SU1068428A1 - N,n-disuccinimidyl sulfite as reagent for synthesis of n-oxysuccinimide ethers of n-substituted amino acids and peptides - Google Patents

Abstract

N, N-disuccinimidyl sulfite of formula Qa-o-s-OHip 6 as a reagent for the synthesis of N-oxysuccinimide esters of M-protected amino acids and peptides. (L yes ace ke 00

Description

This invention relates to a novel N, N -disuccinimidyl sulfite compound, which can be used to synthesize the N-oxysuccinimide esters of Unprotected amino acids and peptides used as intermediates in the synthesis of biologically active peptides. At present, the N-oxysuccinimide esters of N-protected amino acids have been widely used in the synthesis of biologically active peptides. When using these compounds, racemization of the final products is practically not observed, and the byproduct released during the reaction, N-oxysuccinimide, is highly soluble in water, which greatly facilitates the release of the final products f1. A number of methods are known for the preparation of N-oxysuccinimide esters of N-derived amino acids and peptides, among which the carbodiimide method is most widely used. . According to this method, the N-protected amino acid or peptide is introduced into condensation with the N-oxysuccinim house in the presence of dicyclohexylcarbodiimide at a low temperature of 23. However, when using the carbodiimide method, an undesirable formation of acylurea is often observed, which leads to a decrease in the yield of the target product. In addition, dicyclohexylcarboconimide is highly toxic. K is a strong allergen, i. A known method for producing N-hydroxy succinimide esters of L-protected amino acids and peptides by the method of mixed G33 anhydrides. This method makes it possible to obtain activated efnry of N- $ protected amino acids and peptides with a good yield, but lightly hydrolyzing substances such as alkyl chloroformates at lower temperatures are used for its re-formation (which makes the process low-tech especially in industrial conditions. A method is known for preparing N-oxysuccinimide esters N-nitrated amino acids and peptides based on the use of N, N-disuccinimidylcarbonate and G43 - G6 |. As a reagent for the synthesis of N-oxysuccinimide esters: It is necessary to include the inaccessibility of L, S-disuccinimidyl carbonate, which is obtained from high-toxic compounds — trichloromethyl chloroformate or phosgene, which significantly limits the prospects for the synthesis and application of S, H-disuccinimidyl carbonate. peptides, which can be obtained from available raw materials in high yield. The goal is achieved by N, N dialicimidylsulfite formula Kj-0-so-iQ v l which is used as reagent to synthesize N-hydroxysuccinimide esters of N-protected amino acids and peptides ... Synthesis of N, N-disuccinimidyl sulfite is carried out by reacting trimethylsilyl Gly elum of N-oxysuccinimide with thionyl chloride in the presence of the organic solvent rO-SUCH J + OCl-jHH1 8-O-llQ 1-2 "-CCX | (N-Oxysuccinimide esters of N-protected amino acids and peptides are obtained by reacting 1 mol of N-protected amino acid or peptide with 1 mol of N, t -dicycminimidyl sulfite in an organic solvent in the presence of 1 mol pyridine., Example. Preparation of N, N-disuccinimidyl sulfite. A solution of 35.0 g (1.88 mol) of N-oxysuccinimide trimethylsilyl ether in 30 ml of tetrahydrofuran is added dropwise to a solution (11.1 g (0.94 mol) of thionyl chloride in 30 ml of diethyl ether) cooled to a solution while stirring temperature of the reaction mixture from 2 to / fC Then the reaction mixture is kept for 30 min., The precipitated precipitate is filtered off, washed with cold tetrahydrofuran (225 ml), diethyl ether (225 ml), dried in a vacuum.

In the end, 41.0 g (80%) of N, N-dicycminimidyl elfite are obtained in the form of a fine crystalline substance with a melting point of 134-136 ° C.

Elemental analysis

Found,%: C 35.05; H 2.79; N 10.56; S 11.41.

Calculated,%: C 34.79; H 2.92; N 10.14; S 11.61.

IR Spectrum (CM): 1785, 1720, 1230, 1090, 1050, 1010.

EXAMPLE 2. Preparation of N-oxysuccinimide ester of N-Tpier-eyTHn oxycarbonyl-i4-alanine.

To a solution of 1.0 g (5.29 mmol) of N-tert-butyloxycarbonyl-, α-alanine in 5 ml of acetonitrile, 0.42 g (5.29 mmol) of pyridine and 1.46 g (5.29 mmal) are added S, K-disuccinimidylsulbitol. The reaction mixture is stirred until a solution is formed and left for 1 h at 22-2 ° C. Then the solution is evaporated in vacuo, the residue is dissolved in ethyl acetate, the solution is washed with 5% sodium bicarbonate solution (ml), saturated chloride solution; sodium, dried over sodium sulfate and evaporated. The residue is dried under vacuum.

A total of 1.32 g (87%) of N-tert-butyloxycarbonyl-b-alanine N-oxysuccinimide ester is obtained with mp. 1b6-1b7 ° C; otJ | -50.9 (,. Dioxane). Literary data: so pl. r2J, CoiJi -51.0 (c 2, dioxane) C47.

According to the procedure described in Example 2, the N-oxysuccinimide esters of the series of N-substituted amino acids are obtained. The physicochemical constants of the compounds obtained are listed in the table.

84

167-168

Boc-G y-ONSu

135-136 -55 ° (, 1)

IN

Boc-PrO-ONSu 110-111 + 6.2 ° Boc-Seir-ONSU 84 135-136 -34 Wo-Thr-ONSu 75 181-182 -12 ° Wo-Tyr-rONSu

Example 3. Obtaining the N-oxysuccinimide ester of N-carbobenzoxy-1-alanyl-1; -alanine.

To a solution of 2.94 .g (10.0 mmol) N-carbobenzoxy-and-alanyl- {-alanine in: 10 ml of acetonitrile, add 0.79 g (10.0 mmol) of pyridine and 2.76 g (10, 0 mmol) N, N-disuccinimi, g dilsulfite. The reaction mixture is stirred until a solution is formed. After .1 h, the pc solution is evaporated.

M.p. 168-169 ° C 2

.pl. 135-136 С f2 J -55 ° (, 5)

In principle, the residue is dissolved in ethyl acetate, the solution is washed with a 5% sodium bicarbonate solution, with a saturated sodium chloride solution, dried over sodium sulfate and evaporated. A total of 3.40 g (87%) of N-oxysuccinimide eLira of N-carbobenzoxy-C-alanyl-1, -alanine are obtained in the form of a crystalline solid with mp. 155-15 ° C; , 4 (, dioxane) .. Tet.pl. 112-113 ° 5 (, 6) + 6.5 ° (, 5) (, 0) So pl. 134-136 ° C b (C 1.0) (C-1.0) So pl. 180-182 ° C | J5J 06320. 12.5, ()

j.1068428

Routine data:, 5fc 4, l / Usage of S, S-disuccinim dildioxane / S434 sulphite in the synthesis of N-hydroxysuccinic, N cheap and part target compounds with an available raw material yield of .75-87% without further purification.

Claims (1)

Ν, Ν-Disuccinimidylsulfite Formula as a reagent for the synthesis of ок-oxysuccinimide esters of Ν-protected amino acids and peptides. 81) „„ 1068428 > one 1068428 one