SU468427A3 - The method of obtaining derivatives of cephalosporins or penicillins - Google Patents

Description

(54) METHOD FOR OBTAINING DERIVATIVES OF CEFALOSPORIN YLITPENICILLINS i, .., where M.V and (Z) have given values l, t each of the symbols, C I. J means hydrogen, nitro. methylsulfonyl, group, °. cyano,; podvergan:) t interaction with the amine in the presence of acid. Of the amines, aniline, hydrazine or hydrazine derivatives such as phenylhydrazine, 2,4-dinitrophenylhydrazine can be used. The acid catalyst may be a strong organic or inorganic acid, for example, hydrochloric or p-toluenesulfonic acid. It is preferable to use aniline hydrochloride, which serves as an acid and an amine. The conditions of the regeneration reaction are selected so as not to consume undesired hydrazine and in order for de-cyclization to occur. The reaction is carried out preferably in an environment of a lower alcohol containing 1 to 5 carbon atoms, for example methanol, ethanol and the like, but it is also possible in an environment of other solvents, for example dimethoxyethane or dimethyl formamide. The reaction is carried out at 20-22 C.: EXAMPLE. A. Benzn filovy ether | 7-methoxy-7-aminocephalosporanic acid. .:. The mixture is mixed with flOO mg of powdered 2,4-dinitrophenyl Ihydrazine, 85.5 mg of monohydrate P-toluene sulfonic acid in 3 ml of absolute ethanol. ; Add a solution of ZO4 mg of benzhydroxyl ester of 7-methoxy-7 - (, P-IIITrobenzylideneamino) cephalosporanic acid in 3 ml of ethanol and 0.5 ml of methylene chloride. The mixture is agitated for 30 minutes, filtered, the cake is washed with ethanol, the filtrates are evaporated under vacuum at room temperature: or below. The solid (residue) is washed several times with ether and dried with a stream of nitrogen. It is a tosylate honeycomb, 7-me tox-7-.subhns-c phapos (ananoic acid benzhydryl ester). The tosylate salt is converted into free yen as follows. Prepare a mixture of 3.5 ml of ether, 0.5 ml of ethyl acetate, 2 ml. --V; -: -., - --- v -: -; -: ----- r: -:; -: - r-rV-.rvi;: V-3 - ;;:, ::;.;.... iBOflbi and 22 MG of the DkaliyfoofyYT (KgHPO.). –Into it 100 mg of distillate salt, 7-methoxy-7-amino benzhydryl ether: cephalosporic kislot and the mixture of enerZHD After a separation of the phases, the aqueous phase is again extracted with ether, the organic phases are combined, dried magnesium sulfate and evaporated in vacuo, a gummy substance is obtained in the residue. The product is dissolved several times in a small amount of chloroform and evaporated in a deep manner in a deep b5, in the remaining resin: -; IR and NMR spectra of the product confirm the structure 7-Methyl-7-Aminocephalosporanic Acid Benzhydryl Ester B. 7-methyl-7 Aminodephalosporanic Acid B. Benzhydryl Ester A mixture of 109 mg of powdered | 2,4-dinitrofesh1lhydraain, 106 mg of mono > P-toluenesulfonic acid and 10 ml of i-ethylamine; . 30 min. Brings into the mixture a solution of 300 mg b. | 7-methyl-7-H-sh} zydryl ester; tro benzylideneamino) -dephalosporanic acid in 3 ml of ethanol. The mixture is kept stirring for another 30 minutes. The PI horn is filtered well with ethanol, and the filtrates are evaporated under vacuum at room-. temperature or below room temperature. The residue is the 7-methyl-7-aminocephalosporanic acid benzhydryl ester tosylate salt, which is converted to the free base. The toyl salt is converted to a free amine as follows. Prepared: a mixture of 3.5 m of ether, 0.5 ml of ethyl acetate, 2 ml of water and 22 mg. dipotassium phosphate. Add 100 mg of the benzhydrylrohchache tosylate salt of 7-hydroxymethyl-7-aminocephalosporanic acid ester and mix vigorously with a few minutes. After separation of the phases, the aqueous phase is again extracted with ether, the organic phases are combined and dried with anhydrous magnesium sulphate, evaporated under vacuum, and a gummy substance is obtained in the residue. It is dissolved several times in small volumes of chloroform and evaporated in high vacuum, the residue is resin. This substance has an IR and NMR spectra similar to that. B. Benzhydryl ester of 7-hydroxymethyl-7-amino-nephalosporanic acid. A mixture of 100 mg of powdered 2,4-dinitrophenylhydrazine, 85.5 mg of monohydrate in-toluenesulfonic acid and 3 ml of absolute ethanol is stirred for 30 min.

