JP3120456B2 - Optical Resolution of Corey Lactone Esters - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for optically resolving a corely lactone ester which is an intermediate of prostaglandins useful as pharmaceuticals. Prostaglandins are physiologically active substances and play a fundamental role in maintaining homeostasis in living organisms, and are therefore expected to be used as pharmaceuticals in various fields. Among them, it has already been put to practical use in the fields of promotion of parturition, improvement of peripheral blood flow, anti- calligraphy, inhibition of platelet aggregation.

Among the chemical synthesis methods for prostaglandins, the most effective one is the corey lactone (formula [A]) reported by Corey et al. Wherein, R 'and R "represents hydrogen or a hydroxy-protecting group.] In which the key intermediate (Reference:. JACS 92 397 (1970) , JACS
93 1490 (1971)) Corey since still many prostaglandins are synthesized via Corey lactones lactone is an essential compound for the synthesis of prostaglandins.

[0003]

2. Description of the Related Art There are many known methods for synthesizing optically active corely lactone. Among them, the following method is considered to be excellent. 1) Cory method: a synthesis method using the Diels-Alder reaction of cyclopentadiene derivative and the optical resolution of hydroxycarboxylic acid as key steps (Reference: JACS)
92 397 (1970), JACS 93 1490
(1971)) 2) Quinoin method: a synthesis method using the Prince reaction of an optically active bicyclic lactone obtained by optical resolution as a key step (references: JP-A-52-105163, tetrahedron letters ( TL) 4639 (1976)) 3) Pfizer method: a synthesis method using the Prince reaction of norbornadiene and the optical resolution of carboxylic acid as key steps (Reference: JP-A-50-111074, JAC)
S 95 7522 (1973)) 4) Asymmetric Diels-Alder method: A synthesis method using an asymmetric Diels-Alder reaction using optically active pantolactone as an asymmetric source as a key step (reference: Japanese Patent Application Laid-Open No. 63-63).
No. 152339)

[0004]

Problems to be Solved by the Invention 1) to 3) above
All of the methods require optical resolution, so that an expensive optical resolving agent is required, and there is a problem that a dividing operation such as salt formation, filtration, decomposition of salt, and recovery of the resolving agent is complicated. The asymmetric Diels-Alder method 4) is an excellent method that can produce corey lactone with high yield and high selectivity without optical resolution. However, after the asymmetric reaction, the number of steps of the reaction leading to the corey lactone was large, and was still unsuitable as an industrial production method. For the above reasons, a simpler optical resolution method for corey lactone ester has been desired.

[0005]

Means for Solving the Problems The present inventors have made the formulas (Ia) and (Ib)

Embedded image (Wherein, R represents an alkyl group having 1 to 10 carbon atoms or an α-haloalkyl group having 1 to 3 carbon atoms;
R ¹ , R ² and R ³ are the same or different and are each an alkyl group having 1 to 6 carbon atoms,
To 7 cycloalkyl groups, optionally having 1 carbon atom
A C 1-3 alkyl group substituted by a phenyl group substituted by a C 4 alkyl group,
Or a phenyl group optionally substituted by an alkyl group having 1 to 4 carbon atoms or a chlorine atom. In view of the fact that the corey lactone ester represented by) is a useful compound widely used in the synthesis of pharmaceuticals, agricultural chemicals, etc., as a result of intensive studies on its industrial optical resolution method, it has been found that it is completely different from the conventional method. It completes a different, very easy to operate method of the invention. That is, the present invention has the ability construed asymmetric water Corey lactone ester, Rhizopus, Mucor, Aspergillus, Candida, Pseudomonas, Alcaligenes, microorganisms belonging to the genus Achromobacter genus or Bacillus genus
After asymmetric hydrolysis of a mixture of the corely lactone esters represented by the above general formulas (Ia) and (Ib) using a lipase derived from a product or a protease derived from an animal organ , the remaining ester and the produced alcohol are separated. And optical purification of an optically active corey lactone ester.

The alkyl group represented by R in the formula includes, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, octyl and the like.

The α-haloalkyl group includes, for example, chloromethyl, 1-chloroethyl and the like.

The alkyl groups of R ¹ , R ² and R ³ include, for example, methyl, ethyl, n-propyl, iso-
Propyl, n-butyl, sec-butyl, tert-butyl, cyclohexyl group and the like.

The substituted alkyl group includes, for example, benzyl, 1-phenylethyl, cumyl and the like.

As the aryl group, for example, phenyl, p
-Chlorophenyl, p-tolyl group and the like.

The present invention is represented by the following reaction formula. ↓ Or ↓

The enzyme which can be used in the present invention is an enzyme having the ability to asymmetrically hydrolyze an ester, such as Rhizopus, Mucor, Aspergillus, Candida, Pseudomonas, Alcaligenes, Achromobacter or Bacillus. Lipases from microorganisms belonging to each genus
Or a protease derived from an animal organ .

For example, the enzymes shown in Table 1 may be mentioned.
it can.

Table 1

[0015] These enzymes are purified enzyme, crude enzyme, enzyme-containing substance, microbial broth cultures, cells can be used as needed in a variety of forms such as the culture filtrate and those who handle them.

[0016] In the practice of the method of the present invention will depend on the <br/> enzyme used, generally preferably use of a buffer, sodium phosphate, buffer-mentioned inorganic acid salts of potassium phosphate Liquid and a buffer of an organic acid salt such as sodium citrate can be suitably used. An initial pH of 7 to 8 can be suitably used, and it is desirable to keep the initial pH at 4 to 8 during the reaction. The concentration of the buffer varies depending on the type of the buffer, but is 0.05 to 1%.
M can be used, and 0.1 to 0.5 M can be suitably used.

