JP3001332B2 - Method for producing optically active substance (-)-(1S, 2S, 4R) -exo-2-norbornanol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing (-)-(1S, 2S, 4R) -exo-2-norbornanol which is an optically active substance.

[0002]

2. Description of the Related Art Optically active substance (-)-(1S, 2S, 4)
R) -exo-2-norbornanol is useful as an intermediate in pharmaceuticals. For example, (-)-(1S, 2S, 4
(+)-(1S, 4R) -2-norbornanone (formula (3) below) obtained by oxidizing R) -exo-2-norbornanol is a thromboxane A2 receptor antagonist and is a myocardial infarction and asthma. It is an important synthetic intermediate for bicycloheptane-based carboxylic acid derivatives which are considered to be effective for treatment and prevention.

[0003]

Embedded image

[0004] Such optically active (+)-(1R, 2R,
4S)-and (-)-(1S, 2S, 4R) -exo-
2-Norbornanol has conventionally been obtained by resolution of racemic exo-2-norbornanol phthalate monoester with an optically active phenethylamine derivative and hydrolysis to optically active norbornanols, (Irwin et al. American Chemical Society (J. Am. Chem. Soc.) 98 vol.
8476-8481. (1979) According to the literature, enantiomeric enrichment of exo-2-norbornanols is also obtained by incomplete racemic oxidation of horse race alcohol dehydrogenase catalyzed by horse liver. (-)-(1S, 2S, 4R) -exo-2-norbornanol is also produced from norbornene by asymmetric hydroboration. (Brown et al. (Brown
et al. ). Journal of Organic Chemistry (J. Org. Chem.) 47 vol. No.5065-
5069. 1982. )

On the other hand, some chiral alcohols have heretofore been resolved in a nearly anhydrous organic solvent using a transesterification reaction catalyzed by porcine liver lipase. For example, when porcine liver lipase is used for the reaction between racemic 2-octanol and 2,2,2-trichloroethyl butyrate, transesterification proceeds, and butyric acid (R) -2- having a high optical activity at 47% conversion. Octyl ester was obtained.
(Kirchner et al.).
Journal of American Chemical Society (J.
Am. Chem. Soc. ). 107 volumes. 7072-
7076 pages. 1985) Then, when racemic endo-2-norbornanol is applied to this reaction system, about 50%
(-)-(1R, 2S, 4S) -endo-2-norbornanol is obtained at an optical purity of about 90% ee. However, when racemic exo-2-norbornanol is used, both the recovered alcohol and the product butyrate remain racemic, although the transesterification reaction is certainly catalyzed by the enzyme. (JP-A-3-173871). Thus, no effective method for the optical resolution of the exo-isomer has been described for the transesterification of exo-2-norbornanol catalyzed by lipase.

Recently, (+)-(1R, 2R, 4R) utilizing asymmetric hydrolysis of acetate of endo-2-norbornenol by a lipid enzyme in a phosphate buffer.
-End-2-norbornenols are optically resolved. (Eichberger e
t al. ). Tetrahedron Letters
edron Letters). 27 volumes. # 2843-
2844. (1986) Since this reaction proceeds by mixing the enzyme and the substrate in an aqueous solution, the operation is simple and suitable for mass production. The desired (+)-(1R, 2R, 4R) -endo-2-norbornenol was obtained at a reaction conversion of 40% with a yield of 35% and an optical purity of 90% or more. However, when this reaction system is used for the asymmetric hydrolysis of the acetate of racemic exo-2-norbornanol, the desired (-)-(1S, 2S, 4R) -exo-2 is desired.
-Norbornanol is obtained only with an optical purity of 17% ee, and good results have not been found. (Oberhauser et al.) Tetrahedron. 43. 3rd.
931-3944. 1987)

[0007]

An object of the present invention is to establish an efficient method for producing an optically active substance (-)-(1S, 2S, 4R) -exo-2-norbornanol.

[0008]

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have been found to hydrolyze the racemic exo-2-norbornanol aliphatic dicarboxylic acid monoester to form a monosaccharide. And that optically active (-)-(1S, 2S, 4R) -exo-2-norbornanol can be efficiently produced. That is,
The present invention relates to (1) an optically active compound (-)-(1S, 2S) characterized in that a lipolytic enzyme hydrolyzes an aliphatic dicarboxylic acid monoester of racemic exo-2-norbornanol (formula (1)). , 4R) -exo-2-norbornanol (Formula (2))

[0009]

Embedded image (In the formula, A represents a residue consisting of alkylene or alkenylene having 1 to 6 carbon atoms or cycloalkylene having a 5- or 6-membered ring.)

[0010]

Embedded image I will provide a.

The racemic exo-2-norbornanol aliphatic dicarboxylic acid monoester takes a little time for the reaction, but unlike the carboxylic acid esters such as acetic acid ester, the solubility in water is extremely good, so that the reaction efficiency is increased. Don't worry about the effect. Further, it is characterized in that the product after completion of the reaction is very easily recovered, and one enantiomer can be preferentially produced.

