N - benzylphenoxyacetamidino) - penicillanic acid is obtained using 6 (phenoxyacetamido) - penicillanic acid and benzylamine. Found: N 9.64 C23H2sN3S04. Calculated,%: N 9,56. PRI me R 3. According to the procedure written off in Example 1, 6 - (N - l, 5 - pentylene phenoxy acetates Dino) - penicillanic acid is obtained using 6 - (phenoxy acetamido) - penicillan acid and piperidine. Found,%: N 1P, 05. C2iH27N3SO4 Calculated,%: N 10.06. PRI and MER 4. According to the procedure described in Example 1, 6 - (N - benzyldiphenylacetamidino) - penicillanic acid is obtained using the potassium salt of 6 - (diphenylacetamido) - penisillanoic acid and benzylamine. Found,%: N 8.38. CjgHzgNsSOj. Calculated,%: N8.41. Example 5. According to the procedure described in Example 1, 6 - (W - phenyldiphenylacetamidino) - penicillanic acid is obtained using the potassium salt of 6 - (diphenylacetamido) penicillanic acid and aniline. Found: N: 8.40. ° CasHavNsSOg. : Calculated,%: N 8.65. EXAMPLE 6 According to the procedure described in Example 1, 6.- (N-phenylphenoxyacetamidino) -penischainic acid is obtained using 6 (phenoxyacetamido) -penicillanic acid and aniline. Found,%: N 10.07. С22Н2зМз504. Calculated,%: N9.87. Example 7. Zg (0.01 mol) of p - butyl sfir 6 - (N - formylamino) - penicillanic acid is dissolved in 20 ml of CHCl3, 1.1 ml (0.01 mol) of N - methylmorpholine is added, cooled to -40 ° C and pour a solution of 0.085 ml (0.01 mol) of COCIj in 5 ml of CHC1e and mix for 1 hour. Then the solution is cooled to -40 ° C, 2.5 ml (0.022 mol) of hexamethyleneimine is added dropwise and again. stir for 1 hour. The solution is concentrated in vacuo and the residue is dissolved in 200 mp of diethyl ether. The product is extracted from an ethereal solution of 250 ml of water, acidified to pH 3.0. The aqueous layer was basified to pH 7.5 and extracted again with ether. The ether extract is dried over calcined sodium sulphate and after evaporation of the ether, butyl ester 6 (N-1, b - hexyleneformamidino) - peschillanic acid is obtained.

Found,%: N 11.08.

C.sHjiNsSOs.

Calculated,%: N 11.02.

PRI me R 8. According to the procedure described in Example 7, 6 - {N - formylamino) - penicillanic acid nitrobenzyl ester is used and i - 6 - (N - l, b - hexyleneformamidino) - penicillanic acid is obtained and converted into the free acid by known methods.

Use 6 - (N l, b - hexyleneformamidino) - penicillanic acid in the form of white

150-152С; 270 (conc. Needles, so pl. ShgO).

Claims (6)

Invention Formula The method of obtaining penicillin derivatives of formula I CZK H, SNZ foH, .j a / N-C N —CH — CH five -CH-COX  R CO - N where R, R and R are the same or different, a hydrogen atom, a substituted or unsubstituted alkyl with 1-7 carbon atoms, cyclopentyl, cyclohexyl, cycloheptyl, substituted or unsubstituted phenyl, benzyl, phenylethyl, naphthylmethyl, naphthylethyl; B may also be a heterocycle containing 5-8 atoms, including one or two heteroatoms in the form of nitrogen, oxygen or sulfur; R and R can form with the nitrogen atom a cyclic system containing 5-8 atoms, including one or two heteroatoms in the form of nitrogen, hydrogen or sulfur; X is a hydro strong group or an OR group in which R is a substituted silyl group, or substituted or unsubstantiated; the fact that the derivatives of 6 - aminopenicillanic acid of General formula II j oi Tl-CO-NH-CH -CH CO-N-CH-COOR, where R and R are as defined above, are reacted with chlorinating agents in anhydrous organic solvents that are not displaced with water, in the presence of tertiary amines, and the resulting imidochloride of the general formula  CH ll-C-N CH-CH CO-NON-COOTl where R and R are as defined above, then reacted with an amine of the general formula IV15 h t.) nn where R and R are as defined above, followed by isolation of the desired products in the form of acids or their salts by known methods. 2. A method according to claim 1, characterized in that PCIsr PC1z, POC1z, SOCIj (COCOA or COCIj, mainly PCI, are used as chlorinating agents. 3. The method according to claim I, characterized in that the interaction with chlorinating agents is carried out at a temperature of from -50 to + 20 ° C. 4. A method according to claim 1, characterized in that methylene chloride, ethylene chloride, benzene, toluene, diethyl ether, chloroform, ethyl acetate are used as anhydrous organic solvents immiscible with water. 5. A method according to claim 1, characterized in that pyridine, quinoline, isoquinodine, N-alkylpiperidine, N alkylmorpholine is used as tertiary amines. 6. A method according to claim 1, characterized in that the ammonolysis is carried out at a temperature of from -50 to + 50 ° C.