[0017] Using the buffer so as not to extremely acidic by acid generated by the water-decomposable, added <br/> enzyme Moto及 beauty substrate with the asymmetric resolution, several hours to several days, the stirring or shaking Do. Although the reaction can be carried out at 10 to 50 ° C, the reaction is slow at a low temperature, and the enzyme may be deactivated and asymmetric selectivity may be reduced at a high temperature. After completion of the reaction, the remaining coalylactone ester and the produced alcohol are separated and purified by a usual method.

Formulas (Ia) and (Ia) used as substrates
b) The mixture of the corely lactone esters represented by the formula was synthesized by a known method (Cobax et al., Tetrahedron Let., 4639 (197)
6)) The diol (Ic) can be prepared by a method such as silylation and acylation by a conventional method. Although the substrate concentration depends on the conditions, the reaction can be performed at 0.5 to 0.001M, and preferably 0.3 to 0.001M.

[0019]

According to the method of the present invention, an optically active corely lactone ester can be easily and conveniently resolved in one step as an intermediate of a useful drug or the like, and the optically active corely lactone ester and / or the produced optically active corely lactone ester can be obtained. Alcohol can be supplied at low cost.

[0020]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.
Embodiment 1 FIG.

(±) -7α-acetoxy-6β- (t-
Butyldimethylsilyloxy) methyl-2-oxa-bicyclo [3.3.0] octan-3-one (1) 2.3
230 ml of 0.1 M phosphate buffer (pH 7.6) was added to 0 g (7.01 mM), and the mixture was stirred at 30 ° C. for 15 minutes. Next, Pseudomonas sp.lipase
(Amano PS) 1.15 g was added and stirred at the same temperature for 48 hours. After filtering the reaction mixture through celite, the aqueous layer was extracted with ethyl acetate (80 ml × 5). The aqueous layer was salted out and extracted with ethyl acetate (80 ml × 3). The celite layer was washed with ethyl acetate (50 ml × 3), and all the ethyl acetate layers were combined and washed with 20 ml of saturated saline. After drying over magnesium sulfate, the ethyl acetate was distilled off under reduced pressure, and the residue was silica gel 10
The residue was subjected to column chromatography using 0 g to obtain 1.14 g of the (+)-(2) compound as a colorless oil from the n-hexane-ethyl acetate (4: 1) stream. Yield 50%. n-
From the hexane-ethyl acetate (7: 3) stream, 0.994 g of the (-)-(3) form of colorless crystals was obtained. Yield 49.7
%.

(+) − (2) : [α] _D + 48.0 ° (c = 1.016, CHC
l ₃ ); IR (neat): 1764, 1736 cm ^-1 ; NM
R (CDCl ₃ ; 90 MHz): δ 5.05 (m, 2
H), 3.6 (d, 2H, J = 5 Hz), 2.95-
2.1 (m, 6H), 2.0 (s, 3H), 0.90
(S, 9H), 0.06 (s, 6H); MS (m /
z): 329 (M ⁺⁺ 1), 229, 211, 137,
117 (100); high resolution MS (m / z): calculated value 3
29.1784 (C ₁₆ H ₂₉ O ₅ Si (M ⁺ +1) found 329.1777

(−) − (3): [α] _D −14.2 ° (c = 1.008, CHC
l ₃ ); m. p. 60-61 ° C (diethyl ether-hexane) IR (nujol): 3476, 1755 cm ^-1 ; NM
R (CDCl ₃ , 90 MHz): δ 4.95 (m, 1
H), 4.16 (q, 1H, J = 5.7 Hz), 3.8
(Q, 1H, J = 5, 8.8 Hz), 3.6 (q, 1
H, J = 5, 8.8 Hz), 2.88 to 2.30 (m,
5H), 2.13 to 1.86 (m, 2H), 0.90
(S, 9H), 0.06 (s, 6H) MS (m / z):
287 (M ⁺⁺ 1), 229, 211, 137, 75
(100); high resolution MS (m / z): calculated 287.
1679 (C ₁₄ H ₂₇ O ₄ as Si (M ⁺ +1)) Found 287.1670

The determination of the optical purity was performed as follows. (For MTPACl and MTPA in the reaction formula,
(See Note)

[0025]

[0026]

Embodiments 2-5. 100 mg of (±)-(1), 5 mg of lipase shown in Table 2.
Table 2 shows the results of optical resolution performed in the same manner as in Example 1 except that 0 mg and 10 ml of the phosphate buffer were used.

Examples 2 to 5

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields investigated (Int. Cl. ⁷ , DB name) C12P 41/00 BIOSIS (DIALOG) CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A genus of Rhizopus, Mucor, Aspergillus, which has the ability to asymmetrically hydrolyze esters in an optically selective manner.
Candida spp., Pseudomonas spp., Alcaligenes, fine belonging to the genus Achromobacter genus or Bacillus
Using a lipase derived from an organism or a protease derived from an animal organ , the compounds represented by the general formulas (Ia) and (Ib) are used. (Wherein, R represents an alkyl group having 1 to 10 carbon atoms or an α-haloalkyl group having 1 to 3 carbon atoms; R ¹ , R ² and R ³ are the same or different from each other and have 1 carbon atom) To 6 alkyl groups, 3 carbon atoms
To 7 cycloalkyl groups, optionally having 1 carbon atom
A C 1-3 alkyl group substituted by a phenyl group substituted by a C 4 alkyl group,
Or a phenyl group optionally substituted by an alkyl group having 1 to 4 carbon atoms or a chlorine atom. An optical resolution method for an optically active corey lactone ester, comprising subjecting a mixture of the corey lactone ester represented by the formula (1) to asymmetric hydrolysis, followed by separating and purifying the remaining ester and the produced alcohol.