A solution of 304 mg of 7-hydroxymetip-7- (4-nitrobenzyl | idenamino) cephalosporanic acid 304 mg of ethanol is fed in 3 I ml of ethanol and 0.5 ml of methylene chloride I The mixture is kept stirring for another 30 minutes, the cake is filtered, washed with ethanol: LOM , the filtrates are evaporated under vacuum at room temperature or below.

Infrared absorption spectrum (CHC1 vaporous) of the resin obtained in the residue:. β-lactam (5.60 micron) and ether (5.76 micron). The substance is the tosylate salt of 7-hydroxymethyl-7-aminocephalosporanic acid benzhydryl ester.

A mixture of 3.5 ml of ether is prepared,

0.5 ml of ethyl acetate, 2 ml of water and 22 mg j of dipotassium phosphate. A further 1OO mg of methyl 7-aminocephalosporanic acid benzhydryl ester of 7-hydroxy i methyl and 7-aminocephalosporanic acid is added and 1: mg: the mixture is vigorously shaken for several minutes. After separation of the phases, the aqueous phase I is re-extracted with ether, the combined organic phases are dried with anhydrous magnesium sulphate and evaporated under vacuum, the resinous substance is obtained in the residue. It is dissolved several times in small volumes of chloroform and re-evaporated in a high vacuum, the residue is in the resin.

This product, benzhydryl ester of 7-hydroxymethyl-7-aminocephalosporanic acid, is purified by the thin-layer method. Chromatography on graphite (epo using the system. Es | bp / adatate.

I G. Benzyl ester of b-hydroxymethyl-6-aminopenicillan acid.

Using the methods described in steps A, B, and B, the tosylate salt; -bonyzyl-6o 6-hydroxymethyl-b-amino ester is obtained

penicillanic acid, so pl. 168-169 C, Found,%: C 54, O1; H .5.59; N 5.42; S 12,54.

 :

S3H29 N

j Calculated,%: C 54.31; 55 N5.51; Sl2.61, i:

: After treatment with aqueous dipotassium phosphate as described in the steps; A, B, and B give a gum, which is benzyme ester b hydroxymethyl b

i-aminopenicillinic acid. Product

gives mostly one spot with fine-fluid chromatography on 250 silica gel plates, projected with 50% ethyl acetate in benzene.

D. 6-methyl-6-aminopenicillanic acid, benzyl ester. In a similar way, 19.5 mg of benzyl ether are obtained,. , 6

 ra 6-mvtvlg © gaminopenidillanovoj sour; you, ;.. -

I E, Venza new 6-ethyl-6-amino. ipenicillanic acid. five ; In the manner described, 48 m b.onzylamine sijaipa 6-ethyl-6-aminopenicil; l & nova acid,

; The structure of the obtained compounds of the dock; zAnA jAaHHbiMH ICT "NMR spectra. ten ; The following are compounds that; can be synthesized by the 4detodes described in the example. Ether is produced in all cases, especially in penicillinum & a number benzyl ether is formed. In sour 15 cephalosporanic (cephalosporin series, either benzhydryl or three are obtained; chloroethyl ethers:

; 7-amino-7-methylcephalosporanic acid,

20 ; 7-amino-7-ethylcephalosporanic acid,.

; 7-amino-7-propylcephalosporanic acid,

ji. 7-amino-7-methoxycephalosporanic acid 25,

7-amino-7-ethoxycephalosporanic kit, lot,

g 7-amino-7-butoxycephalosporanova: acid,

thirty; 7-amino-7-methylthiocef lospranic acid:

|| 7-amino-7-ethylthiocephalosporanic acid,

7-amino-7-isopropylthioiophenol35 acid,

7 -amino-7-acetylcephalosporanic acid,

7-amino-7-propionylcephalosporanic acid,

 7-amino-7-trifluoromethoxycephalosporanic acid,

7-ac-7-trifluorometh-ltiocephalosporic acid, / - v

7-amino-7-Chlorocephalosporanic acid45 .Tft ,.

