JPH0343270B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides optically active cis-1,3-dibenzyl-
The present invention relates to a method for producing 5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid.

Optically active cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4
-Carboxylic acid (hereinafter abbreviated as half ester) is an important intermediate for biotin and other pharmaceuticals.

Conventional racemic half ester is optically resolved,
There is no known method for obtaining optically active half esters.

In the method of optically resolving a racemate to obtain an optically active form, a so-called priority method involves inoculating a supersaturated solution of the racemate with one optically active form and separating and obtaining the same type of optically active form as the inoculated one. The principle of crystallization is well known. However, this method is generally advantageously applicable only when the racemate forms a racemic mixture, and is said to be inapplicable to racemic compounds. However, it is unclear which compounds form racemic mixtures or whether the preferential crystallization method can be applied, and furthermore, there is no regularity. That is, the case where a racemic mixture can be 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.

As a result of intensive study of optical resolution methods using various methods for racemic half esters, the present inventors have found that racemic half esters form a racemic mixture and can be optically resolved in that form by preferential crystallization. They found that the following conditions were satisfied, and completed the method of the present invention.

That is, according to the method of the present invention, crystals of an optically active half ester are made to exist in a supersaturated solution of a racemic half ester, and an optically active half ester of the same type as the optically active half ester is preferentially crystallized. By collecting this, an optically active half ester can be obtained, and by coordination of the inoculated optically active half ester,
Both optically active half esters with 4R, 5S coordination and 4S, 5R coordination can be obtained arbitrarily.

From the optically active half ester obtained by the method of the present invention, an optically active cis-1,3-dibenzylhexahydro-
1H-furo[3,4-d]imidazole-2,4
- Diones (hereinafter abbreviated as lactones) can be produced.

In this reduction and closure reaction, only one of the methoxycarbonyl group or the carboxyl group of the optically active half ester is selectively reduced, and then the closed optically active lactone can be obtained by acid treatment.

When selectively reducing the methoxycarbonyl group of an optically active half ester, 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, the reduction reaction is carried out using a reducing agent such as diborane, or the carboxyl group is replaced with N-hydroxysuccinimide, p-
After forming the corresponding active ester group with nitrophenol, isobutyl chloroformate, etc., a reduction reaction may be carried out using a reducing agent such as sodium borohydride. 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 from an optically active half ester, the yield can be obtained by reducing the methoxycarbonyl group of the optically active half ester and closing it, or by reducing the carboxyl group and closing it. The coordinations of the optically active lactones obtained are opposite to each other. Therefore, the optically active half esters with 4S, 5R coordination and 4R, 5S coordination obtained by the method of the present invention both have 4aS, 6aR coordination, which are important intermediates in the production of natural biotin. It can lead to optically active lactone bodies. That is, 2 which can be obtained by the method of the present invention
Any of the optically active half esters can be used as an intermediate in the production of natural biotin.

This means that in general optical resolution operations, only one of the two optical isomers obtained is used.
The other feature is that it is racemized and then subjected to optical resolution again, which is a major feature and has great industrial value.

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

A supersaturated solution of the racemic half ester can be prepared by heating and dissolving the racemic half ester in an appropriate solvent and then cooling it, concentrating the solution, or reducing the solubility of the racemic half ester. It is possible to use a method commonly used for preparing general supersaturated solutions, such as a method of adding a solvent that causes

Examples of solvents include alcohol solvents such as methanol, ethanol, and isopropyl alcohol, ketone solvents such as acetone and methyl ethyl ketone, mixed solvents of these and water, aromatic hydrocarbon solvents such as benzene and toluene, and nitrile solvents such as acetonitrile. Although a solvent can be used, hydroalcoholic solvents, hydroalcoholic solvents,
Benzene, toluene or acetonitrile are preferred.

When the solute in the supersaturated solution of the racemic half ester in the present invention is an optically pure racemate, it is necessary to inoculate seed crystals from the outside during separation, but when the solute is optically impure, That is, when one optically active substance is present in a larger amount, that active substance naturally crystallizes, and this acts in the same way as if seed crystals were inoculated, 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; the larger the amount, the easier and more accelerated the splitting will be, but it is usually sufficient to use an inoculating amount of about 1 to 10% by weight of the racemic half ester in the splitting solution. . When the desired optically active substance is present in excess compared to the other,
When inoculating without waiting for spontaneous crystallization, the amount of inoculation may be even smaller, and it is desirable that the optically active substance to be inoculated has high purity considering its intended use.

In the method of the present invention, not only so-called one-sided division in which only one optically active substance is crystallized from a supersaturated solution, but also two division columns connected in parallel or in series,
Alternatively, two types of optically active half esters can be simultaneously obtained by inoculating one of the opposite optically active half esters into each divided tank having compartments and contacting it with a supersaturated solution of the racemic half ester. You can also.

In carrying out the method of the present invention, an organic base such as dimethylaniline, dimethylbenzylamine, or triethylamine, or an inorganic base such as sodium hydroxide or potassium hydroxide is added to a supersaturated solution of the racemic half ester. It is possible to increase the stability of the supersaturated solution by adding 0.05 to 0.6 times the mole of the ester, but this is not a particularly essential condition.

The present invention will be specifically explained below with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 Racemic-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-
500 ml of benzene was added to 10.0 g of carboxylic acid (hereinafter abbreviated as racemic half ester), and the mixture was heated and dissolved. This solution was gradually cooled to 52°C, and (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-
0.50 g of carboxylic acid was inoculated, and the mixture was kept warm and stirred at 50 to 47°C for 2 hours.

