JPH069501A - Optically active 2-alkoxycarbonyl-2-cycloalkene derivative and its production - Google Patents

Abstract

PURPOSE:To obtain optically active 2-alkoxycarbonyl-2-cycloalkene derivatives useful as a starting substance for medicines and agricultural chemicals. CONSTITUTION:The optically active 2-alkoxycarbonyl-1-acyloxy-2-cycloalkene of formula I (* indicates asymmetric carbon; R1 and R2 are alkyl; n is 1 or 2), e.g. (+)-2-ethoxycarbonyl-1-acetyloxy-2-cyclopentene and the optically active 2-alkoxycarbonyl-2-cycloalken-1-ol of formula II, e.g. (-)-2-ethoxycarbonyl-2- cyclopenen-1-ol. These compounds of formulas I and II are obtained by subjecting a dialdehyde derivative of formula III to the Wittig-Horner reaction, providing a racemic-2-alkoxycarbonyl-2-cycloalken-1-ol of formula IV and then carrying out the ester interchange reaction of the resultant compound with an acylating agent in the presence of a lipase, preferably the lipase derived from a bacterium of the genus Pseudomonas.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an optically active 2-alkoxycarbonyl-2-cycloalkene derivative useful as a starting material for medicines and agricultural chemicals, particularly an optically active 2-alkoxycarbonyl-2-cycloalkene-1-ol, The present invention relates to an optically active 2-alkoxycarbonyl-1-acyloxy-2-cycloalkene which is an intermediate, and a method for producing them.

[0002]

2. Description of the Related Art Optically active 2-alkoxycarbonyl-2
-Cycloalkene-1-ol is useful as a starting material for physiologically active substances such as various medicines and agricultural chemicals. That is, it has two functional groups having different hydroxyl groups and carboxyl groups, and can be converted into antipodes by isomerization with each other, so that only one of the desired three-dimensional bodies can be obtained. However, the optically active substance of the compound represented by the following general formula (3) of the present invention has not been conventionally synthesized, and its usefulness could not be sufficiently evaluated.

In recent years, many methods for producing an optically active substance by an optical resolution method using an enzyme have been reported (for example, U.
SP05107039), there has been no example of the compound represented by the general formula (3) of the present invention.

[0004]

SUMMARY OF THE INVENTION In view of these problems, the present inventors have considered that optically active 2-alkoxycarbonyl-2-
In order to obtain both enantiomers of cycloalkene-1-ol, an intensive research was conducted and a production method characterized by transesterification with an acylating agent in the presence of lipase was found.

[0005]

The present invention is based on the general formula (1)

[0006]

[Chemical 6]

(In the formula, * represents an asymmetric carbon, and R ₁ , R ₂
Represents an alkyl group, and n represents 1 or 2. ) An optically active 2-alkoxycarbonyl-1-acyloxy-2-cycloalkene represented by the formula), and a general formula (3)

[0008]

[Chemical 7]

(In the formula, R ₁ represents an alkyl group, and n is 1
Or 2 is shown. ), A racemic-2-alkoxycarbonyl-2-cycloalkene-1-ol represented by the general formula (2) by transesterification with an acylating agent in the presence of lipase.

[0010]

[Chemical 8]

(In the formula, * represents an asymmetric carbon, R ₁ represents an alkyl group, and n represents 1 or 2.) An optically active 2-alkoxycarbonyl-2-cycloalkene-1. -All and general formula (1)

[0012]

[Chemical 9]

(In the formula, * represents an asymmetric carbon, and R ₁ , R ₂
Represents an alkyl group, and n represents 1 or 2. And an optically active 2-alkoxycarbonyl-1-acyloxy-2-cycloalkene represented by the formula (1), respectively. The reaction route of the production method of the present invention is shown by the following formula.

[0014]

[Chemical 10]

The dialdehyde derivative (5) which is the starting material of the present invention can be obtained by, for example, purchasing 2,5-dimethoxytetrahydrofuran when n = 1 and treating with acid. When n = 2, it can be easily obtained by oxidizing 1,6-hexanediol or reducing adipic acid. Desired racemic-2-alkoxycarbonyl-2-cycloalkene-
The conversion to 1-ol can be easily obtained by using the Wittig-Horner reaction (M. Graff, A. Al Dilaimi, P. Seguineau,
M. Rambaud, J. Villieras, Tetrahedron Lett., 24, 1
577 (1986)).

