JPH0435463B2 - - Google Patents

Description

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

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

Conventionally, there is no known method of obtaining an optically active half ester by optical resolution.

Generally, in the method of optically resolving a racemate to obtain an optically active form, one of the optically active forms is inoculated into a supersaturated solution of the racemate, and the optically active form of the same type as the inoculated form is separated and obtained. The principle of preferential crystallization is well known. However, it is generally said that this method can be advantageously applied only to the formation of racemic mixtures, and cannot be applied 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.

The present inventors have discovered (4S,5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid [hereinafter referred to as (4S,5R)-half ester] and (4R, 5S)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid [hereinafter (4R,
As a result of intensive studies on optical resolution methods using various methods for mixtures of 5S)-half esters, we found that the 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, optically active half ester crystals are made to exist in a supersaturated solution in which (4S, 5R)- and (4R, 5S)-half esters are mixed, and optically active crystals of the same type as the optically active half esters are present. Optically active half esters can be obtained by preferentially crystallizing and collecting the active half esters, and the coordination of the inoculated optically active half esters allows the formation of 4R, 5S configurations. position and 4S,
Any optically active half ester with 5R coordination can be obtained as desired.

The optically active half ester obtained by the method of the present invention undergoes reduction and ring-closing reactions to produce optically active cis-1,3-dibenzylhexahydro-1H-fluoro, which is known as an important intermediate in the production of biotin. [3,4-d]imidazole-2,
4-dione (hereinafter abbreviated as lactone) can be produced.

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

When selectively reducing the ethoxycarbonyl 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 resulting optical The coordination of the active lactone bodies is opposite to each other.

Therefore, optically active half esters with 4S, 5R coordination and 4R, 5S coordination obtained by the method of the present invention can be used to produce optical compounds with 4aS, 6aR coordination, which are important intermediates in the production of natural bithione. It can lead to active lactone bodies. That is, any of the two optically active half esters obtained by the method of the present invention 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. (4S,
As a method for preparing a supersaturated solution containing a mixture of 5R)- and (4R,5S)-half esters, the half esters are heated and dissolved in a suitable solvent, and then
Any method commonly used for preparing supersaturated solutions can be used, such as cooling, concentrating the solution, or adding a solvent that reduces the solubility of the half ester.

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, benzene, toluene,
Although aromatic hydrocarbon solvents such as xylene or nitrile solvents such as acetonitrile can be used, xylene,
Toluene is preferred.

(4S, 5R)- and (4R, 5S) in the present invention
- When the solute in a supersaturated solution containing a half ester 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 the solute is an optically pure racemic When there is a larger amount of optically active form, the active form naturally crystallizes and this acts in the same way as inoculating seed crystals, so there is no need for external inoculation. 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 division, but it is usually sufficient to use an amount of inoculation of about 1 to 10% by weight of the half ester in the dividing solution. 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 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, one of the opposite optically active half esters is inoculated into each of the divided tanks having zones, and a supersaturated solution containing a mixture of (4S, 5R)- and (4R, 5S)-half esters is inoculated into this. By doing so, two types of optically active half esters can be obtained simultaneously.

In addition, in carrying out the method of the present invention, (4S, 5R)
- and (4R,5S)-half esters are mixed in a supersaturated solution, and organic bases such as dimethylaniline, dimethylbenzylamine, triethylamine, or inorganic bases such as sodium hydroxide and potassium hydroxide are added to the half esters. 0.05~
It is possible to add 0.6 mole times to increase the stability of the supersaturated solution, but this is not a particularly essential condition.

cis-1,3- used as a raw material in the method of the present invention
Dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (racemic half ester) is a new compound that has not been described in any literature, and is cis-1,3-dibenzyl-hexahydro-
1H-furo[3,4-d]imidazole-2,4,
It can be synthesized from 6-trione and ethyl alcohol.

Furthermore, optically active cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4- which can be produced by the method of the present invention
Carboxylic acid (optically active half ester) is also a new compound that has not been described in any literature, and the optically active half ester used as a seed crystal in the method of the present invention is a racemic half ester of efuedrin or 2-amino-1, It was obtained by performing an optical resolution operation using an optically active amine selected from 1-diphenylpropanol as an optical resolution agent.

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

Reference example 1 cis-1,3-dibenzyl-hexahydro-
1H-furo[3,4-d]imidazole-2,4,
6-trione 70.0g and 99.5% ethanol 16.6g,
1000 ml of benzene was added, and the mixture was heated and refluxed for 2 hours.
Thereafter, about 600 ml of benzene was distilled off at normal pressure, and 200 ml of n-hexane was added thereto, followed by stirring at room temperature overnight. After filtering the precipitated crystals, dry under reduced pressure,
76.2g racemic-cis-1,3-dibenzyl-5
-Ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained. This product was recrystallized from toluene and showed a melting point of 110-111°C.

Reference example 2 764 mg of racemic-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was added to 4 ml of 95% ethanol.
After adding 310 mg of ephedrine to the solution to obtain a homogeneous solution, the solution was left at 0°C to 5°C overnight. Take the precipitated crystals (4R, 5S) cis-1,
3-dibenzyl-5-ethoxycarbonyl-2
-Oxoimidazolidine-4-carboxylic acid・
- efuedrine salt 339mg, mp163-167℃, [α]
^20D _−11.6 ° (c=1.0, CH ₃ OH) was obtained.

Add 20ml of 3% hydrochloric acid to 200mg of the above salt to decompose the salt, and then extract with ethyl acetate (4R,
5S) Cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4
-carboxylic acid 138 mg, mp 133-135°C, [α] ²⁰ ₃₆₅ +21.6° (c = 1.0,
DMF) was obtained.

