JPS58188859A - Preparation of optical active cis-1,3-dibenzyl-5- methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid - Google Patents

Abstract

PURPOSE:To crystallize the titled compound preferentially, by subjecting a supersaturated solution of racemic-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazolidine-4-carbo xylic acid to optical resolution, by using optical active crystal. CONSTITUTION:Racemic-cis-1, 3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazolidine- 4-carboxylic acid is dissolved in a solvent such as benzene, toluene, etc. under heating, the solution is cooled to give a supersaturated solution, and, if necessary, an organic base such as triethylamine, etc. is added to the solution to increase its stability. When crystal of optical active cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid is brought into contact with the solution, crystal occurs naturally, the solution is subjected to optical resolution, and the desired compound, the same kind as that of the optical active substance can be preferentially crystallized from the supersaturated solution. USE:An intermediate for biotin and other drugs.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides optically active j) cis-1,8-dibenzyl-5-
Methoxycarbonyl-2-oxoimidazolidine-4-
The present invention relates to a method for producing carboxylic acid.

Optically active cis-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (hereinafter abbreviated as phester compound) is an important intermediate for biotin and other drugs. .

Conventionally, there has been no known method for optically resolving a racemic no-ph ester to obtain an optically active no-ph ester.

In the method of optically resolving a racemate to obtain an optically active form, one optically active form is inoculated into a supersaturated solution of the racemic form, and the optically active form of the same type as the inoculated form is separated and obtained. The principle of the so-called preferential crystallization method is well known. It is said that this method can be advantageously applied only when the racemate in question forms a racemic mixture, and cannot be applied to racemic compounds. However, it is unclear which compounds form racemic mixtures or whether preferential crystallization methods can be applied, and neither is I7 nor its regularity. That is, the case where a racemic mixture is formed to which this optical resolution method can be applied is a rather special case. Therefore, great effort must be made to find a compound that satisfies these conditions. Moreover, it is extremely rare that the compound to be optically resolved can preferentially crystallize as it is.

The Ministry of the Invention and others have conducted intensive studies on optical resolution methods using various methods for racemic-Hafester forms, and have found conditions under which racemic-Hafesters form a racemic mixture and can be optically resolved in that form by the preferential crystallization method. (That is, according to the method of the present invention, an optically active Hafester compound is present in a supersaturated solution of a racemic Hafester compound, and the optically active compound is It is possible to obtain an optically active Hafester by preferentially crystallizing and collecting the same kind of optically active Hafester, and by the coordination of the inoculated optically active Hafester, 4R, 5S It is possible to arbitrarily obtain optically active Hafester bodies with coordination, 4S, and 5R coordination.

From the optically active Hafester compound that can be obtained by the method of the present invention, optically active cis-1,8, which is known as an important intermediate in the production of biokin, is produced by reduction and ring-closing reactions.
-dibenzylhexahydro-IH-furo (8,4-d)
Imidazole-2,4-dione (hereinafter abbreviated as lactone) can be produced.

In this reduction and ring-closing reaction, only one of the methoxycarbonyl group or the carboxyl group of the optically active Hafester compound is selectively reduced, and then a ring-closed optically active lactone compound can be obtained by acid treatment.

In case A, where the methoxycarbonyl group of the optically active Hafester compound is selectively reduced, the reduction reaction can be carried out using a reducing agent such as lithium borohydride or sodium borohydride, and the carboxyl group can be selectively reduced. In this case, a reduction reaction is performed using a reducing agent such as diborane, or the carboxyl group is converted into a corresponding active ester group using N-hydroxysuccinimide, p-nitrophenol, isobutyl chloroformate, etc., followed by hydrogenation. The reduction reaction may be carried out using a reducing agent such as sodium boron.

After the reduction reaction, an optically active lactone can be obtained by making the reaction solution neutral or acidic with an acid such as hydrochloric acid or sulfuric acid.

In the production of an optically active lactone form from an optically active Hafester form, the results can be obtained by reducing the methoxycarbonyl group of the optically active /'%-fester form and closing the ring, and by reducing the carbonyl group and closing the ring. The coordinations of the optically active lactones obtained are opposite to each other.