By adding the obtained racemic-2-alkoxycarbonyl-2-cycloalkene-1-ol to a suspension of an acylating agent and lipase and stirring at room temperature, either one of the enantiomers takes precedence. Optically acylated, optically active 2-alkoxycarbonyl-2-cycloalkene-1-ol and optically active 2-alkoxycarbonyl-
A 1-acyloxy-2-cycloalkene is obtained. The reaction time is 0.3 to 5 days, depending on the treatment amount.
As a method for separating these, it is possible to separate the enantiomers, for example, by column chromatography.

2-Alkoxycarbonyl-1-acyloxy-2-cycloalkene has a higher optical activity by adding a lipase to a phosphate buffer solution (buffer solution / acetone = 9/1 (v / v)) for hydrolysis reaction. Purity of optically active 2
-Alkoxycarbonyl-2-cycloalkene-1-ol can be obtained. In this case, the lipase may be immobilized. The phosphate buffer has a pH of 4-9, preferably 7-8.

In the above production method, the acylating agent to be used can be widely used as long as it can be a substrate for a transesterification reaction of lipase such as fatty acid ester and benzoic acid ester, but acetic acid is preferable Vinyl esters such as vinyl, vinyl propionate, vinyl butyrate, vinyl valerate, vinyl caproate, and vinyl laurate. The organic solvent used is preferably benzene, toluene, dichloromethane, t-butyl methyl ether, etc.,
Any type may be used as long as it does not inhibit the reaction of lipase.

Commercially available lipase can be used. For example, lipase PS, OF, AY, AK (above,
Amano Pharmaceutical Co., Ltd.), MY (name sugar), PPL (Wako Pure Chemical Industries) and the like. It can also be used directly from the bacterial cells. Pseudomonas, Arthrobacter, Alcaligenes, Aspergillus, Chromobacterium,
There are Candida, Mucor and Rhizopus. It can also be extracted from the internal organs of animals, for example, from the livers of pigs and cows. Among them, those derived from Pseudomonas are particularly preferred.

The immobilized carrier may be chromosolve, celite, cellulose, carrageenan, various polymers, etc. as long as they do not inhibit the activity.

[0021]

INDUSTRIAL APPLICABILITY According to the method described above, the optically active 2-
An alkoxycarbonyl-2-cycloalkene derivative is obtained. By obtaining the present compound, for example, it becomes possible to produce jasmonate or a synthetic intermediate of vitamin D ₃ effective as a therapeutic agent for osteoporosis by the synthetic route shown below.

[0022]

[Chemical 11]

[0023]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Synthesis of (±) -2-ethoxycarbonyl-2-cyclopenten-1-ol 26.53 g (201 mmo) of 2,5-dimethoxytetrahydrofuran
0.6 ml of hydrochloric acid (160 ml) was added to (l) and the mixture was stirred at 70 ° C. for 2 hours. After cooling to room temperature, the mixture was neutralized with 10% aqueous potassium hydrogen carbonate solution, 1 ml of 6M aqueous potassium carbonate solution was added, and the mixture was stirred at room temperature for 30 minutes. Then triethylphosphonoacetate 45.0 g
(201 mmol) was added, and 67 ml of 6M potassium carbonate aqueous solution was added.
Was added dropwise over 20 minutes, and the mixture was stirred at room temperature for 48 hours. It was extracted with ether, and the organic layer was washed with saturated saline. After drying over magnesium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 14.3 g (yield 46%) of a colorless liquid. Boiling point 90-100 ℃ (0.
5mmHg).

Synthesis of optically active 2-ethoxycarbonyl-2-cyclopenten-1-ol (±) -2-ethoxycarbonyl-2-cyclopenten-1-ol 1.027 g (6.58 mmol), vinyl acetate 1.3 ml
(14.1 mmol), and lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.) 66
Suspend mg in 66 ml of t-butyl methyl ether and mix at room temperature for 27
Stir for hours. The lipase was filtered off with Celite, and the filtrate was concentrated under reduced pressure. This was subjected to silica gel column chromatography to obtain the desired alcohol compound and acyl compound respectively.