Dissolve 19.1 g of racemic-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid in 200 ml of isopropyl alcohol, and dissolve S-2-amino-1,1
- After adding 11.4 g of diphenylpropanol to make a homogeneous solution, it was left to stand overnight at room temperature, and the precipitated crystals were collected to obtain 21.1 g of salt, mp 135-144°C. Recrystallize 20.0g of this salt from 500ml of methanol,
(4S,5R)-cis-1,3-dibenzyl-5-
Ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid S-2-amino-1,1
−Diphenylpropanol salt 7.3g, mp150−
151°C, [α] ²⁰ _D +20.9° (c=1.0, CH ₃ OH) was obtained. After adding 300 ml of 3% hydrochloric acid water to 6.0 g of this salt, it was extracted with ethyl acetate and (4S,5R)-cis-
1,3-Dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid, 3.9 g, mp133-135℃, [α] ²⁵ ₃₆₅ -20.7゜(c
= 1, DMF) was obtained.

When this is recrystallized from benzene, mp137.5−
The temperature was 138.5°C, [α] ²⁰ ₃₆₅ −21.8° (c=1, DMF).

The above optical resolution mother liquor and methanol recrystallization mother liquor were combined and concentrated under reduced pressure. After adding 800 ml of 3% hydrochloric acid water, the mixture was extracted with ethyl acetate. The ethyl acetate was distilled off under reduced pressure. The residue was extracted with isopropyl alcohol.
Dissolved in 200ml. 8.4 g of R-2-amino-1,1-diphenylpropanol was added to this solution to make a homogeneous solution, and the mixture was left at room temperature for 6 hours to obtain 15.0 g of precipitated crystals, which were then recrystallized from 400 ml of methanol. (4R,5S)-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid R-2-
Amino-1,1-diphenylpropanol salt
8.2g, mp-150~151℃, [α] ²⁰ _D -21.0 (c=
1.0, CH ₃ OH) was obtained.

6.0 g of this salt was decomposed with hydrochloric acid water, extracted with ethyl acetate, and 3.7 g of (4R,5S)-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid ,
mp134~136℃, [α] ²⁰ ₃₆₅ +21.0゜(c=1,
DMF) was obtained.

Example 1 Racemic-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4
100 ml of toluene was added to 10.00 g of -carboxylic acid (hereinafter abbreviated as racemic half ester), and the mixture was heated and dissolved.

This solution was gradually cooled, and when the temperature reached 42°C, (4S,5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-
0.50 g of carboxylic acid was inoculated, and the mixture was kept warm and stirred at 39 to 41°C for 2 hours. The precipitated crystals were filtered and dried. (4S,5R)-1,3-dibenzyl-5-
1.57 g of ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained.

Melting point: 135-137°C [α] ²⁰ ₃₆₅ -20.5° (c=2, DMF) Optical purity: 94% 2.00 g of racemic half ester was added to the liquid and dissolved by heating. This solution was gradually cooled and when the temperature reached 42°C, 0.50 g of (4R,5S)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was inoculated at 39-41°C.
The mixture was kept warm and stirred for 2 hours.

The precipitated crystals were filtered and dried. (4R, 5S)
-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid
2.23g was obtained.

Melting point 135.5-137.5°C [α] ²⁰ ₃₆₅ +20.9° (c=2, DMF) Optical purity 96% Reference example 3 Obtained in Example 1 in a mixture of 43 mg of lithium borohydride and 3 ml of tetrahydrofuran in 4 ml of tetrahydrofuran. (4S,5R)-1,3-dibenzyl-
A solution containing 249 mg of 5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was added dropwise at room temperature. Next, this reaction solution was refluxed for 2 hours, and then tetrahydrofuran was distilled off. 4 ml of methanol was gradually added to the residue under cooling, and then concentrated hydrochloric acid was added.
Added 0.5g. The mixture was refluxed for 1 hour, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 150 mg of (4aS, 6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione.

Melting point 114-116°C [α] ²⁰ _D +58.1° (c=1, CHCl ₃ ) Reference example 4 (4R,5S)-1,3-dibenzyl-5-ethoxycarbonyl-2- obtained in Example 1 47 mg of sodium borohydride was added little by little to a solution of 382 mg of oxoimidazolidine-4-carboxylic acid and 5 ml of tetrahydrofuran at -20°C. 220 mg of boron trifluoride-ether complex was added dropwise to this, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours. Pour this reaction solution into ice water for 10 minutes.
After stirring at room temperature for 1 hour, the pH was adjusted to 9 with an aqueous potassium carbonate solution, and the mixture was extracted twice with 10 ml of ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography,
(4aS, 6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,
208 mg of 4-dione was obtained.

Melting point 114-117°C [α] ²⁰ _D +58.9° (c=1, CHCl ₃ ) Example 2 Racemic-cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4
- 25 ml of xylene was added to 2.50 g of carboxylic acid and dissolved by heating. This solution was gradually cooled to 60°C, and 0.25 g of (4S,5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was inoculated.
The mixture was kept warm and stirred at 57°C for 2 hours. The precipitated crystals were filtered and dried. 0.72 g of (4S,5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained.

Melting point 117-120℃ [α] ²⁰ ₃₆₅ −13.5゜ (c=2, DMF) Optical purity 62%

Claims (1)

[Claims] 1 (4S,5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxoimidazolidine-4
-carboxylic acid [hereinafter referred to as (4S,5R)-half ester] and (4R,5S)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid [hereinafter (4R) . A method for producing an optically active (4S,5R)-half ester or (4S,5S)-half ester, which comprises preferentially crystallizing an optically active half-ester of the same type from the supersaturated solution.