Therefore, from both the 4S, 5R coordination and 4R, 5S coordination optically active Herfester bodies obtained by the method of the present invention, 4aS, which is an important intermediate in the production of natural biotin, is
, which can lead to an optically active lactone form having a 6aR coordination.3 In other words, both of the two optically active Hafester forms that can be obtained by the method of the present invention can be used as intermediates in the production of natural biotin. It is something that can be used.

This means that in general optical splitting operations, the obtained 2
This is a major feature compared to the fact that only one of the optical isomers of a species is used, while the other is racemized and subjected to optical resolution again, and is of great industrial value.

The method of the present invention will be specifically explained below.

The method for preparing a supersaturated solution of the racemic-Hafester is by heating and dissolving the racemic-Hafester in an appropriate solvent and then cooling it, concentrating the solution, or using a method that reduces the solubility of the racemic-Hafester. Any method commonly used for preparing supersaturated solutions, such as adding a solvent, can be used.

Examples of solvents include alcohol solvents such as methanol, ethanol, and isopropyl alcohol, ketone solvents such as acetone and methyl ethyl ketone, and mixed solvents of these and water, aromatic hydrocarbon solvents such as benzene and toluene, and dichloromethane such as acetonitrile. -IJ solvents can be used, but hydroalcoholic solvents, benzene, toluene, or acetonitrile are preferred for efficient optical resolution.

In the present invention, when the solute in the supersaturated solution of the racemic-Hafester compound is an optically pure racemic compound, it is necessary to inoculate seed crystals from the outside during separation, but when the solute is optically impure, i.e. If one of the optically active forms is present in a larger quantity, the active form crystallizes naturally and acts in the same way as seed crystal inoculation, so external inoculation is not necessarily required. In the method of the present invention, even when such spontaneous crystallization occurs and acts in the same way as external inoculation, it is referred to as inoculated.

There is no particular restriction on the amount of inoculation, and the larger the amount, the easier and faster the division will be, but it is usually sufficient to use an inoculum amount of about 1 to 10 [fi%] of the racemic Hafester in the needle 111J solution. It is.

When the target optically active substance is present in excess compared to the other, the amount of inoculation may be even smaller if it is inoculated without waiting for spontaneous crystallization. It is desirable that the optically active material to be inoculated has high purity in view of its intended use.

In the method of the present invention, not only so-called one-sided splitting in which only one optically active substance is crystallized from a supersaturated solution, but also two splitting groups connected in parallel or in series, or opposing optical activities in each of divided tanks having compartments, are used. It is also possible to simultaneously obtain two optically active Hafester bodies by inoculating one of the Hafester bodies and contacting it with a supersaturated solution of racemic Hafester bodies.In carrying out the method of the present invention, Add an organic base such as dimethylaniline, dimethylbenzylamine, or triethylamine, or an inorganic base such as sodium hydroxide or potassium hydroxide to a supersaturated solution of the racemic Hafester compound by 0.05 to 0.6 moles relative to the racemic Hafester compound. It can be added to increase the stability of supersaturated solutions, but this is not a particularly necessary condition.

The present invention will be specifically explained below by giving examples and reference examples, but the present invention is not limited to these. 511, ゝ・1, \ ゝ\, ゝ\ \ \ Example 1 Racemic-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazosazidine-4-carboxylic acid (hereinafter cooled to racemic half and heated to 52°C) By the way, 0.50 y of (48,5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimitazolidine-4-carboxylic acid was inoculated, and stirred with a fist at 50 to 47°C for 2 hours. did.

The precipitated crystals were filtered and dried. (4s.

5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 2.07
f was obtained.

Optical purity 98% When the temperature reached 52℃, Te (4R, 5S) -1゜8-
Dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 0.50F was inoculated and 50~
The mixture was stirred for 2 hours at 47°C. (4R,5S)-1
, 8 dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 54op was obtained.

