JPS6349099A - Production of optically active 3-chloro-4-hydroxy-2-cyclopentenone - Google Patents

Abstract

PURPOSE:To produce 3-chloro-4-hydroxy-2-cyclopentenone with is a synthetic intermediate for punaglandin at a low cost, by asymmetrically hydrolyzing acetoxy-cyclopentenone with an enzyme or microorganism. CONSTITUTION:A compound expressed by formula II is asymmetrically hydrolyzed with a hydrolase or microorganism, preferably swine hepatic esterase, acetylcholine esterase, etc., in a buffer solution or a mixture solution thereof with an organic solvent to prepare 3-chloro-4-hydroxy-2-cyclopentenone expressed by formula I (* indicates optical active center, same applies hereinafter). Alternatively, an optically active compound, expressed by formula III and obtained by asymmetric hydrolyzing the above-mentioned compound expressed by formula II and removing the hydrolyzate is hydrolyzed with an enzyme or microorganism to produce the 3-chloro-4-hydroxy-2-cyclopentenone expressed by formula I after completing the reaction, the reaction solution is filtered and extracted with an organic solvent. The organic layer is then purified by column chromatography to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides optically active 3-chloro-4-hydroxy-2-
This invention relates to a method for producing cyclobentenone.

Optically active 3-chloro-4-hydroxy-2-cyclobentenone exhibits a strong muscle cell proliferation inhibitory effect (L 12
ICs for 10i cells. =0.02~0.06μ
g/cc) is an important synthetic intermediate of punaglandin (8).

Several synthetic methods for punaglandin have been reported recently, including the 52nd Spring Annual Meeting of the Chemical Society of Japan (1986).
, Lecture Proceedings II, page 1072, optically active (4
R)-3-chloro-4-tcrt-butyldimethylsilyloxy-2-cyclobentenone (1) has an ω side chain, α
Punaglandin (8) was obtained by sequentially linking the side chains.

(Scheme 1) The asymmetry at the 8- and 12-positions of punaglandin (8) is derived from the asymmetry at the 4-position of compound (1). Compound (1) is, for example, J, CheIl, S
oc, Chem, Comm-, 1979], 21 (Scheme 2).
R)-3-' It can be synthesized from chloro-4-hydroxy-2-cyclobentenone (1).

Thus, optically active 3-chloro-4-hydroxy-2-cyclobentenone (1) can be said to be an extremely important synthetic intermediate in the synthesis of punaglandin (8).

Particularly desirable for the synthesis of natural punaglandin is (4
R)-3-chloro-4-hydroxy-2-cyclobentenone [(4R)-11, but (4S)-3-chloro-4-hydroxy-2-cyclobentenone [(4S
)-11 is also useful in bunaglandin analog synthesis and prostaglandin synthesis.

Conventionally, as a method for synthesizing optically active 3-chloro-4-hydroxy-2-cyclobentenone, J. Chew,
A method shown in Scheme 2 described in Soc, Chem, Coma, 1979121 is known.

That is, racemic 3.3.5-trichloro-1,4
-Dihydroxycyclobent-1-carboxylic acid (9) was converted into a salt of brucine, and this salt was fractionally recrystallized (IS
, 4S)-3,5,5-trichloro-1,4-dihydroxycyclobent-1-carboxylic acid (11) was obtained, from which (4R)-3-chloro-4-hydroxy-2- It is called cyclobentenone. However, this method requires an expensive reagent called purusin, and also requires a complicated process of fractional recrystallization.

Halogen-free, optically active 4-hydroxy-2-
The method for producing cyclobentenone is an ester of optically active cyclopropanecarboxylic acid and dl-hydroxy-2-cyclobentenone. There is a method of asymmetrically hydrolyzing a compound represented by the following formula (* represents an optically active center) using an enzyme or a microorganism. (JP-A-6O-22563119) A method for producing optically active 4-hydroxy-2-cyclobentenone substituted at the 2-position by the method shown in Scheme 3 is also known.

