SU747419A3 - Method of producing derivatives of amino acids or their salts or optical isomers - Google Patents

Abstract

1504541 Compositions containing amino acid derivatives CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT 28 April 1975 [29 April 1974 26 March 1975] 17608/75 Heading A5B [Also in Divisions C2 and C3] Cosmetic and pharmaceutical compositions contain (I) and/or salts thereof as active ingredient wherein A<SP>1</SP> stands for hydroxy, C 1-4 alkoxy, cycloalkoxy, aralkoxy, substituted aralkoxy, aryloxy, substituted aryloxy or a group of the general formulae: wherein R<SP>14</SP> is hydrogen, C 1-4 alkyl or aralkyl, R<SP>6</SP> is hydrogen, C 1-5 alkyl, aralkyl, hydroxysubstituted aralkyl, heteroaralkyl or a group of the general formula: Y is hydroxy, amino, alkylamino, dialkylamino, C 1-4 alkoxy or aralkoxy, and r is an integer of from 1 to 10 or an average polymerization grade of up to 2000, B<SP>1</SP> is a group of the formulae -SO 2 OH, -OSO 2 OH, -O-PO(OH) 2 or -S-S-R<SP>11</SP>, wherein R<SP>11</SP> is C 1-4 alkyl, aralkyl or aryl or a residue obtained when removing group B<SP>1</SP> from the general formula (I), R stands for hydrogen, C 1-4 alkyl or aralkyl, R<SP>x</SP> stands for hydrogen or halogen, R<SP>1</SP> stands for hydrogen, C 1-4 alkyl, aryl, aryl having a nitro or alkoxy substituent, aralkyl, substituted aralkyl, alkoxycarbonyl, cycloalkoxycarbonyl, aralkoxycarbonyl, substituted aralkoxycarbonyl having, e.g. a halogen, alkoxy, nitro, phenylazo or alkoxyphenylazo substituent, unsubstituted or substituted aryloxycarbonyl, acyl, arylsulfonyl or group (wherein R<SP>6</SP> has the same meanings as defined above and p is an integer of from 1 to 10 or an average polymerization degree of up to 2000), R<SP>2</SP> stands for hydrogen, C 1-4 alkyl, or aralkyl or R<SP>2</SP> and R<SP>2</SP> may each stand for a -CO- group and form a ring through an o-phenylene, alkylene or -CH=CH- group, R<SP>3</SP> stands for hydrogen, carboxy or carbalkoxy, R<SP>4</SP> stands for hydrogen, halogen, C 1-4 alkyl or hydroxy, R<SP>5</SP> stands for hydrogen, halogen, C 1-4 alkyl, carboxy, carboxamido, carbalkoxy or carboaralkoxy, m is 1, 2 or 3, n is 1, 2, 3 or 4, s is 0, 1, 2, 3 or 4, and t is 1, 2 or 3.

