JPH06165694A - Production of optically active 4-hydroxy-1-pentyne derivative - Google Patents

Abstract

PURPOSE:To obtain an optically active 4-hydroxy-1-pentyne useful as a raw material for pharmaceuticals, agricultural chemicals, etc., by the optical resolution by treating a racemic compound of a 4-hydroxy-1-pentyne derivative with an enzyme or a microorganism capable of asymmetrically acylating hydroxy group and separating the product from unreacted components. CONSTITUTION:The objective optically active compound is produced by treating a 4-hydroxy-1-pentyne derivative expressed by formula I (R is hydroxyl- protecting group) [e.g. (+ or -)-1-(4-methoxyphenyloxy)-4-pentyn-2-ol] with an enzyme (e.g. lipase) and/or microorganism capable of asymmetrically acylating hydroxyl group to effect the asymmetric acylation of the secondary hydroxyl group, separating the remaining (S)-isomer of the alcohol expressed by formula II [e.g. (S)-1-(4-methoxyphenyloxy)-4-pentyn-2-ol] from the produced (R)-isomer expressed by formula III (Ac is acetyl) [e.g. (R)-1-(4-methoxyphenyloxy)-2- acetoxy-4-pentyne] and purifying the objective compound.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to optically active 4-hydroxy-1 which is a compound useful as an intermediate for producing various pharmaceuticals, agricultural chemicals, cosmetics, and a raw material for producing an asymmetric synthesis catalyst.
-A novel method for producing a pentin derivative.

[0002]

2. Description of the Related Art Conventionally, the problems to be solved by the invention
As a method for synthesizing an optically active 4-hydroxy-1-pentyne derivative, a method via an optically active glycidol derivative obtained from natural substances D-mannitol and L-ascorbic acid has been known. Heterocycles, Vol. 16, p38.
1 (1981), Synthesis, p116 (1983). However, these methods require many steps to obtain an optically active glycidol derivative, and are inconvenient for large-scale synthesis. The present invention uses a racemic glycidol derivative that is inexpensive and easily available on the market as a starting material, and asymmetrically acylates or hydrolyzes the acyl group on the hydroxyl group using an enzyme and / or a microorganism having the ability to acylate the hydroxyl group. By asymmetrically hydrolyzing an enzyme and / or a microorganism having the ability to decompose, the object can be achieved easily in a short process.

[0003]

The present invention is based on the formula [(±)-
I]

[0004]

[Chemical 7]

The secondary hydroxyl group is asymmetrically optically selected by an enzyme and / or a microorganism having the ability to asymmetrically acylate the racemic compound represented by the formula (wherein R represents a hydroxyl-protecting group). Alcohol remaining after acylation [(S) -I]

[0006]

[Chemical 8]

And the resulting ester [(R) -II]

[0008]

[Chemical 9]

A method for optical resolution of an optically active 4-hydroxy-1-pentyne derivative characterized by separating and purifying the compound and a formula [(±) -II]

[0010]

[Chemical 10]

The racemic compound represented by the formula (wherein R represents a hydroxyl-protecting group) is optically and selectively on the secondary hydroxyl group by an enzyme and / or a microorganism having an ability to asymmetrically hydrolyze an acyl group. Ester remaining after asymmetric hydrolysis of the acyl group [(S) -II]

[0012]

[Chemical 11]

And the produced alcohol [(R) -I]

[0014]

[Chemical 12]

The present invention relates to a method for optically resolving an optically active 4-hydroxy-1-pentyne derivative, which comprises isolating and purifying the compound.

Optically active 4-hydroxy-in the present invention
The production of the 1-pentyne derivative comprises the steps of the chart shown below.

[0017]

[Chemical 13]

[0018]

[Chemical 14]

In the formula, R represents a protective group for a hydroxyl group shown below.

It represents an allyl group which may be unsubstituted or substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, nitro, C ₁ -C ₄ alkylenedioxy, preferably phenyl, 2 -Tolyl, 3-Tolyl-, 4-Tolyl, 2-
Methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-nitrophenyl, 3-nitro Phenyl,
It represents 4-nitrophenyl, 3,4-methylenedioxy, 1-naphthyl and 2-naphthyl, with 4-methoxyphenyl being particularly preferred.

It represents a benzyl group which may be unsubstituted or substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen or nitro, and is preferably benzyl, 2-methylbenzyl or 3-methylbenzyl. Methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2,
4,6-trimethoxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-nitrobenzyl, 3-
Represents nitrobenzyl and 4-nitrobenzyl.