(+)-2-ethoxycarbonyl-1-acetyloxy-2-cyclopentene 623.5 mg (yield 47.9
%, 100% ee), [α] _D ³¹ + 3.23 ° (c1.456, CHCl ₃ ),
Boiling point 45 ° C (0.1 mmHg) (-)-2-ethoxycarbonyl-2-cyclopenten-1-ol, 484.3 mg (yield 47.1%, 99.3% ee),
[Α] _D ³¹ −33.52 ° (c1.256, CHCl ₃ ), boiling point 45 ° C. (1 mmH
g) Optical purity was determined using Chiralcel OD (manufactured by Daicel).

Examples 2 to 6 Table 1 below similarly shows an example in which (±) -2-ethoxycarbonyl-2-cyclopenten-1-ol was used as a starting material. All lipases used were manufactured by Amano Pharmaceutical Co., Ltd. The reaction time for all was 72 hours, and the proportion of the mixture was (±) -body 1 mmo
l, vinyl acetate 2 mmol, solvent 10 ml, lipase 100 mg.

[0028]

[Table 1]

Example 7 Hydrolysis of (+)-2-ethoxycarbonyl-1-acetyloxy-2-cyclopentene 623.5 mg (3.147 mmol) of (+)-2-ethoxycarbonyl-1-acetyloxy-2-cyclopentene 10% (v /
v) Acetone-containing phosphate buffer (30 ml) was mixed, 30 mg of lipase PS was added, and the mixture was shaken at 27 ° C. After 24 hours, the reaction solution was filtered through Celite, and the filtrate was extracted with ether. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and colorless oily (+)-2-ethoxycarbonyl-2-
442 mg (yield 90%) of cyclopenten-1-ol was obtained. [Α] _D ³⁰ + 34.2 ° (c1.43, CHCl ₃ )

Claims (8)

[Claims] 1. A compound represented by the general formula (1): (In the formula, * represents an asymmetric carbon, R ₁ and R ₂ represent an alkyl group, and n represents 1 or 2.) An optically active 2-alkoxycarbonyl-1-acyloxy-2-
Cycloalkene. 2. A general formula (2): (In the formula, * represents an asymmetric carbon, R ₁ and R ₂ represent an alkyl group, and n represents 1 or 2.) An optically active 2-alkoxycarbonyl-2-cycloalkene-1
-All. 3. A general formula (3): (In the formula, R ₁ represents an alkyl group, and n represents 1 or 2.) Racemic-2-alkoxycarbonyl-
2-cycloalkene-1-ol in the presence of lipase,
By transesterification with an acylating agent, the compound of the general formula (2): (In the formula, * represents an asymmetric carbon, R ₁ represents an alkyl group, and n represents 1 or 2.)
-Alkoxycarbonyl-2-cycloalkene-1-ol and general formula (1) (In the formula, * represents an asymmetric carbon, R ₁ and R ₂ represent an alkyl group, and n represents 1 or 2.) An optically active 2-alkoxycarbonyl-1-acyloxy-2-
A process for producing an optically active 2-alkoxycarbonyl-2-cycloalkene derivative, which comprises obtaining cycloalkenes respectively. 4. The optically active 2-alkoxycarbonyl-1-acyloxy-2-cycloalkene represented by the general formula (1) obtained in claim 3 is hydrolyzed in the presence of lipase to give an optically active compound. Process for producing 2-alkoxycarbonyl-2-cycloalkene-1-ol. 5. The method for producing an optically active 2-ethoxycarbonyl-2-cycloalkene derivative according to claim 3, wherein R ₁ is an ethyl group. 6. The method according to claim 3, wherein R ₁ is an ethyl group and R _{2 is}
Optically active 2-ethoxycarbonyl-2 in which is a methyl group
-A method for producing a cycloalkene derivative. 7. The optically active 2-alkoxycarbonyl-2-wherein the acylating agent according to claim 3 is a vinyl ester.
Process for producing cycloalkene derivative. 8. The method for producing an optically active 2-alkoxycarbonyl-2-cycloalkene derivative according to claim 3, wherein the lipase is derived from Pseudomonas.