Method for Manufacturing Optically Active Tetrahydrothiophene Derivative and Method for Crystallization of Optically Active Tetrahydrothiophene-3-Ol

Abstract

A method for manufacturing (R)-tetrahydrothiophene-3-ol denoted by formula (II):

Description

EXAMPLES

The present invention will be described in greater detail below based on specific examples. However, the present invention is not limited to these examples.

Example 1

A 25 mL quantity of F1 medium (potato starch 20 g/L, glucose 10 g/L, soy flour 20 g/L, potassium dihydrogenphosphate 1 g/L, magnesium sulfate heptahydrate 0.5 g/L) was poured into a 250 mL conical flask and sterilized with high-pressure steam for 20 minutes at 121° C. This mixture was inoculated with Aspergillus ochraceus ATCC18500, and shaking culturing was conducted for 72 hours at 25° C. A 30 mg quantity of tetrahydrothiophene-3-one was added to the culture solution obtained, and the mixture was shaken for 24 hours at 25° C.

The reaction solution obtained was extracted with ethyl acetate (15 mL×3). The organic layers were combined and dried over sodium sulfate and then concentrated after filtration. The residue was separated and purified by preparative TLC (hexane/ethyl acetate=1/1) to give 12 mg of the target product (a yield of 39 percent) with an optical purity of 81 percent e.e. (R).; [α]_D=+8.8(c=0.5, CHCl₃); ¹H—NMR(CDCl₃) δ(ppm): 1.75(m, 2H), 2.15(m, 1H), 2.82-3.17(m, 4H), 4.5(m, 1H).

In the present invention, optical purity was determined by high-performance liquid column chromatography (mobile phase: hexane/isopropanol=96/4, flow rate: 1 mL/minute, temperature: 30° C., detection: 210 nm) equipped with a chiral column (Chiralpak AS-H (φ 0.46×25 cm) made by Daicel Chemical Industries). The absolute configuration was determined by comparison with the optically rotation given in J. Am. Chem. Soc. 108, 2049 (1986).

Example 2

With the exceptions that Penicillium vinaceum IAM7143 was employed and a 50 mg quantity of substrate was added, the conversion reaction was conducted in the same manner as in Example 1. This yielded 11 mg of target product (a yield of 22 percent) with an optical purity of 91 percent e.e. (R).

Example 3

With the exception that Streptomyces michiganensis NBRC12797 was employed, the conversion reaction was conducted in the same manner as in Example 2. This yielded 32 mg of target product (a yield of 79 percent) with an optical purity of 88 percent e.e. (R).

Example 4

F1 medium (potato starch 20 g/L, glucose 10 g/L, soy flour 20 g/L, potassium dihydrogenphosphate 1 g/L, magnesium sulfate heptahydrate 0.5 g/L) that had been sterilized with high-pressure steam for 20 minutes at 121° C. was poured in 1.5 L quantities into each of three mini-jars of three-liter capacity. The media were inoculated with Penicillium vinaceum IAM7143, and shaking culturing was conducted for 72 hours at 25° C. A 4 mL quantity of tetrahydrothiophene-3-one was added to each of the culture solutions obtained, and the mixtures were shaken for 24 hours at 20 to 23° C.

The reaction solution obtained from one of the three-liter mini-jars was extracted with ethyl acetate (total 1.75 L). The same extract operation was conducted for the remaining two mini-jars. The organic layers were combined, dried over sodium sulfate, and then concentrated after filtration. The residue was purified by distillation. This yielded 8.0 g (a yield of 55 percent) of (R)-tetrahydrothiophene-3-ol with an optical purity of 87 percent e.e.

Example 5

Hexane (6.8 mL) and acetone (2.8 mL) were added to 8 g of the (R)-tetrahydrothiophene-3-ol with an optical purity of 87 percent e.e. from Example 4. The mixture was stirred overnight at −15° C. Stirring was continued overnight in this state. The white crystal that precipitated out was collected by filtration with a Kiriyama funnel (φ 40 mm, No. 4 filter paper). The crystal obtained by filtration gradually became liquid (R)-tetrahydrothiophene-3-ol.

5.7g (a yield of 71 percent); optical purity of 95% e.e.; [α]D=+11.6(c=0.1, CHCl₃); ¹H—NMR (CDCl₃) δ(ppm): 1.75(m,2H), 2.15(m,1H), 2.82-3.17(m, 4H), 4.5(m,1H).