Description

the protective group of the a-amino group is cleaved by reacting with hydrogen bromide in glacial acetic acid, after which the compound obtained is total iijT-CI-CO-A (CJhb CO-NH - ((; H.2) 2 OZ in the presence of water of alcohol and / or acetone is subjected to alkaline hydrolysis with the help of an alkali metal hydroxide. The desired product is isolated in free form or as a salt, or otic isomers. The structure common to all compounds of formula (I) is that they contain a substituted L-position dicarboxylic acid or e (also still substituted in other is a derivative that is bound by its W-carboxyl group by an amic acid bond to a primary or secondary alkylamine, which, in addition to the various substituents in the alkyl side chain, contains in its b-position a group of strongly acidic character. cystamine or its substituted derivatives can be acylated in the amino group with the derivatives of w -amino dicarboxylic acid. The acylation of cystamine can be carried out in various ways (the method of activated complex zfir, the method with mixed anhydrido m). The resulting compound is reacted with hydrogen peroxide or peracids, the disulfide bond is subjected to oxidative cleavage, and after removing the protective groups, a compound of formula (I) is formed. For example. a) 40.85 g (0.11 mol) of o-benzyl ester of bobenzyloxy-1-glutamic acid are dissolved in 500 ml of acetonitrile. The solution is cooled to -15-C in the absence of moisture. Under stirring, 15.4 m (0.11 mol) of triethylamine and then 15.4 ml (0.11 mol) of isobutyl chloroformate are added dropwise to the cooled solution with stirring. The reaction mixture is stirred at -1 for 40 minutes, after which 28 ml (0.2 mol) of triethylamine, then 11.26 g (0.05 mol of cystamine hydrochloride and finally 250 ml of acetonitrile) are added to it. Siviot for another 2 hours and then for 4 hours at room temperature.After the reaction is completed, the mixture is evaporated in a vacuum at 30 ° C. The residue is stirred in 200 ml of ice-water with stirring and cooling and the solution is again evaporated in a vacuum at 35 ° C. The residue together with 250 ml of water and) 00 ml of ethyl acetate are transferred to a separatory funnel and the organic phase. The latter is successively shaken in a separatory funnel with 250 ml of water, then twice with a 5% solution of sodium carbonate in portions of 250 tAHf twice a day. hydrochloric acid in portions of 250 MP and, finally, with 250 ml of water. From the aqueous phase obtained by shaking with a solution of sodium carbonate by acidifying it with hydrochloric acid and shaking in a separating funnel with ether, about 5 g of unreacted carbobenzyl csi-1-gl 0 -saminoic acid can be obtained. The ethyl acetate phase is dried over anhydrous sodium sulphate and then evaporated to dryness in vacuo at. The result is a thick oily residue, which soon solidifies into a crystalline mass. This mass is triturated with 250 ml of absolute ether and the crystals are filtered off. The crude product (40-42 g) is recrystallized from a mixture of 100 ml of ethyl acetate and 170 ml of ether. The result of 29.3 g of N, M-bis-m-carbobenzyloxy-5- (X-beneyl) -1 glutag / shl-cystamine, so pl. 91-920С. Found,%: C 60.85; H 5.91, 6.61; S 7.72. C / mN AG DOEDB, Calculated,%: C 61.52; H 5.89 N 6.52; S 7.46. b) 29.3 g (0.0359 mol) obtained in accordance with paragraph a), N-bis-M-carbobenzyloxy-5- (s.-benzyl) -L-glutamyl-cystamine is dissolved in 75 g of glacial acetic acid. acid. A freshly prepared mixture of 75 pll of 30% hydrogen peroxide and 225 ml of glacial acetic acid is added dropwise to the ice-cooled solution over 15 minutes. At the end of the addition of the reactants, the cooling is stopped and the reaction mixture is stirred at room temperature for 4 hours, after which it is evaporated in vacuo at 30 ° C. The oily product is dried in a desiccator first over phosphorus pentoxide and then above solid hydroxide; potassium oxide. The result of 32.4 g of carbobenzyloxy - - (C-benzyl) -L-glutamyltaurine. The crude product can be used without additional purification for y-L-glutamyl taurine. c) 32.4 g (68 mol) of carbobenzyloxy-g- (L-benzyl) -1-glutamyltaurine obtained in paragraph b) is dissolved in 50 ml of glacial acetic acid and 4 mol of hydrogen bromide is added to the resulting solution. dissolved in 50 ml of acetic acid. At the same time, an energetic release of gaseous -two-carbon dioxide gas is observed. The reaction mixture was left to stand for 2 hours at room temperature, and then evaporated at cuum at. The oily residue is dissolved in 170 ml of water and shaken 5 times in a separatory funnel in 70 ml portions of ether. The aqueous phase is evaporated in vacuo at 35 ° C. The precipitate gives 25.1 g of - (o (-benzyl) glutamyl taurine, which is recrystallized from 90% ethanol. Rf. (N-butanol-pyridine-ice for acetic acid) water 15: 10: 3: 12) 0.53. Rf (n-butanol-ice on acetic lot - water 4: 1: 1) 0.39. d) Obtained in accordance with paragraph (c) 7 C benzyl) -L -glutamyl taurine (25.1 g) is dissolved in 150 m 1 n. Potassium hydroxide solution. The thief is left to stand for 4 hours at room temperature and then poured into a 2 x 100 cm column filled with Dowex 50x2 ion exchange resin (FEuka, 100,200 mesh) in H-form. Elution is dried with water. From the moment of leaching start, 300 ml of the eluate is collected and evaporated in vacuo at .. 8-10 ml of water and about 100 ml of ethanol are added to the oily residue, resulting in a crystalline precipitate from the mixture. After filtering, washing with alcohol and drying, 16 are obtained. 9 g - L-glutamyltaurin. The pure product melts at 219220 ° C, cAj + 14 ° (water / s 1.02). The relative mobility with respect to cysteic acid, determined by electrophoresis on paper at pH 6.5, is equal to O, 73, and at pH 1.8-0.53. The crystalline product is recrystallized from an 80% aqueous solution of alcohol. As a result, 12.05 g of pure product is obtained, which, based on N, N-bis-N-carboxybenzoyl-jf- (D-benzyl) -Lglutamyl-cystamine, corresponds to a yield of 43%. If the corresponding D-isomer, carbobenzyloxy-jy- (L-benzyl) -O-glutamyltaurin, is used as the starting compound, the result is α-D-glutamyltaurine,. m.p. 219-2200С, -13.9 °

Claims (1)

1. A method for preparing amino acid derivatives of the general formula tt V-BL-SOBCH (} H2) Z co-HH-tOHjIj-ftOa®, in the presence of water, alcohol and / or acetone, the alkali metal hydroxide is subjected to alkaline hydrolysis, followed by isolation of the desired product in the free state or in the form of a salt, or optical isomers. n is the integers 1,2 or 3, whether their salts or optical ers, characterized in that the compound of the general formula 8-CH-CH-CO-A CO-A; R is alkoxycarbonyl with 1-4 carbon atoms or C-Cd-phenylalkoxycarbonyl not substituted or substituted by halogen, C-C4-alkoxy or nitro, or phenoxycarbonyl; - benzyloxy or p-methoxybenzyloxy, or p-nitrobenzyloxy; - hydroxyl, nitrophenoxy-, pentachlorophenoxy- or alkoxycarbonyloxy group with 2-4 carbon atoms, reacts with the formula NH2- (CH2) in the absence of a tertiary base, a compound of the general form n- 5N-; -HH- (CHalj- $) a mixture of glacial acetic acid and 30% hydrogen peroxide of the resulting compound of the formula I -CH-CH.-CO-A CO-irn- (CH5) 2-SO, OH, interacting with methyl bromide in glacial acetic acid, the protective group is L-amino, after the resulting compound of the general formula H-CH-CO-A (iHjb CO-NH- (Priority on April 29, 74; R is benzyloxycarbonyl; A - benzyloxy group; A, p have the above values. 26.03.75 with: all other values of R. A radicals. Sources of information taken into account during the examination 1. K. Buhler, D. Pearson. Organic syntheses, I. M., Mir, 1973, pp. 504.