Tetrahedron, 32.1713 (197
6) describes a method of hydrolyzing dl-4-acetoxy-2-cyclobentenone using Wheatgorm Lipase, but there is no information regarding the optical purity of the obtained 4-hydroxy-2-cyclobentenone. There is no description.

In this way, until now, Scheme 3 containing halogen in the molecule
Chemical Society of Japan 52nd Spring Annual Meeting Lecture Preliminary Collection II 15
07 (1986) ○ 0 There are no reports of asymmetric hydrolysis of 4-acyloxy-2-cyclobentenone using enzymes or microorganisms with good optical purity and good yield.

The present inventors investigated a method for industrially producing optically active 3-chloro-4-hydroxy-2-cyclobentenone, which is a useful synthetic intermediate for punaglandin, and found that the present invention reached. That is, it is a method for producing optically active 3-chloro-4-hydroxy-2-cyclobentenone by asymmetrically hydrolyzing an ester represented by the formula using enzymes or microorganisms, and also for producing optically active 3-chloro-4-hydroxy-2-cyclobentenone. As a result of asymmetric hydrolysis, the remaining substrate is represented by the formula, (wherein the book represents the optically active center),
Optically active ester is hydrolyzed using enzymes or microorganisms to produce optically active 3-chloro-4-hydroxy-2
-A method for producing cyclobentenone (1).

In the present invention, the raw material ester (n) is obtained by combining 3-chloro-4-hydroxy-2-cyclobentenone synthesized by a known method with acetic anhydride or acetyl halide such as acetyl chloride, and pyridine, triethylamine, etc. It can be obtained in good yield by reacting in the presence of a base in a solvent such as methylene chloride, tetrahydrofuran, or benzene, or without a solvent.

The asymmetric hydrolysis of ester (II) is carried out using an enzyme or microorganism capable of hydrolyzing either optically active form of the ester.

Examples of asymmetric hydrolases include animal esterases such as liver esterase, pancreatic esterase, and acetylcholinesterase, and plant esterases, and furthermore, microorganisms such as the following microorganisms, lichens, and algae that live in various organisms. Alternatively, hydrolytic enzymes obtained from these may be mentioned.

Rhodortoula+Trichoderma+C
andida, trans-nula+Pseud
omonas, Bacillus+Achromob
acter-Nocardia+Chromobact
erium = Flavobacterium.

Rhizopus SMucor-Aspergillus
s-A1kalj4cnes.

Torulopsis-Corynebacterium
m-Endomyces.

Saccharormyces-Arthrobact
er+He1minthospo-rium+Brev
ibacterium1ε5cherichia+C1
troba-cter, Absidia-Micro
coccus, Pediococcus.

Klebsie11a+Geotrichum+Lac
tobacillus-Cry-ptococcus+
Pichia%Aureobasidiun++Aet
ino-mueor, Enterobacter, M
icrobacterium, Pen1ci-11i
urn, Schizophylium.

In the present invention, the form of use of the hydrolyzed VF element used includes sperm enzyme, crude enzyme, enzyme-containing material, microorganism culture fluid, culture, bacterial cells, culture filtrate, or processed products thereof. It can be used in various forms depending on the situation.

Furthermore, it can be immobilized on a resin or the like and used as an immobilized enzyme or an immobilized bacterial cell.

In the asymmetric hydrolysis reaction, ester (■) or (111)
and the above hydrolase, or a microorganism, preferably pig liver esterase, acetylcholinesterase, Pse
Candi derived from purified or crude enzyme of udomonas yamaki
The purification or crude enzyme derived from D. da cylindracea is usually carried out in a buffer solution or a mixture of an organic solvent and a buffer solution, with the addition of a surfactant if necessary, and vigorous stirring.

When using a mixture of an organic solvent and a buffer, the organic solvent used is usually a water-soluble solvent, such as alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, and nitriles such as acetonitrile and propionitrile. etc. can be used.

As the buffer, commonly used buffers such as sodium phosphate, potassium phosphate, sodium citrate, etc. can be used. Use purified X water instead of a buffer solution, and adjust the pH by adjusting the pH
It can also be done with a stat.

The reaction temperature is preferably -20 to +40'C1 and the reaction time is preferably 2 to 50 hours, but is not limited thereto.

After the reaction is completed, the hydrolysis reaction solution is filtered as necessary, extracted with an organic solvent such as methyl isobutyl ketone, ethyl acetate, diethyl ether, dichloromethane, etc., and the organic layer is concentrated and purified by column chromatography to obtain the desired product. optically active 3-chloro-4-hydroxy-2-cyclobentenone (I), and optically active 4-acetoxy-3-chloro-2-cyclobentenone (I), which is an unhydrolyzed product.
Tll) is obtained.

The separated optically active ester (]■) is hydrolyzed to form the previously obtained optically active alcohol (
Optically active alcohol (1) with the opposite coordination to 1)
You can get

The hydrolysis reaction of optically active ester (III) to alcohol (1) can be carried out in the same manner as the above-mentioned asymmetric hydrolysis of ester (II) to alcohol (I).

According to the method of the present invention, one optically active 3-chloro-4-hydroxy-2-cyclobentenone (I) is obtained by asymmetric hydrolysis of the ester (TI), and the unobtained compound simultaneously obtained. Optically active ester (In
) to obtain optically active 3-chloro-4-hydroxy-2-cyclobentenone having the opposite coordination to that obtained previously.

Optically active 3-chloro-4-hydroxy- as described in Examples
The optical purity of 2-cyclobentenone (1) was determined by the method shown in Scheme 4.
The diastereomer ratio was determined by high performance liquid chromatography.

(I) (IV) (In the formula, this represents an optically active center.) Next, examples will be specifically described, but the present invention is not limited to only stiff particles.

Reference example 1 4-acetoxy-3-chloro-2-cyclobentenone dl-3-chloro-4-hydroxy-2-cyclobentenone (synthesized according to the method described in J, Chem, Soc, y bile η121 ) 6.8 g was cooled to -5°C, and 100 m12 of pyridine was reduced by δ4. After adding 0.6 g of N,N-dimethylamino-4-pyridine, 15.0 mM of acetic anhydride was added dropwise at -5°C.

After the dropwise addition, the mixture was stirred at -5°C for 4 hours, and the reaction solution was poured into cold water and extracted with methylene chloride. The present layer was washed sequentially with IN-hydrochloric acid, brine, sodium bicarbonate solution, and brine, dried with anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography, and purified with di-4-acetoxy- 3-chloro-
6.2 g of 2-cyclobentenone was obtained.

”) I-NMR (100MHz) δ (CDCI, ):
6.40 (1,1(,d).

5.88 (ill, ddd), 3. OII (I
H, dd), 2.46 (IH.

dd), 2.18 (311,s) I R(neat) -y am-1: 1750.
1730.1600°1435.1405. 1375
゜Reference Example 2 4-acetoxy-3-chloro-2-cyclobentenone 10.0 g of dl-3-chloro-4-hydroxy-2-cyclobentenone and 150 g of methylene chloride were cooled to 0°C, and 20.0 g of triethylamine was added. Add R dropwise.

After adding 0.1 g of N,N-dimethylamino-4-pyridine, 15.0 mQ of acetyl chloride is added dropwise.

After stirring at 0'C/2 hours, post-treatment was carried out in the same manner as in Reference Example].
Purification was performed to obtain di-4-acetoxyl 3-chloro-2-
9.7K of cyclobentenone was obtained.

Example 1 3.9 g of di-4-acetoxy-3-chloro-2-cyclobentenone and 300 mQ of Pl+ 7.0 phosphate buffer
and pig liver esterase (manufactured by Sigma) 0.2 mQ
and stir vigorously at 37°C for 5 hours.

The reaction solution was extracted five times with 50 m9 of methylene chloride.

The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (ethyl acetate/n-hexane =
i/3) and (4R)~3-chloro4-
Hydroxy-2-cyclobentenone 1.2g ([aE
= +32.6°(c], CHCl,), optical purity 90%ee) and (4S)-4-acetoxy-3
-chloro-2-cyclobentenone 2.2 g ([α]o=
+10.0°(c 1 , CHCl3)) Example 2 To 2.2 g of (4.3)-4-acetoxy-3-chloro-2-cyclobentenone obtained in Example 1, J ton X
-1000,3g, PH7,OU:/8% acid solution 110
- and Candida cylindracea crude enzyme] and stirred vigorously for 720 hours at 20°C. The reaction solution was post-treated and purified in the same manner as in Example 1.
S)-3-chloro-4-hydroxy-2-cyclobentenone 1.4 g ([α$= -27,5° (c 1.
CHCl, ), optical purity 75%ee) was obtained.

Example 3 To 2.0 g of dl-4-acetoxy-3-chloro-2-cyclobentenone, 150 ml of PH7.0 phosphate buffer was added.
, Triton X-1003001E and stir.

- Add crude enzyme 1100III derived from Candida cylinclracea and stir vigorously at 7°C for 7 hours.

The reaction solution was filtered, and the reaction solution was post-treated and purified in the same manner as in Example 1 to obtain (4R)-3-chloro-4-hydroxy-2-
Cyclobentenone 570 mg ([a H: +36.9°
(c O, 5, CHCl,) + optically pure L97%ee
) and (4S)-4-acetoxy-3-chloro-2-cyclobentenone 850mg ([αY:+12.5° (
c 1.0. CllCl, )) is n.

Example 4 830 mg of <43)-4-acetoxy-3-chloro-2-cyclobentenone obtained in Example 3 was mixed with 200+nQ of phosphate buffer of Pl+7.0, Aspcrgillus
Add the crude enzyme 40-derived and stir vigorously at 30°C for 18 hours.The reaction mixture was filtered, and the '05 solution was post-treated and purified in the same manner as in Example 1 to obtain (4S)-3-chloro- 530 mg of 4-hydroxyl 2-cyclobentenone ([α packed = -32,8° (cO,5, CHCl5).

An optical purity of 92%ee) was obtained.

Example 5 To 2.1 g of dl-4-acetoxy-3-chloro-2-cyclobentenone were added 20 g of methanol and 8 offli1 of water, and the mixture was heated to -5°C. 110+ng of crude S derived from Pseudomonas was added, and while adjusting the pH of the reaction solution to a range of 6.5 to 7.5 using a P)I stat, -
Stir vigorously for 15 hours at 5°C.

The reaction solution was filtered, and the solution was post-treated and purified in the same manner as in Example 1 to obtain (4R)-3-chloro-4=hydroxy-2-
Cyclobentenone 560B (CaM= +32.2°(
cO,9,CHCl,), optical purity 93%ee) and (
4S)-4-acetoxy-3-chloro-2-cyclobentenone 790 mg ([α waist=+12.6° (c 0
, 9, CIICL) were obtained.

Example 6 dl-acetoxy-3-chloro-2-cyclopentene 2
．． Add acetone Sod and 200 mQ of water to 5 g and cool to 7°C. Mu m derived from Psaudomonas
After adding 3200 mg, the pH of the reaction solution was adjusted to 6.5 to 7.5 using a PH stat, and the mixture was vigorously stirred at 7° C. for 7 hours at F151. The reaction solution was filtered, and the final solution was post-treated and purified in the same manner as in Example 1 to obtain (4R)-3-chloro-4-hydroxy-2-cyclobentenone (CaM = +33.9°
(c 1. CllCl,), optical purity 97.0%ee
) and (4S)-4-acetoxy-3-rioo-2-cyclopente/'/ ([a@= +7.9'(c 1.
0. CIICL)) was obtained.

Claims (1)

[Claims] 1. Formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) The compound represented by enzyme or microorganism It is characterized by asymmetric hydrolysis using formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, * represents an optically active center.) The optically active 3-chloro-4- Production of hydroxy-2-cyclopentenone Law. 2. Formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) The compound shown in , an enzyme or a microorganism to perform asymmetric hydrolysis and remove the hydrolyzate. Then, we get the formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, * represents an optically active center.) The optically active compound shown in is hydrolyzed using microorganisms. Characterized by the formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, * represents an optically active center.) The optically active 3-chloro-4-hydroxy Method for producing droxy-2-cyclopentenone.