7-amino-7-bromocephalosporanic acid,

I

7-amino-7-fluorocephalosporanic acid; Ta,

50

7-amino-7-difluoromethyl pefalosporanova acid,

; 7-amino-7-acetoxycephalospribranic acid, 7-amino-7-h1-propionyloxycephalosporino 55

wa acid

7-amino-7-hydroxymethyl cephalosporanic acid.

Mr.-ii: j. ,,. l :.

L 7-amino-7- (D-methyl) oxymethyl cef flospranoic acid, 7 aminr-7- (rt-isopr0 1 chl) oxymethyl cephalosporanic acid, 7-amino-7- (-4 daanoethyl) cephalosporic acid, 7-amino-7- (J3 -nitroethyl) cephalosporic acid, 7-amino-7- (-4 0-rmilethyl) cephalosporacic acid, 7-am; alko-7-allylcephalosporanic acid, 7-amino-7-benzylcephalosporanic acid, 7-a 4 ino- 7-cyano-cephalopropanQva acid, 7-amino-7-nitrosocephalosporanic acid, 7-ymino-7-carb amoylceph-losporoic acid ,. 7-amino-7-carboethoxycephalosporanic acid, 7-amino-7-sulfocephalosporane acid, 7-amino-7-sulfoylcephalosporanic acid 7 -amino-7-methanol, lyfocephalosporanic acid, 7-amino-7-phosphocefadosporane acid, 7 amino-7-nitrocephalosporanic acid. lot, 7-amino-7 5 oxycephalosporanic acid,;: 7 -amine-7-Ditiocarboxycephalosporanic acid ,. 7-amio-7-dimethylaminomethyc lecephalosporanic acid, 7-amino-7-methyl-3-methyldecephalosproic acid, 7-amino-7-ethyl-3-chloromethyldecephalosporanic acid, 7-amino-7-propyl-3-carbamoyloxydephalosporanic acid, 7-amino-7-meroxy-3-methylene decephalosporanic acid, 7-amino-7-ethoxy-3-chloromethyl decephalosporanic acid, I 7-amino-7-butoxy-3-carbamoipoxime-tylodecephalosporoic acid, 7-amino-7-methylthio- 3-methyldecephalo sporacic acid, 7-amino-7-ethylthio-3-chloromethyldecef: losporoic acid ;, 7-amino-7-iaopropylthio-3-carbamoxide efalosporanova acid,

oft 7-ymino-7-acetyl-3-methyldecephalosporanic acid, 7-aminr-7-lopyrnyl-3-chloromethyldecephlospranic acid, 7-amino-7-trifluoromethoxy-3-methycephalosporanic acid,; 7-amino -; - 7-trifluoromethyltits "-3-methy de, ce-shlosporoic acid,: 7-amino-7-chloro-3-methydedephalosporic acid,: 7-amino-7-bromo-3-carbamoyloxymethyl-decephalosporanic acid, I 7-amino-7-fluoro-3g-carbamoyloxymethyl1 decyne | allo-11 oranic acid, 7-amyo 7-difluoromethyl-3-methyldecef-losporanic acid,: 7-amino-7-acetoxy-3-methyl decene (| spororano acid, i 7-amino-7-pronionyloxy-3-carbamoyl hydroxymethyl dedephalosporanic acid, j 7-amino-7-hydroxymethyl-3-methyldecephalo; spranoic acid, i 7-amino-7- {0-methyl-oxymethyl-3-methyldephalosporano and the acid, I 7-Amino-7- (01 -isopropyl) oxymethyl; -3 -carbamoyloxymethyl decephalosporanic acid, 7-amino-7: -. (-CyaceethylX-3-methyl-cephalosporanic acid, 7-amino-7- (. -Nitroethyl) -3-g-methyldecephalosporoic acid, 7-amino-7- ( α-formylethyl) -3-carbamoyloxymethyl decephalosporanic acid, 7-amino-7-allyl-3-chloromethyl-decephalo, sporanic acid, 7-amino-7-benzyl-3-methyl-decephalosporanic acid, 7-amino-7-cyano-3-carbamoxyloxymethyl decephaloshorane , 7-amino-7-nitroso-3-chloromethyldedephalosporanic acid, 7-amino-7-carbamoyl-3-methyldecephalrosphoranic acid, 7-amino-7-carboethoxy-3-x Ormetipdecephalosporanic acid, 7-amino-7-sulfo-3-carbamoyloxymethyldephalosporanic acid, 7-amino-7-sulphamoyl and l-3-chloromethy lde cephalosporanic acid, 7-amino-7-methylsulfo-3-methyldecephalosporanic acid, 7-amino 7-phospho-3-carbamoyloxymethyl decephalosporanic acid, 7-aminr-7-nitro-3-methyldedephalospo, ranova acid, i 7-amino 7-carboxy-3-chloromethyldecephalosporoic acid.

