WO1995033845A1

WO1995033845A1 - Process for producing optically active propargyl alcohol compound

Info

Publication number: WO1995033845A1
Application number: PCT/JP1995/001064
Authority: WO
Inventors: Kazuya Kameo; Tohru Tanami; Hideo Tanaka; Yohichi Shimazaki; Masaru Mutoh; Mie Tsuboi; Naoya Ono; Katsuo Hatayama
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1994-06-02
Filing date: 1995-05-31
Publication date: 1995-12-14
Also published as: AU2575295A

Abstract

A process for stereoselectively obtaining an optically active O-acylpropargyl alcohol compound represented by general formula (2) (wherein R?1 and R2¿ represent each hydrogen or C¿1?-C3 alkyl; R?3¿ represents phenyl which may be substituted by C¿1?-C5 alkyl, halogeno or trifluoromethyl at an arbitrary position of the ring, C1-C8 alkyl or C5-C8 cycloalkyl; R?4¿ represents C¿1?-C10 alkyl or phenyl which may be substituted by phenyl or halogeno at an arbitrary position of the ring; and the asterisk represents optical activity) by the reaction of an (RS)-propargyl alcohol compound represented by general formula (1) (wherein R?1, R2 and R3¿ are each as defined above) with an acylating agent R4COOR (wherein R4 is as defined above; and R represents arbitrary alkyl or alkenyl) in the presence of an enzyme; and a process for obtaining an optically active propargyl alcohol compound either by hydrolyzing the above O-acyl compound or from the solution of the above acylation reaction.

Description

-1 ― Description Method for producing optically active propargyl alcohol compound

The present invention relates to an optically active propargyl alcohol compound and a method for producing an acylated product thereof.

These optically active propargyl alcohol compounds and their acylated compounds are important as synthetic intermediates for various biologically active substances.

'It is important as a synthetic intermediate of the _ω side chain of the derivative. Background art

Conventionally, methods for producing optically active propargyl alcohol include (1) a method of optically reducing ketones (Gooding OW et al., J. Org. Chem., Vol. 58, p. 368, page 1). (2) Method for synthesis from 2,3-0-isopropylidene-slate (Niidas P. et al., Eesti NSV Tead Akad. Toim., Keem., Vol. 38 ( 4), pp. 285-6, 1989).

However, the conventional method has many steps and cannot be said to be an appropriate method. An object of the present invention is to provide a simpler method for producing an optically active propargyl alcohol compound having excellent optical purity and an acylated product thereof. Disclosure of the invention

The present inventors have conducted intensive studies for the purpose of solving the above-mentioned problems, and as a result, by stereoselectively acylating a racemic propargyl alcohol compound using an enzyme, a high purity and a high yield of the optically active compound are obtained. The present inventors have found that a propargyl alcohol compound can be produced, and have completed the present invention.

That is, the present invention provides the following formula (1):

(Wherein, R ¹ and R ² each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ³ represents a phenyl group, a `` alkynol group having 1 to 5 carbon atoms, a halogen atom, a trifluoromethyl group, Represents a phenyl group substituted at an arbitrary position by the above, a carbon atom number: an alkyl group having 8 to 8 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms, R ⁴ represents an alkyl group having 1 to 10 carbon atoms, A phenyl group or a phenyl group substituted at an arbitrary position with a “phenyl group or a halogen atom”, and the * symbol indicates that the compound is optically active. In producing an alcohol compound, the formula

(2)

(Wherein R ¹ R ² and R ³ have the same meanings as described above.). A Lugyl alcohol compound is reacted in the presence of an enzyme with an acylating agent represented by the formula R ⁴ COOR (where R ⁴ has the same meaning as described above, and R represents any alkynole or alkenyl group). A method for producing an optically active 0-acylpropargyl alcohol compound represented by the formula (1), characterized by comprising: Another aspect of the present invention provides a method of formula (3), comprising separating an optically active 0-acylpropargyl alcohol compound of the formula (1) from the reaction solution after the above reaction, and hydrolyzing the compound.

(Wherein, RR ³ and * have the same meanings as described above.) No ,. This is a method for producing a noregyl alcohol compound. Furthermore, another aspect of the present invention is to provide an optically active compound, comprising separating an optically active pergyl alcohol compound having a steric configuration different from that of the compound of the formula (3) from the reaction solution after the reaction. This is a method for producing a propargyl alcohol compound.

In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The alkyl group having 1 to 3 carbon atoms is a chain or branched alkyl group, for example, a methyl group, an ethyl group, and an isopropyl group. Of these, a methyl group or an ethyl group is preferred. The alkyl group having 1 to 5 carbon atoms is a chain or branched alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and an isopentyl group. . Among them, preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group. An alkyl group having 1 to 8 carbon atoms is a chain or branched alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, and the like. Xyl, isohexynole, heptyl and isoheptyl groups. Of these, a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group is preferred. An alkyl group having 1 to 10 carbon atoms is a chain or branched alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a Examples include a sopentyl group, a hexyl group, an isohexyl group, a heptyl group, and an isoheptyl group. Among them, preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group. Examples of the cycloalkyl group having 5 to 8 carbon atoms include a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like. The arbitrary alkyl group or alkenyl group represented by R may be any group which does not affect the reaction at all, for example, a methyl group, an ethyl group, a propynole group, an isopropyl group, a butyl group Group, isobutyl group, pentyl group, isopentyl group, hexyl group, isohexyl group, heptyl group, isoheptyl group, vinyl group, aryl group, 1-propenyl group, 2-buteninole group, isopropyl group And so on.

The enzyme used in the present invention refers to an optically active 0-acylpropargyl alcohol compound of the formula (1) formed from a (RS) -proparginole alcohol compound of the formula (2) An enzyme having the activity of causing Preferred is an enzyme produced by a microorganism belonging to the genus Pseudomonas, and more preferred is lipase PS (Amano Pharmaceutical). Further, vinyl acetate, isopropenylpropionate, or isopropenylbenzoate can be used as the acylating agent, and is preferably isoprobenyl acetate.

Hereinafter, the present invention will be described in detail. However, the case where isoprobenyl acetate is used as the acylating agent will be described.

Prono of the above formula (2), which is a raw material. The racemic form of lugyl alcohol can be easily obtained, for example, by reacting the corresponding aldehyde form (4) with the acetylene Grignard reagent (5) as shown below (in the reaction formula, RR ² and R ³ are as defined above, and X represents a bromo or chloro atom.

() (2) The reaction with isopropenyl acetate is carried out by adding 0.1 to 50 times by weight of the enzyme and 1 to 50 parts by weight of the racemic propargyl alcohol of the formula (2). The reaction is carried out in an inert solvent at 0 to 50 ° C. using 100 equivalents. Examples of the inert solvent include methylene chloride, toluene, ether, t-butyl methyl ether and the like.

The reaction time varies considerably depending on the substrate, the reaction temperature and the amount of the enzyme, and varies from as little as one hour to several days, and is it possible to obtain the preferred isomer as an acetyl form? It is desirable to adjust as appropriate depending on whether the alcohol is obtained as unreacted alcohol. In the former case, it is preferable to keep the reaction rate at 50% or less, and in the latter case, conversely, when the reaction rate is raised to 50% or more, a compound with good optical purity can be obtained.

After completion of the reaction, a commonly used method is used, that is, the enzyme is filtered off, the solvent is concentrated, The acetyl and alcohol forms can be easily separated and purified by silica gel column chromatography, distillation, recrystallization, etc. The acetyl group can be easily hydrolyzed by an ordinary method for hydrolyzing an ester to lead to an alcoholic body. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

(3RS) — 3-Hydrosea 4-phenoxy-1-butyne

Under a stream of argon, a solution of phenoxyacetaldehyde (11.16 g) in tetrahydrofuran (THF) (16 Om 1) and 0.5 M ethynylmagnesium bromide in THF (197 ml) were added under ice-cooling. Was added and stirred at the same temperature for 10 minutes. A saturated aqueous ammonium solution was added to the reaction solution, and the mixture was extracted with ether. The organic layer was washed with water and saturated saline, dried and concentrated, and the resulting crude product was subjected to silica gel column chromatography [developing solvent: ethyl acetate (AcOEt): hexane = 1: 2]. The title compound (13.2 g) was obtained.

Ή-NMR (CD C 13, 200 MHz) 5 p pm;

2.53 (d, J = 2.3Hz, 1H), 2.56 (d, J = 5.4Hz, 1H), 4.03-4.21 (m, 2H), 4.70-4.83 (m, 1H), 6.88-7.04 (m, 3H) , 7.23-7.36 (m, 2H)

IR (neat) cm— ¹ :

3412, 3282, 2940, 2865, 2126, 1602, 1589, 1499, 1456 1327, 1309, 1295, 1254, 1173, 1082, 1049, 969, 895, 752, 693, 674

Example 2

'(3 R) — and (3 S) — Process for the production of 3-hydroxy-14-phenoxy-1-butyne

(1) Isopropenyl acetate (1.5 ml) was added to a toluene solution (10 ml) of (3RS) —3-hydroxy-41-phenoxy obtained in Example 1 and 1-butyne (300 mg). In addition, lipase PS (1.0 g) was further added, and the mixture was stirred at 35 ° C for 12 hours. After filtering the insoluble matter and concentrating the solvent under reduced pressure, the residue was subjected to silica gel chromatography to obtain acetyl from the effluent of AcOEt-n hexane (1:10). An unreacted alcohol form (13 Omg) was obtained from the effluent of AcOEt-n-hexane (1: 5).

Alcohol form [] _D ²³ = — 26.9 C (C = 0.9, black form) The obtained alcohol form was prepared according to the method of Niidas P. et al. (Eesti NSV Tead Akad. Toim., Keem., Volume 38 (4 ), Pp. 285-6, 1989), and confirmed to be S-form.

The purity was measured (98% e e) by liquid chromatography (OD cell (Daicel Industries), developing solvent; isopropyl alcohol: hexane = 2: 8).

(2) Dissolve the acetyl group (19 Omg) obtained in (1) [a] _D ²³ = — 40.8 ° C (C = 0.93, methanol) in methanol (10 m 1) and add potassium carbonate (13 Omg). The mixture was stirred at room temperature for 20 minutes. After neutralization with 3N hydrochloric acid, the mixture was extracted with ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and concentrated. The residue was subjected to silica gel chromatography, and the acetyl compound (19 Omg) was obtained from the AcOEt-n-hexane (1:10) effluent. The unreacted alcohol (13 Omg) (96% ee) was obtained from the effluent of Ac0Et-n-hexane (1: 5).

This was confirmed to be R-form in the same way as (1).

Absolute coordination in the compounds of the following examples is based on the method of Mosher et al. (J. Am. Chem. 30., Vol. 95, p. 512, 1973). Nylacetic acid ester (） ester) led to fifet. By NMR

Example 3

'(3R) mono- and (3 S)-3-Hydroxy- 1, 4, 4-dimethyl- 4-phenoxy 1

(1) The same operation as in (1) of Example 2 was performed using (3RS) —3-hydroxy-4,4-dimethyl-4-pentoxy-1-butyne obtained by the same method as in Example 1.

At (35, 20 hours), (3S) —3-Hydroxy-4,4-dimethyl-41-phenoxy-1-butyne (47%, 87% ee) and (3R) —3-Acetyloxy-1,4,4 One-dimethyl-41-phenoxy-one-butyne (47%) was obtained. (3 S) —.3-hydroxy-1,4,4-dimethyl-1-4-phenoxy-1-butyne [a] _D ²³ = — 9.73 ° (C = 1.5, methanol)

Ή-NMR (CDC 1 a, 20 OMH z) <5 p pm;

1.36 (3H, s), 1.0 (3H, s), 2.29-2.93 (1H, br s), 2.49 (1H, d, J = 2.2Hz), 4.42 (1H, d, J = 2.2Hz), 6.80-7.45 (5H, m)

(3 R) — 3-Acetyloxy 4,4-dimethyl 4-phenoxy — 1-Putin

[a] _D ²³ = — 33. 69 ° (C = 0.93, methanol)

(2) By the same operation as (2) in Example 2, (3R) -3-hydroxy-4,4-dimethyl-4-phenoxy-11-butyne (95% ee) was obtained.

[a] _D ²³ = 9.81 ° (C = 1.5, methanol)

Example 4

(3R) —, and (3S) — 3-Hydroxy-4-cyclohexyloxy — 1-butyne

(1) The same operation as (1) in Example 2 (35, 4 days) using (3RS) -3-hydroxy-4-cyclohexyloxy-1-butyne obtained in the same manner as in Example 1 (3S) — 3-Hydroxy-4-cyclohexyloxy-1-butyne (41%, 99% ee) and (3R) — 3-Acetyloxy-4-cyclohexyloxy-1butin (41%) I got

(3 S) —3-Hydroxy-1-4-cyclohexyloxy-1-butyne

[a]. ²³ = 1 1.10 ° (C = 1.28, methanol)

Ή-NMR (CDC 1 a, 20 OMH z) (5 ppm;

1.08-2.1K10H, m), 2.44 (1H, d, J = 2.2Hz), 2.60-2.85 (1H, br s),

3.26-3.44C1H, m), 3.53C1H, dd, J = 7.4, 9.7Hz), 3.66C1H, dd, J = 3.7, 9.7Hz), 4.36-4.66 (1H, m)

(3 R) — 3-acetyloxy— 4-cyclohexyloxy 1-butyne

[a] ³ = — 56. 67 ° (C = 1.0, methanol)

(2) By the same operation as in (2) of Example 2, (3R) -3-hydroxy-4-six-hexoxyl-1-butyne (94% ee) was obtained. [a] _D ²³ = — 1 0.76 ° (C = 1.5, methanol) Example 5

(3R)-, and (3S)-3-Hydroxy- 4-hexyloxy 1-Peptide Production Process

(1) The same operation as (1) in Example 2 (35 ° C, 16 hours) using (3RS) -3-hydroxy-4-hexyloxy-1-butyne obtained by the same method as in Example 1 (3S) —3-hydroxy-4-hexyloxy-1-butyne (29%, 93% ee) and (3R) —3-acetyloxy-4-cyclohexyloxy-1-butyne (46%, 60% % ee).

(3 S) — 3-Hydroxy 4-hexyloxy 1-butyne

[a] _D ²³ = 1 3.71 ° (C = 0.7 °, methanol)

Ή-NMR (CDC 13, 20 OMH z) (5 p p m;

0.89 (3H, t, J = 6.4Hz), 1.15-1.77 (8H, m), 2.28-2.5K1H, in),

'2.45 (1H, d, J = 2.2Hz), 3.5K1H, dd, J = 9.8, 7.0Hz), 3.53C2H, t, J = 6.7Hz), 3.61 (1H, dd, J = 9.8, 3.8Hz) , 4.53 (1H, ddd, J = 7.0, 3.8, 2.2Hz)

(3 R) 1 3-acetyloxy 4 1-hexyloxy 1 1-butyne

[]. ²³ = — 42.4 Γ (C = 1.03, methanol)

INDUSTRIAL APPLICABILITY The present invention is useful as a simpler method for producing an optically active propargyl alcohol compound having a higher optical purity and an acylated product thereof. These optically active propargyl alcohol compounds and their acylated compounds are important as intermediates for the synthesis of various physiologically active substances, but are particularly important as intermediates for the synthesis of the ω side chain of prostaglandin derivatives useful as pharmaceuticals. is there.

Claims

1 set

(In the formula, R ¹ and R ² each represent a hydrogen atom or an alkyl group having 13 carbon atoms, and R ³ is a phenyl group, an `` alkyl group having 15 carbon atoms, a halogen atom, or a trifluoromethyl group. '' A phenyl group substituted at any position, an alkyl group having 18 carbon atoms or a cycloalkyl group having 58 carbon atoms, and R ⁴ is an alkyl group having 1 10 carbon atoms, a phenyl group, or a `` phenyl A halogen or a halogen atom ”, and the symbol * indicates that the compound is optically active. In producing the optically active 0-acylpropargyl alcohol compound represented by the following formula: formula

(Wherein R ¹ R ² and R ³ have the same meanings as above.) R ⁴ COOR (where R ⁴ is as defined above) in the presence of an enzyme represented by the formula (RS) —propargyl alcohol compound. A process for producing an optically active 0-acylpyrgyl alcohol compound, characterized by reacting with an acylating agent represented by the formula:

2. Expression

(In the formula, R ^{1 and} R ² each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ³ represents a phenyl group, `` an alkyl group having 1 to 5 carbon atoms, a halogen atom, trifluoromethyl, Represents a phenyl group substituted at any position with a “group”, an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms, and the symbol * indicates optical activity.) In producing the optically active propargyl alcohol compound represented by the formula:

(Wherein RR ² and R ³ have the same meanings as described above.). In the presence of an enzyme, a rugyl alcohol compound is treated with a compound of the formula R ⁴ CO OR (where R ⁴ is an alkyl group having 1 to 10 carbon atoms, a phenyl group or a phenyl group or a halogen atom at any position. And R represents any alkyl or alkenyl group.) By reacting with an acylating agent represented by the formula:

(Wherein R ′, R ² , R ³ , R ⁴ and * are as defined above.) Stereoselectively obtain an optically active 0-acylpropargyl alcohol compound represented by the formula: A method for producing an optically active pro- and lugyl alcohol compound, characterized in that it is hydrolyzed after separation.

3. Expression

(Wherein, R ¹ and R ² each represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ³ represents a phenyl group, a `` alkyl group having 15 carbon atoms, a halogen atom, or a trifluoromethyl group '' Represents a phenyl group substituted at any position, an alkyl group having 18 carbon atoms or a cycloalkynole group having 58 carbon atoms, and the symbol * indicates that the compound is optically active. In producing the propargyl alcohol compound, the formula

(Wherein RR ² and R ³ have the same meanings as described above.) A compound represented by the formula (RS) —Pulgyl alcohol compound is prepared in the presence of an enzyme by the formula R ⁴ COOR (where R ⁴ is the number of carbon atoms) 110 represents an alkyl group, a phenyl group, a phenyl group or a phenyl group substituted at any position with a halogen atom, and R represents an arbitrary alkyl group or an alkenyl group. An optically active compound, which is separated from a solution reacted with an acylating agent.

4. The production method according to claim 13, wherein the enzyme is an enzyme produced by a microorganism belonging to the genus Sydmonas.

5. The production method according to claim 13, wherein the acylating agent is isoproenyl acetate.