In practicing the present invention, examples of enzymes used include lipase, phospholipase, cholesterol esterase, sphingomyelease, and esterase present in animal organs, which play a role of lipid degradation in vivo. Can be done. The organism from which this is derived is not particularly limited, such as microorganisms, plants, and animals.
Recently, lipases produced by yeasts, bacteria, molds and the like are commercially available. These can be sufficiently used as enzymes in the production method of the present invention. Some of these examples are listed below.

Lipase AY, Lipase A, Lipase M, Lipase D, Lipase GC, Lipase R, Lipase L, Lipase CE, Lipase F-AP manufactured by Amano Pharmaceutical Co., Ltd.
-15, Lipase P, Lipase P manufactured by Meito Sangyo Co., Ltd.
L, lipase OF, lipase MY, lipase sequen by Osaka Bacteria Research Institute, protease, paratase, lipolase, lipozyme, lipozyme, lipase from Nagase Seikagaku Corporation, etc. In the present invention, esterases present in horse's watermelon and liver can also be used as enzymes in the present invention. As the enzyme used in the production method of the present invention, the above-mentioned examples, which are industrially available at low cost, are desirable, but are not limited thereto.

In practicing the present invention, examples of the aliphatic dicarboxylic acid monoester used as the substrate include racemic exo-2-norbornanol malonic acid monoester and racemic exo-2-norbornanol monosuccinic acid monoester. Esters, racemic exo-2-norbornanol maleate monoester, racemic exo-2-norbornanol fumaric acid monoester, racemic exo-2-norbornanol glutaric acid monoester, racemic exo-2-norbornanol adipine Acid monoester, racemic exo-2-norbornanol pimelic acid monoester, racemic exo-2
-Cyclopentane 1,2-dicarboxylic acid monoester of norbornanol, racemic exo-2-norbornanol cyclohexane 1,2-dicarboxylic acid monoester, and the like.

In general, these aliphatic dicarboxylic acid monoesters are preferably prepared by adding equimolar amounts of racemic exo-2-norbornanol and various acid anhydrides in toluene, heating to 100 ° C., and stirring for 10 hours or more. Can be synthesized in yield. When no ethylene bond is present in the acid anhydride used, the reaction is promoted by adding an equimolar amount of pyridine, and the reaction can be completed in several hours.

The solvent for the reaction in the present invention is preferably water, but a mixture of an organic solvent and water can also be used. As the organic solvent, benzene, toluene, n-hexane and other slightly low-polar ones, methanol, ethanol, acetonitrile, dimethylsulfoxide, dimethylformamide and other high-polarity solvents can be used. In this case, care must be taken because enzyme inhibition may occur.

The reaction method is as follows: a solvent and racemic exo-2-
It suffices to only charge and stir the aliphatic dicarboxylic acid monoester of norbornanol and the enzyme, and the amounts used, concentration reaction conditions, and the like will be described below. The solvent is
It is preferable to use 10 to 400 times (weight ratio, the same applies hereinafter) of the ester, of which water is preferably 5 to 200 times. Industrially, it is preferable to make water 10 times to 100 times. The amount of enzyme used is 0.2-30% of the ester
Good to use. During the reaction, the pH is preferably maintained at about 3 to 9. For this, a buffer solution may be used, or a control method according to the progress of the reaction may be used.

The reaction temperature ranges from room temperature to 80 ° C., especially 20 ° C.
Performing in the range of 〜50 ° C. gives good results. The reaction time may require about 3 to 20 days depending on the enzyme, but the reaction conversion must be stopped at 20% to 45%, and preferably the reaction is adjusted to be stopped at 30 to 45%.

After completion of the reaction, the optically active (-)-(1S, 2S, 4R) -exo-2- produced by hydrolysis.
The norbornanol and the unreacted ester are extracted with an organic solvent (for example, n-hexane, dichloromethane, chloroform, diethyl ether, ethyl acetate), the aqueous layer is removed, and the organic layer is washed with a 10% aqueous potassium carbonate solution to remain. The fatty acid monoester and dicarboxylic acid thus obtained are removed, and dried with sodium sulfate (anhydrous). afterwards,
By completely evaporating the organic solvent, (-)-(1S,
2S, 4R) -exo-2-norbornanol can be extracted with high purity.

In the production method of the present invention, the asymmetric hydrolysis of aliphatic dicarboxylic acid monoester to optically active (-)-(1S, 2S, 4R) -exo-2-norbornanol by a lipolytic enzyme is performed in a yield. The optical purity is 50% or more and the optical purity is 50% or more. The progress of the reaction and the purity of the target product can be known by GLC or HPLC.

Reference Example An example of a method for synthesizing a succinic acid monoester of racemic exo-2-norbornanol will be described below.

