JPH0432832B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for asymmetrically reducing an acid anhydride having intramolecular symmetry to obtain an optically active lactone.

More specifically, formula (I) The cis-acid anhydride represented by the general formula (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a benzyl group or phenyl group which may be substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and R ² and R ³ are the same or different. different, represents a hydrogen atom or a lower alkyl group, R ⁴ and R ⁵ are the same or different,
It represents a hydrogen atom, a lower alkyl group, or a phenyl group which may be substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and the * mark represents an asymmetric carbon. ) Optically active amino alcohol or general formula (In the formula, R' represents a benzyl group optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group.) An optically active diol represented by; and a boron-based compound or an aluminum-based compound are reacted. Formula (I) characterized by carrying out asymmetric reduction using a compound obtained by The present invention relates to a method for producing an optically active lactone compound shown in the following.

The optically active lactone () that can be obtained by the method of the present invention is useful as a synthetic intermediate for optically active bithione, etc.
(Japanese Patent Publication No. 58-192886) Conventionally, methods for producing optically active lactone bodies () have been disclosed in Japanese Patent Publication No. 49-3255 (method A),
Publication No. 53-35076 (B method) and JP-A-58-
Publication No. 128376, Japanese Patent Application Laid-open No. 128386, Japanese Patent Application Publication No. 1983-128386,
Publication No. 58-192886, Japanese Unexamined Patent Publication No. 58-201785 (C
The method described in the Act) is known.

In method A, (±)-cis-1,3-dibenzyl-5-(3'-cholesteryloxycarbonyl)
-2-Oxoimidazolidine-4-carboxylic acid is optically resolved as a salt with triethylamine to obtain an optically active cholesteryl half ester, which is reduced with lithium borohydride to obtain a lactone (). How to get or (±)
-cis-1,3-dibenzyl-5-cyclohexyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid is optically resolved as a salt with efuedrin to obtain an optically active cyclohexyl half ester, which is then converted to borohydride. This method involves reduction with lithium to obtain the lactone (2), but it requires the use of expensive optically active compounds such as ephedrin and cholesterol, and the yield of the lactone (2) is low.

For method B, cis-1,3-dibenzyl-2
-Oxoimidazolidine-cis-1,3-dibenzylhexahydropyrrolo[3,4-d]imidazole-2,4 obtained by dehydration from 4,5-dicarboxylic acid and an optically active organic primary amine , 6-trione derivative is asymmetrically reduced with sodium borohydride or the like, and then hydrolyzed to obtain a lactone ().

Method C is an optically active cis-1,
3-Dibenzyl-2-oxoimidazolidine-5
-lower alkoxycarbonyl-4-carboxylic acid (abbreviated as half ester) or an optically active half ester obtained by optically resolving racemic half ester by preferential crystallization. This is a method in which an ester moiety or a carboxylic acid moiety is selectively reduced using a reducing agent to produce an optically active lactone ().

The present inventors have further studied a more economical method for producing optically active lactone (), and by asymmetric reduction of an acid anhydride having intramolecular symmetry,
The present inventors discovered a method of the present invention capable of obtaining optically active lactone (2) and completed the method of the present invention.

The method of obtaining an optically active lactone by asymmetric reduction of an acid anhydride having symmetry in the molecule is a method completely unknown until now, and was discovered for the first time by the present inventors.

According to the method of the present invention, an optically active lactone () can be obtained by using a reducing agent modified with a chiral alcohol or a chiral amine, and the chirality of the chiral alcohol or chiral amine can be reduced. By changing , an optically active lactone () having any coordination can be obtained.