7-amino-7-dithiocarboxy-3-carbamoyloxymethyl decephaposporanic acid,

7-amino-7-Dimethylaminomethyl-3-megthyl decephaposporanic acid;

b-amino-b-propylpenicillanic acid,

6-amino-6-methoxypenicillanic acid,

b-amino-b-ethoxypenicillanic acid,

6-amino-6-butoxypenicillanic acid,

b-amino-b-methylthirpenicillanic acid,

6-amino-6-propiolthiophenyl cyllanic acid,

6-amino-6-butylthiophene III-llanic acid,

6-amino-6-acetylpenicillan acid: one

6-amino-b-propionylpenicillanic acid,

6-amino-6- (D-cyanoethyl) penicillanoic acid,

; 6-amino-6- (J5 -nitroyl) penicillanic acid,

; 6-amino-6- {S-formylethyl) penicillanic acid,

6-amino-6-allylpenicillan acid,.

i 6-amino-6-benzylphenylpanic acid6

one

: that

6-amino-6-cyanopa -: ;; cyllanic acid,

i b-amino-b-nitroaopenicillan kis; lot,

J 6-amino-in-carbamoylpenicillanic acid,

i 6-amino-6-carboethoxypenicillan

(acid,

. 6-amino-6-sulfophenyl 1 -shlanic acid,

6-amino-6-sulfamoylpenicillanic acid,

6-amino-6-methylsulfopenicillanoa

acid,

; 6-amino-6-phosphopenis dianoEa acid;

I 6-amino-6-nitropenis 1-lanic acid, ...

6-amino-6 carboxypenis 1LlanoBa acid,

i 6-amino-6-dithiocarboxypenicillanic acid,

6-amino-6-diamethylaminomethylpenicyl lanoic acid.

b-amino-6-trifluoromethoxypenyl cyllanic acid,

6-amino-6-trifluoromethylthiopenicion lanoic acid, 5 6-amino-6-chloropenicillanic acid,; . b-amino 6-bromopenyl 1-hillanic acid, 6-amino-6-fluoropenicillan acid, 6-amino-6-difluoromethyl pivni llanic acid,

ten; 6-amino-6-acetoxypenicillanic acid,

6-amino-6-propionyloxypenhengllanic acid,

6-amino-6-hydroxymethylpenicillanic acid 15,

  6-amino-6 - ((L-methyl) oxymethyl 1enicil.

 lanova sour. 6-amino-6- (rt-isopropyl) oximetry ne

nicillanic acid.

Subject invention

I 1. The method of obtaining derivatives of phalosporic or penicillins common forum

soy

.. i where M is benzyl, benzhydryl, trimethylsilyl, trichloroethyl, methoxymethyl, benzoyl 35methyl, or m txybetzyl ;.

(i.) will represent

1: - V

(SNS) 2

 WITH

or

401 where A means hydrogen, lower alk1: oyl-; hydroxy, carbamoyloxy, thiocarbamoxy hydroxy,; G4 is lower alkylcarbamoyloxy; N is lower alkylthiocarbamoyloxy; N, M is a lower alkyl alkylcarbamoyloxy; .N 5 N is lower alkyl 45 alkylthyrcarbamoyloxy, pyridine, alkyl pyridine, pyridine or aminopyridine;

R means lower alkyl, lower al-; canoyl, lower alkoxy, halo-lower | 50 | alkoxy, halo-lower alkylthio, halogen, (halo-lower alkyl, lower alkanoylszh.1si, (cH-oxy) -lower alkyl, ( 0 -oxy): I-branched lower alkyl, {jB-substituent (-vdenny) ethyl, allyl, benzyl, nitroso, 55 carbamoyl, carbonized alkoxy, sulfo, sulfamoyl, lower and gilsulfo, phospho, nitro, carboxy, dithiocarboxy, carbobene -