In a glass 500 ml four-necked round bottom flask, 20 g of succinic anhydride, 22.4 g of racemic exo-2-norbornanol and 15.8 g of pyridine were added to 200 ml of toluene, and the mixture was heated and stirred at 100 ° C. for 8 hours in an oil bath. . After cooling to room temperature, 200 g of water was added, and 35 g of concentrated hydrochloric acid was added dropwise with stirring to adjust the pH of the aqueous layer to 1. Then, the toluene layer was separated in a 1 L separating funnel,
The toluene layer and 200 ml of water were mixed and stirred in a ml beaker, and 35 g of a saturated aqueous potassium carbonate solution was added thereto to adjust the pH of the aqueous layer to 9. The toluene layer was separated and removed in a 1 L separating funnel, and the remaining aqueous layer was transferred into a 500 ml beaker.
After 200 ml of toluene was newly added, 50 g of concentrated hydrochloric acid was added thereto with mixing and stirring to adjust the pH of the aqueous layer to 1. Then 1L
The toluene layer was extracted and separated in a separating funnel, and the toluene layer was dried over sodium sulfate (anhydrous), and then the solvent toluene was removed under reduced pressure. As a result, the target racemic exo-2-norbornanol succinic acid monoester was obtained in a yield of 33.5 g and a yield of 79%.

[0023]

EXAMPLES The production method of the present invention will be described more specifically with reference to the following examples.

Example 1 A racemic exo-2-norbornanol malonic acid monoester (6.0 g) was added to a glass corbene (water) (400 m).
1, lipase AY-30 (Amano Pharmaceutical) 1.2 g, potassium dihydrogen phosphate 8.0 g, dipotassium hydrogen phosphate 12.
0 g and stirred at 30 ° C. for 8 days (pH in the reaction system =
6.8). After the reaction is completed, the conversion is 38% by HPLC analysis.
It was confirmed that alcohol was generated. 200 ml of n-hexane was added thereto for extraction, and after removing the aqueous layer, the resultant was washed with 50 ml of a 10% aqueous potassium carbonate solution and dried over sodium sulfate (anhydrous). Thereafter, the organic solvent was completely distilled off to obtain (-)-(1S, 2S, 4).
R) -exo-2-norbornanol was isolated in 55% yield. Optical purity is measured by polarimeter (DIP-360 polarimeter)
It measured using. As a result, the optical purity was 76%.

Example 2 A racemic exo-2-norbornanol maleic acid monoester (6.0 g) was added to a glass corbene (water: 400 m).
1, 1.2 g of lipase MY (Meito Sangyo), 8.0 g of potassium dihydrogen phosphate, and 12.0 g of dipotassium hydrogen phosphate were stirred at 30 ° C. for 21 days. HPLC after reaction
Analysis confirmed that alcohol was produced at a conversion of 30%. 200 ml of n-hexane was added thereto for extraction, and after removing the aqueous layer, the resultant was washed with 50 ml of a 10% aqueous potassium carbonate solution and dried over sodium sulfate (anhydrous). Then, by completely distilling the organic solvent,
(-)-(1S, 2S, 4R) -exo-2-norbornanol was isolated in a yield of 50%. Optical purity was measured using a polarimeter (DIP-360 polarimeter). As a result, the optical purity was 70%.

Example 3 In a glass corbene, 6.0 g of succinic acid monoester of racemic exo-2-norbornanol was added to 400 m of water.
1, lipase P-3 (Amano Pharmaceutical) 1.2 g, potassium dihydrogen phosphate 8.0 g, dipotassium hydrogen phosphate 12.0 g
Was stirred at 30 ° C. for 21 days. HPL after reaction
C analysis confirmed that alcohol was produced at a conversion of 40%. 200 ml of n-hexane was added thereto for extraction, and after removing the aqueous layer, the resultant was washed with 50 ml of a 10% aqueous potassium carbonate solution and dried over sodium sulfate (anhydrous). Then, by completely distilling the organic solvent,
(-)-(1S, 2S, 4R) -exo-2-norbornanol was isolated in 60% yield. Optical purity was measured using a polarimeter (DIP-360 polarimeter). As a result, the optical purity was 68%.

[0027]

EFFECT OF THE INVENTION (-)-(1S, 2S, 4R) -exo- by enzymatic hydrolysis of racemic exo-2-norbornanol monoester of aliphatic dicarboxylic acid.
A method for easily and efficiently producing 2-norbornanol has been established. The production method of the present invention is characterized in that the target substance can be easily isolated.

────────────────────────────────────────────────── ─── Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) C12P 1/00-41/00 C07C 27/02 C07C 35/29 C07C 49/433 BIOSIS (DIALOG) WPI (DIALOG) )

Claims (1)

(57) [Claims] 1. A racemic exo-2 by a lipolytic enzyme.
-Optically active substance (-)-(1S, 2S, 4R) -exo-2-norbornanol (formula (2)) characterized by hydrolyzing an aliphatic dicarboxylic acid monoester of norbornanol (formula (1)) Production method of (In the formula, A represents a residue comprising alkylene or alkenylene having 1 to 6 carbon atoms or cycloalkylene having a 5- or 6-membered ring.)