Examples of chiral alcohols or amines in the method of the invention include menthol, borneol,
1-phenylethan-1-ol, 1-(1-naphthyl)ethane-1-ol, 1-(2-naphthyl)ethane-1-ol, 1-phenylpropan-1-ol, 1-phenylpropane- 2-ol, 1-phenylbutan-2-ol, 1,2:
5,6-di-O-isopropylidene-α-glucofuranose, 1,2:5,6-di-O-cyclohexylidene-α-glucofuranose, 2,2′-dihydroxy-1,1′-binaphthyl , cholesterol, quinine, quinidine, cinchonidine, cinchonine, efuedrin, N-methylephedrin, norephedrin, α-phenylethylamine, α
-(1-naphthyl)ethylamine, α-(2-naphthyl)ethylamine, 2-aminobutan-1-ol, 2-amino-3-phenylpropane-1-
ol, 2-amino-2-phenylethane-1-
ol, 2-amino-3-methylpentane-1-
ol, 2-amino-3-methylthiopropane-
1-ol, 2-amino-4-methylpentane-
1-ol, 2-amino-3-benzylthiopropan-1-ol, 2-amino-3-[(p-benzyloxy)phenyl]propan-1-ol,
2-(N-phenylaminomethyl)pyrrolidine-
2-amino-1,1-diphenylpropane-1-
ol, 2-amino-4-methyl-1,1-diphenylpentan-1-ol, 2-amino-1,
1,3-triphenylpropan-1-ol,
Examples include 1,4-bis(p-chlorobenzyloxy)-butane-1,2-diol. A modified reducing agent is prepared using a chiral alcohol or a chiral amine and a boron-based reducing agent or an aluminum-based reducing agent. Examples of the boron-based reducing agent used at this time include sodium boron hydride, lithium boron hydride, diborane, etc. Examples of aluminum-based reducing agents include lithium aluminum hydride and aluminum trihydride.

Modified reducing agents can be used, for example, in J.Chem.Soc.Perkin
Trans.I 1673 (1983), Bull.Chem.Soc.Jap., 54
1424-1428 (1981), Chem. Letters 981-984
(1980), Tetrahedron 35, 2797 (1979), etc., or the method described in the Examples below.

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

The modified reducing agent modified with the chiral alcohol or chiral amine prepared as described above and the cis-acid anhydride (I) are mixed in an aromatic hydrocarbon solvent such as toluene or benzene, or dichloromethane or dichloroethane. In ether solvents such as halogenated alkyl solvents, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, -
An optically active lactone () can be obtained by reacting at a reaction temperature of 80 to 50°C.

The modified reducing agent is 1 to cis-acid anhydride (I).
~10 times the molar amount should be used.

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

(Example 1) 110 mg of sodium borohydride was added to a suspension of 790 mg of (s)-2-amino-1,1-diphenylpropan-1-ol hydrochloride and 20 ml of 1,2-dichloroethane at 0 to 5°C. , a solution of 3 ml of dimethylformamide was added dropwise. After dropping, the mixture was stirred at 20-25°C for 1 hour. Cis-1,3-dibenzyl-2 was added to this reaction solution.
A suspension of 340 mg of -oxoimidazolidine-4,5-dicarboxylic anhydride and 10 ml of 1,2-dichloroethane was added, and the mixture was stirred at 20-25°C for 2 hours. to this
30 ml of 1N HCl was added dropwise, and after the dropwise addition, the mixture was stirred at 50-60°C for 2 hours. Add 100ml of ethyl acetate to the reaction solution,
It was extracted and separated. The organic layer was washed with water and concentrated under reduced pressure.
The obtained residue was subjected to silica gel column chromatography (elution solvent: benzene: ethyl acetate = 1:
1) to obtain 120 mg of (4aS, 6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione. [α] ²⁵ _D
+29.1° (c=1.0, chloroform) mp 107-109°C (Example 2) (s)-2-amino-4-methyl-1,1-diphenylpentan-1-ol hydrochloride 920 mg, 1 ，
A solution of 110 mg of sodium borohydride and 3 ml of dimethylformamide was added dropwise to a suspension of 20 ml of 2-dichloroethane at 0 to 5°C. 1 at 20-25℃ after dropping
Stir for hours. A suspension of 340 mg of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic anhydride and 10 ml of 1,2-dichloroethane was added to this reaction solution, and the mixture was stirred at 20-25°C for 5 hours. . To this were added 10 ml of 1N HCl and 10 ml of methanol, and after stirring at 50°C for 1 hour, the mixture was concentrated under reduced pressure. 100 ml of ethyl acetate and 50 ml of water were added to the residue for extraction and separation.
The organic layer was washed with water, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (elution solvent:
Purified with benzene:ethyl acetate=1:1),
(4aS, 6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,
126 mg of 4-dione was obtained.