Melting point 148-149℃ 0 [Ql] +27.00 (C-2
, DMF) 65 Optical purity 97% Reference Example 1 A mixture of sodium borohydride (820N, isopropyl alcohol 35*/) obtained in Example 1 (4S, 5R
)-1,8-dibenzyl-5-methoxycarbonyl-2
-Oxoimida (Silysine-4-carboxylic acid 1.2 of
and tetrahydrofuran 15. / was added dropwise at room temperature, and then the reaction solution was stirred at 60-70°C for 7 hours. This reaction solution was cooled, 2.6 y of concentrated hydrochloric acid was added, and the reaction solution was concentrated under reduced pressure. 250 d of water was added to the residual liquid, and the mixture was extracted twice with 100 d of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue of 1.105F.

This is then recrystallized with water-containing inpropyl alcohol.
4aS, 6aR)-18-dibenzylhexahydro-I
H-furo (8,4-d,:l imidazole-2,4-dione 0.90F was obtained.

Melting point 116-118°C Reference example 2 (4R,5S)-1,8-dibenzyl- obtained in Example 1
5-Methoxycarbonyl-2-oxoimidazolidine-
4-carboxylic acid 1.842 and tetrahydrofuran 1
5. / Sodium borohydride 226 at -20°C in a solution of
■ was added little by little. To this was added dropwise 1.06 y of boron trifluoride-ether complex, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 8 hours. This reaction solution was mixed with 50 ml of ice water and 50 ml of ethyl chloride. / at 2
Extracted twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The remaining liquid was purified by column clost using silica gel. 4aS, 6aR)-1
,8-dibenzylhexahydro-1H-furo(8,4,
-d) Imidazole-2,4-dione i, t o y
I got it.

Melting point: 116-118°C Example 2 850 Wt of toluene was added to 5.02 kg of racemic-cis-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimida]silidine-4-carboxylic acid, and the mixture was heated and dissolved. Cool this solution thoroughly and
When the temperature reached 2°C, 0.50 y of (45,5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was inoculated, and 60-6
The mixture was kept warm and stirred at 2°C for 2 hours.

The precipitated crystals were filtered and dried. (4s.

5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 1.51
F was obtained.

Melting point 147.5-148.5°C 0 [α1 -26.8° (C-2, DMF) 65 Optical purity 96% Example 8 Racemic-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxo imidazolidine-4-carboxylic acid 2
．． OOy was inoculated with 0.20 F of acetonitrile (4S, 5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidic 4-carboxylic acid, and
The mixture was kept warm and stirred at 80°C for 2 hours.

The precipitated crystals were filtered and dried (4S.

5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 0.4
Of was obtained.

Touch point 148-145°C 0 [α] -28,9° (C-2, DMF) 65 Optical purity 86% Example 4 Racemic-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine -4-carboxylic acid 2
．． When benzene reached 50 y (4S,
5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (+
25 y was inoculated, and the mixture was kept warm and stirred at 50 to 48°C for 2 hours. The precipitated crystals were filtered and dried.

(4S,5R)-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid Q, 6tp was obtained.

Melting point 148.5-145℃ 20 -26.6" (C-2, DMF) [ol]86
5 Optical purity 95% Example 5 Racemic-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 2.50
Add 50~ of toluene and 70~ of triethylamine to F,
Warming-dissolved. This solution was gradually cooled, and when the temperature reached 67°C, (4S, 5R)-1,8-ditresilyl-5-methoxycarbonyl-2-oxoimidazolidine-
4-Carboxylic acid 0252 was inoculated, and the mixture was kept warm and stirred at 67 to 65°C for 2 hours. The precipitated crystals were filtered and dried.

(4S,5R)-1,8-dibenzyl-5methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 0
．． 52 i! was gotten.

Melting point: 145-146.5℃ 20-27.4″ (C=2.DMF’) [Q!]865 Optical purity 98%

Claims (1)

[Claims] Optically active cis-1,8-dibenzyl-
5-Methoxycarbonyl-2-oxoimidazolidine-
4-carboxylic acid crystals are present, and optically active cis-1,8-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid of the same type as the optically active form is preferentially used over the supersaturated solution. A method for producing optically active cis-1,8-dibenzyl-6-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid, characterized by crystallizing it.