METHOD FOR PREPARING OPTICALLY ACTIVE DIALKYL TRANS-EPOXYSUCCINATES

Abstract: A method for preparing an optically active dialkyl trans­ epoxysuccinate comprises esterifying a diastereoisomer salt which is obtained by reacting DL-trans-epoxysuccinic acid with an optically active arginine, with a lower alcohol in the presence of an acid catalyst.

Description: METHOD FOR PREPARING OPTICALLY ACTIVE DIALKYL TRANS-EPOXYSUCCINATES BACKGROUND OF THE INVENTION 1. Field of the invention This invention relates to a method for preparing optically active dialkyl trans-epoxysuccinates. 2. Description of the Prior Art In the past, there have been known the following methods for optically active dialkyl trans-epoxysuccinates: (1) a method which comprises esterifying D-transepoxysuccinic acid which is obtained by fermentation or its barium salt, with a lower alcohol in the presence of sulfuric acid [Max W. Miller; Journal of Medicinal Chemistry, 6, 233 (1963)1, and (2) a method for preparing a diethyl D- (or L-)trans-epoxysuccinate which comprises resolving DL-trans-epoxysuccinic acid which is obtained by epoxidation of fumaric acid, with (+) or (-) (l-naphthyl)ethylamine and the like, and then esterifying the resulting D- or L-trans-epoxysuccinic acid with ethanol in the presence of sulfuric acid (Nohira et al, the previous substances II of the lectures at the 48th National Meeting of the Chemical Society of Japan, page 831). However, in the method through fermentation indicated in the above item (1), there can be obtained dialkyl D-trans-epoxysuccinate only. On the other hand, in the method through resolution indicated in the above item (2), there are drawbacks such as necessity of the complicated step for preparing diethyl D- or Ltrans-epoxysuccinate after resolution. SUMMARY OF THE INVENTION As a result of earnest studies to overcome the prior drawbacks, the present inventors have succeeded in preparing an optically active dialkyl transepoxysuccinate easily in better yield by esterifying directly a diastereoisomer salt which is obtained by reacting DL-trans-epoxysuccinic acid with an optically active arginine, with a lower alcohol in the presence of an acid catalyst, without the necessity for isolating the optically active trans-epoxysuccinic acid. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method for preparing an optically active dialkyl transepoxysuccinate (hereinafter referred to as Compound II) which comprises esterifying a diastereoisomer salt (hereinafter referred to as compound I) which is obtained by reacting DL-trans-epoxysuccinic acid with an optically active arginine, with a lower alcohol in the presence of an acid catalyst. The acid catalyst, herein, means sulfuric acid, hydrochloric acid, p-toluenesulfonic acid and the like, and is used in amounts of 1.1 to 3.0 moles per mole of Compound I. The esterification is carried out at a temperature ranging from 20 to 1000C, preferably 40 to 1000C, for 1 to 24 hours, preferably 4 to 7 hours. The lower alcohol means an aliphatic alcohol preferably having 1 to 3 carbon atoms, and includes concretely methyl, ethyl, n-propyl and i-propyl alcohols, among which methyl and ethyl alcohols are preferred. The compound I of the starting material may be prepared, for example, as follows: DL-trans-epoxysuccinic acid is dissolved in methanol while warming to 40 to 600C. To the resulting solution is added an aqueous solution of D-arginine or L-arginine with stirring, the mixture is allowed to stand at room temperature overnight, and the resulting crystals is collected by filtration to give D-trans-epoxysuccinic acid.D-arginine salt or L-trans-epoxysuccinic-acid-L- arginine salt. On the other hand, the filtrate is treated by a conventional manner to give L-transepoxysuccinic acid D-arginine salt or D-tans-epoxysuccinic acid L-arginine salt. The objective compound of the compound II is prepared as follows: The compound I is suspended in a lower alcohol which has a desired ester moiety of the compound II, the suspension is heated in the presence of an acid catalyst for esterification to give the compound II, which is then purified according to a conventional manner. The compound II thus obtained