Example 6

(R)-tetrahydrothiophene-3-ol (50 g) with an optical purity of 91.8 percent e.e. was added to a mixed solution of acetone (217 mL) and heptane (43 mL). This mixture was gradually cooled with stirring to a final temperature of −15° C. Stirring was continued overnight in this state. The white crystal that precipitated out were collected by filtration with a Kiriyama funnel (φ 40 mm, No. 4 filter paper). After thoroughly removing the solvent from the crystal that had been obtained by filtration, the crystal was heated to obtain 31.6 g (a yield of 63 percent) of liquid (R)-tetrahydrothiophene-3-ol with an optical purity of 96 percent e.e.

Example 7

Acetone (23.6 mL) and hexane (100 mL) were charged to a 300 mL container, and the mixture was cooled to −18° C. (R)-tetrahydrothiophene-3-ol (122.32 g) with an optical purity of 91.8 percent e.e. was added dropwise with stirring. The container employed for the dropwise addition was washed with acetone (11.8 mL). Following overnight stirring, crystal was collected by filtration with a Kiriyama funnel (φ 60 mm, No. 5B filter paper). After thoroughly removing the solvent from the crystal that had been obtained by filtration, the crystal was heated to obtain 86.0 g (a yield of 70 percent) of liquid (R)-tetrahydrothiophene-3-ol with an optical purity of 97 percent e.e.

Example 8

Methyl ethyl ketone (23.5 mL) and hexane (100 mL) were charged to a 300 mL container, and the mixture was cooled to −18° C. (R)-tetrahydrothiophene-3-ol (128.03 g) with an optical purity of 91.8 percent e.e. was added dropwise with stirring. The container employed for the dropwise addition was washed with acetone (11.8 mL). Following overnight stirring, crystal was collected by filtration with a Kiriyama funnel (φ 60 mm, No. 5B filter paper). After thoroughly removing the solvent from the crystal that had been obtained by filtration, the crystal was heated to obtain 83.9 g (a yield of 66 percent) of liquid (R)-tetrahydrothiophene-3-ol with an optical purity of 96 percent e.e.

Example 9

With the exceptions that (R)-tetrahydrothiophene-3-ol (1.37 g) with an optical purity of 92 percent e.e., hexane (1.2 mL) and acetone (0.48 mL) were employed as well as crystallization was conducted at 1° C., the same processing was conducted as in Example 5. This yielded (R)-tetrahydrothiophene-3-ol of 95 percent e.e. at a yield of 65 percent.

INDUSTRIAL APPLICABILITY

According to the present invention, (R)-tetrahydrothiophene-3-ol with high optical purity, that is useful as an intermediate in the synthesis of pharmaceuticals can be obtained.

Claims

1: A method for manufacturing (R)-tetrahydrothiophene-3-ol denoted by formula (II):

2: The method according to claim 1, wherein said strain capable of the bioconversion is a strain belonging to Penicillium vinaceum, Aspergillus ochraceus, or Streptomyces michiganensis.

3: The method according to claim 1, wherein said strain capable of the bioconversion is Penicillium vinaceum IAM7143 (Deposit Number: NITE BP-35), Aspergillus ochraceus ATCC18500 (deposit Number: NITE BP-41), or Streptomyces michiganensis NBRC12797 (Deposit Number: NITE BP-36).

4: A method for crystallization of optically active tetrahydrothiophene-3-ol of improved optical purity, characterized by maintaining a solution comprising optically active tetrahydrothiophene-3-ol and organic solvent at equal to or lower than 1° C. to cause optically active tetrahydrothiophene-3-ol to crystallize from said solution.

5: A method for crystallization of optically active tetrahydrothiophene-3-ol of improved optical purity, characterized by adding optically active tetrahydrothiophene-3-ol dropwise to organic solvent at a solution temperature of equal to or lower than 1° C. to cause optically active tetrahydrothiophene-3-ol to crystallize.

6: The method according to claim 5, wherein said dropwise addition of optically active tetrahydrothiophene-3-ol is conducted with stirring said organic solvent.

7: The method according to claim 4, wherein the organic solvent is compatible with optically active tetrahydrothiophene-3-ol, and does not solidify at a temperature at which the crystallization is conducted.

8: The method according to claim 4, wherein the optically active tetrahydrothiophene-3-ol comprises excess amount of R-isomer.

9: The method according to claim 4, wherein said organic solvent is at least one solvent selected from the group consisting of hexane, heptane, ethyl-acetate, butyl acetate, acetone, methyl ethyl ketone, ethanol, 2-propanol and toluene, or a mixed solvent thereof.

10: The method according to claim 4, wherein the crystallization temperature of said optically active tetrahydrothiophene-3-ol is equal to or lower than 1 ° C.