Represents a tri-substituted silyl group, preferably trimethylsilyl, triethylsilyl, tri-n-propylsilyl, tri-i-propylsilyl, tri-n-butylsilyl, tri-i-butylsilyl, tri-n-hexylsilyl. , Dimethylethylsilyl, dimethyl-n-propylsilyl, dimethyl-n-butylsilyl, dimethyl-
i-butylsilyl, dimethyl-tert-butylsilyl, dimethyl-n-pentylsilyl, dimethyl-n-octylsilyl, dimethylcyclohexylsilyl, dimethylthexylsilyl, dimethyl-2,3-dimethylpropylsilyl, dimethyl-2- (bicycloheptyl ) Silyl, dimethylbenzylsilyl, dimethylphenylsilyl, dimethyl-p-tolylsilyl, dimethylfuromesylsilyl, methyldiphenylsilyl, triphenylsilyl, diphenyl-t-butylsilyl, tribenzylsilyl, diphenylvinylsilyl, diphenyl-n-butylsilyl. And phenylmethylvinylsilyl and the like.

A C ₁ -C ₅ acyl group or a phenyl moiety represents a benzoyl group which may be substituted with C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen or nitro, preferably acetyl or propionyl. , Butyryl, isobutyryl, valeryl, pivaloyl, benzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-
Methoxybenzoyl, 2,4-dimethoxybenzoyl, 2,4,
Represents 6-trimethoxybenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl.

The C ₁ -C ₄ alkoxycarbonyl or phenyl moiety represents an allyloxycarbonyl group which may be substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen or nitro, preferably methoxy. Represents carbonyl, ethoxycarbonyl, t-butoxycarbonyl, phenoxycarbonyl.

It represents a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a 1,4-dioxan-2-yl group and a tetrahydrofuranyl group.

It represents a trityl group or a diphenylmethyl group.

Represents an alkoxymethyl group or an allyloxymethyl group, preferably methylthiomethyl, t-butylthiomethyl, phenyldimethylsilylmethoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, 4-methoxyphenoxymethyl, 2- Methoxyphenoxymethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, methoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl ) Ethoxymethyl, 1- (2-chloroethoxy) ethyl,
Represents 2-trimethylsilylethyl.

Next, each step will be described in more detail.

(Step a) Step of adding acetylide to racemic glycidol derivative [(±) III] to obtain racemic 4-hydroxy-1-pentyne derivative [(±) -I] Racemic glycidol derivative [(±) III] ] Can be synthesized from commercially available racemic glycidol, eg R =
4-Methoxyphenyl derivatives are described in Heterocycles, Vol. 34, p.
173 (1992).

The racemic glycidol derivatives are Synthesis, p
139 (1987), a lithium acetylide ethylenediamine complex can be added to the corresponding racemic 4-hydroxy-1-pentyne derivative in DMSO (dimethylsulfoxide). This reaction is from -15 ° C to 8
It is carried out at 0 ° C., preferably 15 ° C. to 50 ° C., and 1 to 2 equivalents of the lithium acetylide ethylenediamine complex is used with respect to the substrate. (Step b) Racemic 4-hydroxy-1-pentyne derivative [(±)-
I] is acetylated to obtain a racemic 4-acetoxy-1-pentyne derivative [(±) -II] Racemic 4-hydroxy-1-pentyne derivative [(±) -II]
I] is a known method, for example, a racemic 4-acetoxy-1-pentyne derivative [(±) is obtained by reacting acetic anhydride or acetyl chloride in the presence of a base such as pyridine or triethylamine.
-II]. The amount of the base and the acylating agent used varies depending on the substrate, but it is preferably 1 to 2 equivalents based on the substrate. This reaction is carried out in an ether solvent such as tetrahydrofuran, a halogen solvent such as chloroform, methylene chloride or dichloromethane,
It is carried out at 0 ° C to 50 ° C, preferably 15 ° C to 35 ° C.

(Step A) Step of Asymmetrically Acylating the Racemic 4-Hydroxy-1-pentyne Derivative Obtained in Step a by Using an Acylase This reaction can be carried out in water or an organic solvent. As a preferable organic solvent, any solvent which does not inactivate the enzyme or the microorganism and does not react with the substrate and the produced ester (acyl compound) may be used. For example, ether type solvents (eg, dimethyl ether, diethyl ether, t-butyl methyl ether, tetrahydrofuran, etc.), aromatic solvents (eg, benzene, toluene, xylene, chlorobenzene, etc.), halogen type solvents (eg, chloroform, methylene chloride, etc.) Such as dichloroethane),
In particular, toluene and methylene chloride are preferable.

This reaction is carried out in a suspended state, but it is possible to remarkably accelerate the reaction by applying ultrasonic waves as appropriate.

