CS200425B3 - Process for preparing alkylen-n,n'-bis-prolines - Google Patents

Description

The present invention relates to the preparation of alkylene-Ν, Ν'-bis-proline in a non-aqueous medium.

Alkylene-Ν, Ν'-bis-proline are complexons based on the natural amino acid proline. These are substances synthesized by a new procedure, not yet described in the literature. In Patent Literature / Bersworth F.C .: Brit. U.S. Pat. 723316 (1955)], although condensation of lower amino acids is found, but only in an aqueous environment. A disadvantage of the process of the cited patent is that it is operated under pressure and the yields of the reaction are very low. The condensation of proline-type cyclic amino acids with an alkylene dihalide in a non-aqueous medium has not been described at all.

The present invention provides the preparation of alkylene-Ν, Ν'-bis-proline by condensation (preferably in an alkaline environment) of proline with a C 2 -C 8 alkylene dihalide (preferably ethylene dibromide) wherein the molar ratio of amino acid to alkylene dihalide is 2: 1 to 5 : 1, preferably 2: 1 or 3: 2 and condensation is carried out under gentle reflux at a pressure ^{of 5} to 1O 5.10® Pa, preferably from ⁵ to 1.1Ο 5.1Ο ⁵ Pa. Condensation is carried out in a non-aqueous environment.

The condensation of proline with an alkylene dihalide follows the equation:

200 425

200 425

-COOH + X (CH ₂ ) _n X

N

AND

H where X = halogen and n = 2 to 8.

^C0 ° H

N (C ^H a) _n + 2HX N / -COOH

The reaction produces alkylene-Ν, Ν'-bis-proline and hydrogen halide, which ee β advantageously binds by the addition of alkali in the form of the corresponding alkali metal (or alkaline earth metal) halide, thereby moving the reaction to the right, which is favorable for alkylene-vznik. Bis'-bis-proline.

In non-aqueous condensation, proline must first be converted by esterification with an alcohol to the corresponding ester. This is condensed at reflux with an alkylene dihalide, preferably in an alkaline medium. The precipitated alkylene-Ν, Ν'-bis-proline ester precipitate is purified by recrystallization from alcohol. The alkylene-Ν, Ν'-bis-proline is liberated from the corresponding ester by saponification.

An advantage of the preparation of the alkylene-Ν, Ν'-bis-proline according to the invention is that the condensation proceeds sufficiently quickly already under normal pressure and with a higher yield than in the procedures described for the condensation of lower amino acids in an aqueous medium.

Example 1

In a 230 ml flask equipped with stirrer, gas inlet and outlet, 23 g (0.2 mol) of finely divided L-proline are suspended in 150 ml of absolute methanol. Dry HCl is then bubbled through. When the acid dissolves after about 1 hour, the solution is heated on a water bath for 10 minutes and then cooled in an ice-NH 4 Cl cooling mixture. The precipitated L-proline methyl ester hydrochloride is filtered off with suction and washed with cold methanol and ether. Concentration of the mother liquor yielded a further portion of the product.

To a suspension of 18 g / 0.1 mol / hydrochloride thus obtained L-proline in 20 ml of CHC1 ₃ was added at 0 ° C with 100 ml of a 2% solution of NH ₃ in CHCl. The mixture was shaken alternately for 15 minutes and cooled. Leave to stand at 0 ° C overnight and filter the precipitate the next day. The solvent was distilled off under reduced pressure at 20 ° C. 10 g of crude L-proline methyl ester is obtained in the form of a pale yellow, viscous liquid.

In a 250 ml three-necked flask equipped with stirrer, reflux condenser and dropping funnel, 10 g (0.08 mol) of L-proline methyl ester is heated to 90 ° C. Is then added with stirring 9.4 g / 0.05 mole / of ethylene and 15 g / 0.1 mol / KgC0 ₃ as an aqueous solution. After hours of condensation under reflux and with vigorous stirring, a white precipitate of white ethylene-N, N'-bis-L-proline methyl ester began to precipitate from the initially clear solution. This was purified by recrystallization twice from 99% ethanol.

23 g (0.08 mol) of ester and 0.4 mol of KOH in 30 ml of water and 100 ml of ethanol are heated in a 250 ml flask for 4 hours. Then, under a slight vacuum, most of the ethanol was distilled off and the solution was acidified to pH 1 by dropwise addition of concentrated HCl, cooled to 0 ° C and allowed to stand overnight.

200

The liberated ethylene-Ν, Ν'-bis-L-proline is obtained by precipitation with the addition of absolute ethanol and purified several times by recrystallization from acetic acid. 19 g of product were obtained, which is a 30% yield. 300 DEG C. (decomposition). For C ₁₂ »20 2®4 ^ / ^{n <l e} * ° ^{in the} L and weight 256.3 / calculated: C 56.24%, 10.93% N, 7.86% H; found: 55.91% C, 10.42% N, 7.64% H. The obtained compound was characterized by IR spectrum.

OBJECT OF THE INVENTION

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of alkylene-Ν, Ν'-bis-proline according to the author's certificate No. 200424, characterized in that in non-aqueous medium proline is first converted by esterification to the corresponding ester which is condensed with a C 2 -C 8 alkylene dihalide parts, particularly of ethylene, preferably in an alkaline medium at reflux, and the pressure ranges ^{from 5} to 1.10 5.10® Pa, preferably from 1.10 ⁵ to 5.10 ⁵ Pa in a molar ratio of proline to alkylendihalogenid 2: 1 to 5: 1, preferably 2: 1 to 3: 2, the alkylene N, N'-bis-proline is liberated from the ester by saponification and the crude product is precipitated with an alcohol, preferably absolute ethanol, and then recrystallized with acetic acid. FIXED DESCRIPTION OF THE INVENTION TO THE COPYRIGHT CERTIFICATE δ. 200,425 Int, Cl? OJ C 07 D 207/16 In the description of the invention for an author's certificate 200 425 there is an erroneous code in the header. Correctly: 200,425 (11) (B-j) OFFICE FOR INVENTIONS AND DISCOVERIES