is useful not only as an intermediate of ethyl (2S, 3S)-3-[(S)-3methyl-l-(3-methyl-butyrylcarbamoyl)butylcarbamoyl]oxirane-2-carboxylate and the compounds related thereto but also as an synthetic material of various natural products having physiological activity. The method of the present invention makes it possible to obtain an optically active dialkyl transepoxysuccinate easily in better yield by reacting a diastereoisomer salt which is formed by reacting DL-trans-epoxysuccinic acid with D- or L-arginine, with a lower alcohol in the presence of an acid catalyst, without the step of isolating the optically active trans-epoxysuccinic acid, and therefore, the method is very useful as a industrial method of intermediates of medicines. The present invention will be more concretely illustrated below by the following Examples, but the invention is not limited thereto. Example 1 (1) To a solution of 66.05 g of DL-trans-epoxysuccinic acid dissolved in 1000 ml of methanol was added a solution of 87.1 g of L-arginine dissolved in 250 ml of water while warming to 500C with stirring. The mixture was allowed to stand at room temperature overnight. The crystals formed were collected by filtration, and washed with a small amount of methanol to give 73.1 g (yield : 95.5 %) of L-trans epoxysuccinic acid.L-arginine salt m.p. 181 - 1830C [aj 26 = +51.60 (C = 1.02, H2O) D (2) In 150 ml of ethanol was suspended 15.3 g of L-trans-epoxysuccinic acid.L-arginine salt obtained above. To the suspension was added gradually 14.7 g of conc. sulfuric acid under ice-cooling with stirring, and the mixture was heated at 600C with stirring for 4 hours. Subsequently, the excess ethanol was removed by evaporation under reduced pressure. To the resulting residue was added 150 ml of ice waterr and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and distilled to give 7.2 g of diethyl L-trans-epoxysuccinate. b.p. 800C/0.9 mmHg 26 = +110.50 (C = 1.12, C2H5OH) [&alpha;] Example 2 (1) To a solution of 66.05 g of DL-trans-epoxysuccinic acid dissolved in 1000 ml of methanol was added a solution of 87.1 g of D-arginine dissolved in 250 ml of water while warming to 500C with stirring. The mixture was allowed to stand at room temperature overnight. The crystals formed were collected by filtration, and recrystallized from a mixture of methanol and water (2 : 1 by volume) to give 73.1 g of D-trans-epoxysuccinic acid.D-arginine salt as needles. m.p. 172 OC (decomposition) 26 = -54.00 (C = 1.00, H2O) [ cr3, (2) To a suspension of 17.5 g of D-trans-epoxysuccinic acidD-arginine salt in 160 ml of ethanol was added 16.8 g of conc. sulfuric acid, and subsequently the mixture was treated by the method similar to that of Example 1 to give 7.6 g of diethyl D-trans-epoxy -succinate. b.p. 850C/1.0 mmHg [a]26 = -109.50 (C = 1.11, C2H5OH) Example 3 To a suspension of 15 g of D-trans-epoxysuccinic acidD-arginine salt dissolved in 150 ml of methanol was added 14.4 g of conc. sulfuric acid and consequently the mixture was treated by the method similar to that of Example 1 to give 5.1 g of dimethyl D-trans-epoxysuccinate. m.p. 74 - 750C [&alpha;]D26 = -125 (C = 1.00, C2H5OH)

Claims: CLAIMS:- 1. A method for preparing an optically active dialkyl trans-epoxysuccinate which comprises esterifying a diastereoisomer salt which is obtained by reacting DL-trans-epoxysuccinic acid with an optically active arginine, with an lower alcohol in the presence of an acid catalyst. 2. A method accoding to Claim 1, wherein the lower alcohol is methyl alcohol, ethyl alcohol, npropyl alcohol or i-propyl alcohol. 3. A method according to Claim 1 or 2, wherein the acid catalyst is sulfuric acid, hydrocloric acid, or ptoluenesulfonic acid. 4. A method according to Claim 1, 2 or 3, wherein the acid catalyst is used in an amount of from 1.1 to 3.0 moles per mole of the diastereoisomer. 5. A method according to Claim 1, 2, 3 or 4, wherein the esterification is carried out at a temperature ranging from 20 to 1000C for 1 to 24 hours.

Inventors: HATAYAMA, KATSUO, MURATA, MITSUO, SOTA, KAORU, YOKOO, CHIHIRO
Applicants: TAISHO PHARMACEUTICAL CO. LTD
Application year: 1984
Main classification: C07D303
IPC codes: C07D303