[α] ²⁵ _D +18.0° (c = 1.0, chloroform) mp 107-108°C (Example 3) (R)-2-amino-1,1,3-triphenylpropan-1-ol hydrochloride 510mg, 1,2
- 55 mg of sodium borohydride, dimethylformamide in a suspension of 10 ml of dichloroethane at 0-5°C.
1.5 ml of solution was added dropwise. After dropping, the mixture was stirred at 20-25°C for 1 hour. A suspension of 170 mg of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic anhydride and 4 ml of 1,2-dichloroethane was added to this reaction solution, and the mixture was stirred at 20-25°C for 5 hours. .

After that, it was processed in the same manner as in Example 2, and (4aR, 6aS)
-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione 50
I got mg.

[α] ²⁵ _D -20.1° (c = 1.0, chloroform) 107-108°C (Example 4) 92 mg of lithium aluminum hydride, 10 ether
A solution of 430 mg of 1-N-methylefedrin and 12 ml of ether was added dropwise to 10 to 15° C. of the suspension. After the dropwise addition, the mixture was refluxed for 1 hour. Add N to this reaction solution at 10-15℃.
- A solution of 580 mg of ethylaniline and 5 ml of ether was added dropwise, and the mixture was refluxed for 1 hour. This reaction solution -
Cool to 70°C, cis-1,3-dibenzyl-2-
A suspension of 170 mg of oxoimidazolidine-4,5-dicarboxylic anhydride and 10 ml of ether was added dropwise, and -70
After stirring for 3 hours at ℃, 1 hour at -30 to -35℃, and 1 hour at -10 to 0℃, 30 ml of 1N HCl was added dropwise.
Add 20 ml of water and 50 ml of ethyl acetate to the reaction solution, extract and
The liquid was separated. After washing the organic layer with water, it was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent: benzene: ethyl acetate = 1:1).
6aS)-1,3-dibenzylhexahydro-1H-
31.5 mg of furo[3,4-d]imidazole-2,4-dione was obtained.

[α] ²⁵ _D -31.8° (c = 1.0, chloroform) mp 107-108°C (Example 5) Lithium aluminum hydride 92 mg, ether 10
D(-)-1,4-bis(p-chlorobenzyloxy)-butane-1,2-
A suspension of 890 mg of diol and 10 ml of ether was added dropwise. After the dropwise addition, the mixture was refluxed for 1 hour. Add 10−15 to this reaction solution.
A solution of 290 mg of N-ethylaniline and 2.5 ml of ether was added dropwise at °C, and the mixture was refluxed for 1 hour. The reaction solution was cooled to -60°C, and a suspension of 170 mg of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic anhydride and 10 ml of ether was added dropwise to the solution, and the temperature was -55 to -60°C. After stirring at ℃ for 2 hours and at -30 to -35℃ for 3 hours, 30 ml of 1N HCl was added dropwise. The following process was performed in the same manner as in Example 4, and (4aS, 6aR)-1,3
-dibenzylhexahydro-1H-furo[3,4
-d] 41.3 mg of imidazole-2,4-dione was obtained.

[α] ²⁵ _D +4.3° (c=1.0, chloroform) mp 105-107°C.

(Example 6) d-norpheedrin hydrochloride 560mg, 1,2-
A solution of 110 mg of sodium borohydride and 3 ml of dimethylformamide was added dropwise to a suspension in 20 ml of dichloroethane at 0 to 5°C. After the dropwise addition, the mixture was stirred at 20 to 25°C for 1 hour. To this reaction solution, 340 mg of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic anhydride and 10 mg of 1,2-dichloroethane were added.
ml of suspension was added and stirred at 20-25°C for 18 hours.

After that, it was processed in the same manner as in Example 1, and (4aR, 6aS)
-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione 52
I got mg.

[α] ²⁵ _D -7.5° (c=1.0, chloroform) mp 105-108°C.

Claims (1)

[Claims] 1 formula The cis-acid anhydride represented by the general formula (In the formula, R ¹ represents a hydrogen atom, a lower alkyl group, or a benzyl group or phenyl group which may be substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and R ² and R ³ are the same or different. different, represents a hydrogen atom or a lower alkyl group, R ⁴ and R ⁵ are the same or different,
It represents a hydrogen atom, a lower alkyl group, or a phenyl group which may be substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, and the * mark represents an asymmetric carbon. ) Optically active amino alcohol or general formula (In the formula, R' represents a benzyl group optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group.) An optically active diol represented by; and a boron-based compound or an aluminum-based compound are reacted. It is characterized by carrying out asymmetric reduction using a compound obtained by formula A method for producing an optically active lactone shown in