SU383712A1 - METHOD OF OBTAINING ETHYL AIR DIPEPTIDES - Google Patents

Description

one

The invention relates to a process for the preparation of new compounds, ethyl esters of o-di- (2-chloroethyl) -amino-L-acetyl-Dphenylalanine dileptides, which can be used in organic peptide synthesis.

Known methods for producing peptides based on l-di- (2-chloroethyl) -amipo-1M-acetylphenylalanine are used as physiologically active compounds.

For the preparation of dipeptides o-di- (2-chloroethyl) -aminophenylalanine, the commonly used methods could not be used, since the latter is not readily available for the preparative preparation. y -phenylalanine is that o-nitro-M-acetylphenylalaninamic acid ethyl esters are reduced by hydrogen in the presence of Rene nickel, the reaction products are condensed with ethylene oxide in 40-70% acetic acid at 20 ° C to form ethyl esters - (2-hydroxy yl) amino-N-acetyl-L - fenilalaiinamiiokislot which by reaction with thionyl chloride in ethyl esters prevrashayut dipeptides o-di- (2-chloroethyl) amino-N-acetyl) L-phenylalanine.

The proposed method is of practical and theoretical interest, since it allows one to synthesize o-isomer dipeptides without using the hard-to-reach o-di- (2-chloroethyl) aminophenylalanine, the preparation of which is associated with cyclization of intermediate compounds by ortho position.

Example 1. O-nitro-N-acetylphenylalanylphenylalanine ethyl ester. a solution of 2.06 g (0.01 mol) of N, NIfl is poured. To a suspension of 2.52 g (0.01 mol) of o-nitroN-acetylphenylalanine in 20 ml of chloroform, a solution of 2.06 g (0.01 jol) of N, N dicyclohexylcarbodiimide in 20 ml of chloroform and 1.93 g (0.01 mol ) ethyl phenylalanine ester in 20 ml of chloroform. Cook in for 3 hours and leave in the fridge overnight. Filter, evaporate in vacuo and after crystallization from alcohol, a crystalline substance is obtained with m.p. 181 - 182 ° C. The yield of 3.42 g (80%).

Found,%: C 61.48; N 9.98. CaaHssNsOo.

Calculated,%: C, 61.83; H 5.80; N 9.84. 16. Substance t. Pl. 156-157 ° C. Found,%: C 57.18, H 6, 72; N 10.95. CigHssNsOe.

Calculated,%: C 56.99; H 6.59; N 11.07. 1e. The substance obtained in this way has a m.p. 138-148 ° C (a mixture of diastereoisomers with t. PL1. 163-165 and 140-142 ° C). The reaction of these substances proceeds as shown below.

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NO, CeH, CH, CHCOOH + R - CH - COOC.H II

NHCOCHsNH, - O - NOsCeH CH CHCONHCH

(I)

N - NH.C..CHCONHCH (P)

O - (), - N - C.H.CHaCH - CONHCH

(Iii)

o - (C1CH, CH,), N - C.H4CH2CH - CONHCH

R a) - CH., C.H ,; 6) - CH (CHg) ,; c) - CH.COOC.Hs

P p and M e p 2. Ethyl ether o-aMHHO-N-aue ethylphenylalanylphenylalanine, On.

Pa. 4.27 g of nitro rosocompounds (0.01 m, ol) in 100 M of alcohol are hydrogenated in the presence of Rene nickel at 45-50 ° C. The warm solution is filtered, evaporated by s-vacuum and 3.37 g (85%) of the amino compounds are obtained as colorless crystals with m.p. 166-168 ° C (from alcohol).

Found,%: C 66.59; N 10.46.

C22H27N3O4.

Calculated,%: C, 66.49; H 6.80; N 10.57.

Pb, t. Pl. 214-216 ° C.

Found,%: C 61.86; H 7.88; N 12.21.

Ci8H27: N304.

Calculated, i%: C 61.89; H 7.73; N 12.03.

Not, so pl. 155-158 ° C.

Found,%: C 58.10; H 7.00; N 10.98.

Ci9H27N3O6.

Calculated,%: C 58.01; H 6.86; N 10.68.

Example 3. O-di- (2-hydroxyethyl) -amino-N-acetylphenylalanylphenylalanine ethyl ester.

Ilia. A mixture of 1.55 g (0.0026 mol of the amino compound, 10 ml of ethylene oxide and 60 ml of 40% acetic acid is left for 48 hours at 20 ° C. After the usual treatment, the solvent is distilled off, the residue is kept in a refrigerator with sulfuric ether 48 hrs. - The solid is recrystallized from alcohol and 0.76 g (42%) of Ilia is obtained with a melting point of 90-94 ° C.

Found,%: C 64.20; H 7.08; N 8.98.

C26H35N3O6.

383712

R /

,

NHCOCH, COOCaHj

NHCOCHg COOCaH,

COOC.Ha J

/

,

NHCOCH, COOCjH,

Calculated,%: C 64.33; H 7.21; N 8.66.

III6 - without isolation.

Ills - without highlighting.

Example 4. O-di- (2-chloroethyl) -amino-N-acetylphenylalanylphenylalanine ethyl ester.

Iva. 2.43 g (0.005 mol) of the hydroxy compound, 50 ml of dry chloroform and 3.35 ml of thioiyl chloride — boils for 25 minutes and evaporated to dryness. The resulting oil is dissolved in absolute spirta, neutralized with diethylamine, filtered and again evaporated. The residue is dissolved in ethyl acetate, filtered and planted with non-ether. After crystallization from op-ryt, 0.54 g (20.7%) of the substance with m.p. 117 - (119 ° C.

Found,%: C 60.03; H6.49; C1 13.23; N8,18.

С22НззС12НзО4.

Calculated,%: C 59.77; H 6.32; C1 13.60; N 8.04.

IV6, so pl. 140-142 ° C.

Found,%: C 55.79; H 7.07; 01 14.72; N 8.79.

С22Нз5С12Ыз04.

Calculated,%: C 55.69; H 7.35; C1 14.91; N 8,82.

IVe, so pl. 88-92 ° C.

Found,%: C 53.60; H 6.36; C1 13.17; N8.01.

S2zNzzS12.MzOb.

Calculated,%: C 53.26; H 6.48; C1 13.51; N 8,10.

The subject of invention

A method for producing a dipeptide ethyl ester; in an o-di- (2-chloroethyl) amino-M-acetyl-1B phenyl-alipip, characterized in that the o-nitro-N-acetyl-1) /.-phenyl-ananiphenyl amino acid is reduced in hydrogen In the presence of Rene nickel, the resulting product is condensed with ethylene oxide in acetic acid to form o-di- (2-hydroxyethyl) -amino-N-acetyl-Db-phenyl-alaninoic acid ethyl ester, which reacts with thionyl chloride in chloroform and is converted into dispeptide ethyl ester -di- (2 chloro. 1) -amino-1-acetyl - /) b - phenylalawium and c left vyl.el product in a known manner.