The precipitated crystals were filtered and dried. (4S, 5R)
-1.3-dibenzyl-5-methoxycarbonyl-
2-Oxoimidazolidine-4-carboxylic acid 2.07
g was obtained.

Melting point: 148-149°C [α] ²⁰ ₃₆₅ -27.3° (C = 2, DMF) Optical purity: 98% 3.10 g of racemic half ester was added to the liquid and dissolved by heating. This solution was gradually cooled and when it reached 52℃, (4R,5S)-1.3-dibenzyl-
0.50 g of 5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was inoculated, and the mixture was kept warm and stirred at 50 to 47°C for 2 hours. 3.40 g of (4R,5S)-1.3dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained.

Melting point 148-149℃ [α] ²⁰ ₃₆₅ +27.0゜ (C = 2, DMF) Optical purity 97% Reference example 1 A mixture of 320 mg of sodium borohydride and 35 ml of isopropyl alcohol was added with the (4S) obtained in Example 1. ，
5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid
A solution of 1.20 g dissolved in 15 ml of tetrahydrofuran was added dropwise at room temperature. Next, add this reaction solution to 60-70℃.
The mixture was stirred for 7 hours. The reaction solution was cooled, 2.5 g of concentrated hydrochloric acid was added, and the reaction solution was concentrated under reduced pressure. 250 ml of water was added to the residue, and the mixture was extracted twice with 100 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue.
Obtained 1.10g. This was recrystallized from aqueous isopropyl alcohol to obtain 0.90 g of (4aS, 6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione.

Melting point 116-118°C [α] ²⁰ _D +62.5° (C = 1, CHCl ₃ ) Reference example 2 (4R, 5S)-1.3-dibenzyl-5-methoxycarbonyl-2-oxoimidazo obtained in Example 1 Sodium borohydride in a solution of 1.84 g of lysine-4-carboxylic acid and 15 ml of tetrahydrofuran at -20°C.
226 mg was added in small portions. 1.06 g of boron trifluoride-ether complex was added dropwise to this, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. This reaction solution was poured into 50 ml of ice water, stirred at room temperature for 1 hour, adjusted to pH 9 with an aqueous potassium carbonate solution, and extracted twice with 50 ml of ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was purified by column clost using silica gel (4aS, 6aR)-1,3-dibenzylhexahydro-
1H-furo[3,4-d]imidazole-2,4
-1.10 g of dione was obtained.

Melting point 116-118°C [α] ²⁰ _D +62.2° (C=1, CHCl ₃ ) Example 2 Racemic-cis-1.3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-
Add 350 ml of toluene to 5.0 g of carboxylic acid, heat and
Dissolved. This solution was gradually cooled, and when it reached 62℃, (4S, 5R)-1.3-dibenzyl-5-
0.50 g of methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was inoculated, and the mixture was kept warm and stirred at 60 to 62°C for 2 hours.

The precipitated crystals were filtered and dried. (4S, 5R)
-1.3-dibenzyl-5-methoxycarbonyl-
2-oxoimidazolidine-4-carboxylic acid 1.51
g was obtained.

Melting point 147.5-148.5℃ [α] ²⁰ ₃₆₅ -26.8゜ (C=2, DMF) Optical purity 96% Example 3 Racemic-cis-1.3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-
Add 10ml of acetonitrile to 2.00g of carboxylic acid,
Heated and dissolved. Gradually cool this solution to 35°C.
At that point, 0.20 g of (4S, 5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was inoculated, and 27 to 30
The mixture was kept warm and stirred at ℃ for 2 hours.

The precipitated crystals were filtered and dried. (4S, 5R)
-1.3-dibenzyl-5-methoxycarbonyl-
2-oxoimidazolidine-4-carboxylic acid 0.40
g was obtained.

Melting point 143-145℃ [α] ²⁰ ₃₆₅ -23.9゜ (C=2, DMF) Optical purity 86% Example 4 Racemic-cis-1.3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-
50 ml of benzene and 70 mg of triethylamine were added to 2.50 g of carboxylic acid and dissolved by heating. This solution was gradually cooled and when it reached 50℃ (4S, 5R)
-1.3-dibenzyl-5-methoxycarbonyl-
2-oxoimidazolidine-4-carboxylic acid 0.25
g was inoculated, and kept warm and stirred at 50 to 48°C for 2 hours. The precipitated crystals were filtered and dried. (4S, 5R)
-1.3-dibenzyl-5-methoxycarbonyl-
2-oxoimidazolidine-4-carboxylic acid 0.61
g was obtained.

Melting point 143.5-145℃ [α] ²⁰ ₃₆₅ -26.6゜ (C=2, DMF) Optical purity 95% Example 5 Racemic-1.3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid 2.50 g toluene 50ml, triethylamine 70ml
mg was added, heated and dissolved. This solution was gradually cooled to 67°C, and then 0.25 g of (4S, 5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was inoculated, and the temperature was kept at 67-65°C. The mixture was kept warm and stirred for 2 hours. The precipitated crystals were filtered and dried. 0.52 g of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained.

Melting point 145-146.5℃ [α] ²⁰ ₃₆₅ -27.4゜ (C=2, DMF) Optical purity 98%

Claims (1)

[Claims] 1 Racemic-cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazolidine-
Optically active cis-
1.3-dibenzyl-5-methoxycarbonyl-2
- Presence of crystals of oxoimidazolidine-4-carboxylic acid, and the same type of optically active cis-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid as the supersaturated solution. Optically active cis-1,3-dibenzyl-5 characterized by preferential crystallization
-Method for producing methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid.