JPH04273835A - Production of optically active alcohol - Google Patents

Abstract

PURPOSE:To readily produce an optically active alcohols required in fields belonging to medicine, agricultural chemical, etc., and other fields. CONSTITUTION:The production process comprises reacting a N-substituted-(S)- phenylalanyl chloride with (+ or -)-alcohols or alcohols having low optical activity and obtained by asymmetrical synthesis, enzymatic method, etc., to lead these alcohols to ester derivatives and enhancing optical purity of the resultant ester derivatives by a physical procedure and then hydrolyzing the ester derivatives.

Description

[Detailed description of the invention]

0001

[Industrial Application] The present invention allows optically active alcohols to be easily produced with high purity, and provides optically active alcohols that are required in the fields of medicine, agricultural chemicals, etc. and other fields. be.

0002

[Prior Art] (S)- or (R)- with high optical purity in the field of medicine, agricultural chemicals, etc. and other fields.
Alcohol is requested and used. for example,(
S)-1-octin-3-ol is useful not only as an omega side chain unit for the synthesis of prostaglandins, but also for the synthesis of arachidonic acid metabolites such as levuglandin, dihydroxyeicosatetraenoic acids, and lipoxin A4. It is known as a unique compound, and various resolution and synthesis methods have been reported so far. The division method is (±
) - Hydrogen phthalate is produced from alcohol and phthalic acid, and this hydrogen phthalate is resolved using (S)-1-phenylethylamine (Annals
New York Academy of Science,
1971, 180, 38), method for resolving crystalline 3β-acetoxy-5,16-ethiadienate (Annals New York Academy of Sciences, 1971, 180, 64), enzymatic resolution method for racemic acetate (Agricultural and
Biological Chemistry, 1980, 44, 240
7, Tetrahedron, 1987, 43, 5791, Journal of Chemical Society, Chemical Communication, 1988, 971). As a synthesis method, 1-octyn-3-one (S)-binaphthol-lithium aluminum hydride reagent (
Journal of the American Chemical Society, 1984, 106, 6717), (-)-B-Isopinocampheyl-borabicyclo[3.3.1]nonane (
Chemical Reviews, 1989, 89, 1553), 9
-borabicyclo[3.3.1]nonane-nopole benzyl ether adduct (Chemical Reviews, 1989,
89, 1553), and a method using Sharpless's epoxidation reaction (Tetrahedron Letters, 1989, 30, 7083; Journal
(Journal of Chemical Society, Chemical Communications, 1989, 1344), Enantioselective addition reaction of dipentylzinc to 3-trimethylsilyl-2-propynal using a chiral amino alcohol as catalyst (Journal of Chemical Society, Perkin Transactions 1, 19)
90,937), chiral (2S,4S)-
2,4-pentanediol (Journal of American Chemical Society, 1983, 105, 29
04), (R)-O-tetrahydropyranylglycidol (Journal of Chemical Society, Parkin Transactions 1, 1989, 21
A method using 31) as a starting material has been reported.

0003

[Problems to be Solved by the Invention] However, in these methods, the amount of (S)-1-octyn-3-ol obtained is small, the optical purity is low, or the operation is complicated. , or the reagents used are expensive, making it impractical. Therefore, the inventors conducted extensive research and completed the present invention, which uses inexpensive reagents, has high optical purity with simple operations, and can be mass-produced.

0004

[Means for solving the problem] As a preferred example,
(±)-1- using N-(4-methylbenzenesulfonyl)-(S)-phenylalanyl chloride as a resolving agent
Octin-3-ol to (S)-1-octyne-3-
A method for obtaining oars will be described, but the present invention is not limited thereto. N-(4-methylbenzenesulfonyl)-(S)-phenylalanyl chloride is (S)-
It can be easily obtained by 4-methylbenzenesulfonylation of phenylalanine and then chlorination with phosphorus pentachloride. (±)-1-octyn-3-ol to N-(4-
Diastereomeric ester derivatives are obtained by reacting methylbenzenesulfonyl)-(S)-phenylalanyl chloride in tetrahydrofuran in the presence of a base. By repeating recrystallization of this diastereomer four times from a solvent of ethanol-hexane (5:1), (S)-1-octyn-3-yl N-(4-
Crystals of methylbenzenesulfonyl)-(S)-phenylalaninate are obtained in a yield of 32% (theoretical yield 64%). Then, by hydrolyzing this ester, (S)-1-octin-3-ol [α]D-22 is obtained with high purity.
．． 2° (c1.16, ether) (Journal of American Chemical Society, 1972, 94,
The value listed in 9256 is [α]D-21°(c1
．． 0, ether) can be obtained.

[0005]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present invention will be described below, but these are for illustrative purposes only and are not intended to limit the present invention. It will be apparent to those skilled in the art that modifications may be made within the scope of the invention. Example 1 Synthesis of (S)-1-octin-3-yl N-(4-methylbenzenesulfonyl)-(S)-phenylalaninate (±)-1-octin-3-ol (36.5 g) was added to 45 ml of tetrahydrofuran. Dissolve in 117 ml of pyridine.
Add. Next, a suspension of 152 g of N-(4-methylbenzenesulfonyl)-(S)-phenylalanyl chloride in 240 ml of tetrahydrofuran is added with stirring at 10 DEG C. under an argon atmosphere. After stirring at this temperature for 15 minutes, 5 ml of ice-cold water was added and the stirring was continued for 30 min.
Stir for a minute. To this reaction mixture were added 700 ml of ethyl acetate-hexane (10:1) and 200 ml of water, and the organic layer was separated. The organic layer was mixed with 150 ml of 20% hydrochloric acid (twice), 50 ml of water, and a saturated aqueous solution of sodium bicarbonate-water (
Wash sequentially with 60 ml (2 times) of 1:1). Add sodium sulfate for dehydration, filter, and remove the solvent under reduced pressure to obtain 136 g of yellow crude crystals. This crude crystal was recrystallized four times from ethanol-hexane (5:1, 42 ml per 10 g of crude crystal) to obtain pure (S)-1-octin-3-yl N-(4-methylbenzenesulfonyl). -(S)-Phenylalaninate crystals 39.7g (
A theoretical yield of 64%) is obtained. The main physical properties are as follows. Melting point 124.5-125.5°C; [α]D2
2-48.4° (c2.21, chloroform); IR (
Nujol) 3330, 3300, 1720, 1600
, 1497, 1327, 1270, 1164 cm-1;
1H NMR (deuterated chloroform) δ0.90 (3H,
t, J = 7.0Hz), 1.20-1.34 (6H, m
), 1.51-1.64 (2H, m), 2.39 (3H
, s), 2.46 (1H, d, J=2.1Hz), 3.
07 (2H, d, J = 5.5Hz), 4.22 (1H,
dt, J=5.5, 9.5Hz), 5.02(1H, d
, J=9.5Hz), 5.09(1H, dt, J=2.
1,6.7Hz), 7.12-7.17(2H,m),
7.20-7.28 (5H, m), 7.63 (2H, d
, J=8.2Hz); MS m/z427.1806
(M+, calculated value of C24H29NO4S 427.181
5); Elemental analysis values C67.37, H6.85, N3.1
6 (Theoretical value of C24H29NO4S C67.42, H6
．． 84, N3.28) Synthesis of (S)-1-octyn-3-ol (S)-1-
Octin-3-yl N-(4-methylbenzenesulfonyl)-(S)-phenylalaninate 38.5 g, ethanol 65 ml and 40% potassium hydroxide aqueous solution 37
ml and kept at 40°C for 1.5 hours. The solution was concentrated to one-quarter volume under reduced pressure and ether-hexane (
Add 150 ml of 10:1) and 50 ml of water and separate the organic layer. The aqueous layer was further mixed with 75 ether-hexane (10:1).
Repeat the extraction operation twice with ml and combine the organic layers. This organic layer was mixed with 10 ml of water and a saturated ammonium chloride aqueous solution.
Wash sequentially with 15 ml of brine (1:1) and 15 ml of brine (twice). Next, sodium sulfate was added for dehydration, and after filtration, the solvent was removed under reduced pressure to obtain 11.1 g of crude (S)-1-octin-3-ol. Ether-hexane (10:1-1:1) if necessary
After column (silica gel) purification using this as an eluent, the product was distilled under reduced pressure (20 mmHg) at 100°C to obtain 10.3 g of pure (S)-1-octin-3-ol as a colorless transparent liquid. The main physical properties are as follows. [α]D22-22.2° (c1.16, ether)
;1H NMR (deuterochloroform) δ0.90 (3H
, t, J=7.0Hz), 1.28-1,40 (4H,
m), 1.40-1.54 (2H, m), 1.68-1
．． 78 (2H, m), 1.89 (1H, br s),
2.46 (1H, d, J = 2.1Hz), 4.37 (1
H, ddt, J=2.1, 6.4, 6.4Hz); (S
)-1-octyn-3-ol (R)-(+)-MT
1H NMR (deuterochloroform) δ0 of PA ester
．． 89 (3H, t, J=7.0Hz), 1.26-1.
37 (4H, m), 1.40-1.57 (2H, m),
1.80-1.92 (2H, m), 2.49 (1H, d
, J=2.1Hz), 3.55(1H, q, J=1.2
Hz), 5.51 (1H, dt, J=2.1, 6.7H
z), 7.38-7.45 (3H, m), 7.51-7
．． 58 (2H, m)

Claims (4)

[Claims] Claim 1: N-substituted-(S)-phenylalanyl chloride is reacted with (±)-alcohols or low optically active alcohols obtained by asymmetric synthesis, enzymatic methods, etc. to form ester derivatives, and physical A method for producing optically active alcohols, which involves increasing the optical purity by a method of conventional methods and then hydrolyzing it. 2. The method according to claim 1, wherein the optically active alcohol is (S)-1-octyn-3-ol. Claim 3: N-substituted-(S)-phenylalanyl chloride is N-(4-methylbenzenesulfonyl)-(S)
-phenylalanyl chloride, N-(2,4,6-trimethylbenzenesulfonyl)-(S)-phenylalanyl chloride, N-(2-nitrobenzenesulfonyl)-
(S)-Phenylalanyl chloride, N-(3-nitrobenzenesulfonyl)-(S)-phenylalanyl chloride, N-(4-nitrobenzenesulfonyl)-(S)
-phenylalanyl chloride, N-(4-bromobenzenesulfonyl)-(S)-phenylalanyl chloride,
N-(4-acetamidobenzenesulfonyl)-(S)
2. The method according to claim 1, wherein one selected from the group consisting of -phenylalanyl chloride and N-(1-naphthalenesulfonyl)-(S)-phenylalanyl chloride. 4. The method according to claim 1, wherein the physical method is at least one of crystallization and column chromatography.