The enzyme which can be used in the present invention is an enzyme having an ability to asymmetrically acylate a hydroxyl group, and is genus Rhizopus, Mucor, Aspergillus, Candida, Pseudomonas, Alcaligenes, Achromobacter. , And an enzyme obtained from a microorganism or an animal organ belonging to each genus of the genus Bacillus. For example, the enzymes shown in Table 1 can be mentioned.

[0034]

[Table 1]

Microorganisms that can be used in the present invention are microorganisms belonging to the genera Rhizopus, Mucor, Aspergillus, Candida, Pseudomonas, Alcaligenes, Achromobacter, and Bacillus. . For example, the microorganisms shown in the "Origin" section of Table 1 can be mentioned.

These enzymes or microorganisms may be used in various forms such as purified enzyme, crude enzyme, enzyme-containing material, microbial culture solution, culture, bacterial cells, culture filtrate, and processed products thereof, if necessary. it can. Furthermore, an enzyme and a microorganism can be used in combination.

In carrying out the method of the present invention, it depends on the enzyme or microorganism to be used, but it is usually racemic 4-hydroxy- of the formula [(±) -I] which is a substrate in an organic solvent.
A mixture of 1-pentyne derivatives is dissolved, and an acylating agent and an enzyme and / or a microorganism are added to this solution to react.

As the acylating agent, vinyl acetate, vinyl propionate, vinyl octoate, vinyl oleate,
Fatty acid enol esters such as 2-propylenyl acetate
Fatty acid esters such as tributyrin and 1,1,1-trichloroethyl butyric acid, fatty acid anhydrides such as acetic anhydride,
Examples thereof include aromatic acid enol esters such as phenyl vinyl acetate. Of these, acetylation with vinyl acetate is a preferred example.

The reaction is carried out by stirring or shaking for 1 hour to several days. The reaction can be carried out at 5 to 50 ° C., but the reaction becomes slow at low temperature, and enzyme deactivation and asymmetric selectivity decrease at high temperature. Therefore, 10 to 35 ° C. is preferable. After completion of the reaction, the remaining alcohol and the ester formed are separated and purified by a usual method.

(Step B) Step of asymmetrically hydrolyzing the racemic 4-acetoxy-1-pentyne derivative obtained in step b using an asymmetric hydrolase This reaction is carried out in water or a mixed system of water / organic solvent. be able to. Preferably, sodium phosphate, a buffer of an inorganic acid salt such as calcium phosphate, sodium acetate,
Examples include buffers of organic acid salts such as citric acid. The concentration of these salts used for buffering varies depending on the type of buffer solution, but is preferably 0.05 to 2M. Further, an organic solvent such as acetone may be appropriately added to this. The pH value at the start of the reaction is preferably in the range of 7 to 10, and preferably kept at 5 to 10 during the reaction. The enzyme and substrate are added to a buffer solution sufficient to neutralize the carboxylic acid produced by hydrolysis, and the mixture is stirred or shaken until the desired hydrolysis rate is obtained.

The reaction temperature is preferably 10 to 50 ° C., and the reaction becomes slow in the low temperature region of this range, and the enzyme partially loses its activity in the high temperature region, so 20 to 40 ° C. is preferable. The reaction time varies depending on the reaction temperature, the type of enzyme, the purity, the amount used, and the like, and varies from one in which the reaction is completed in 1 to 2 hours to one in which several days are required until the reaction is completed.

The lipase used in this reaction is an enzyme having the ability to asymmetrically hydrolyze an ester, and those mentioned in step A can be used in the same manner. Further, the optically active 4-acetoxy-1-pentyne derivative obtained in step A or B can be obtained as an almost pure product by recrystallization in an organic solvent such as hexane. In addition, lipase enzyme is styrene resin (eg, polyaminopolystyrene), carboxy chloride resin (eg, Amberlite)
IRC-50, XE-97, etc.), porous glass and microcapsules can also be used for immobilization. (Step c) A step of hydrolyzing the optically active 4-acetoxy-1-pentyne derivative [II] obtained in the step A or the step B to obtain an optically active 4-hydroxy-1-pentyne derivative [I] Optical activity 4 The -acetoxy-1-pentyne derivative can be hydrolyzed under a suitable basic condition, for example, using sodium hydroxide, potassium hydroxide or the like to give the corresponding optically active 4-hydroxy-1-pentyne derivative.

This reaction is carried out in a solution prepared by appropriately adding water to an ether solvent such as tetrahydrofuran or dioxane or an alcohol solvent such as methanol or ethanol,
It is carried out at 0 to 50 ° C, preferably 15 to 35 ° C.

[0044]

【Example】

Reference Example 1 (±) -1- (4-methoxyphenyloxy) -4-pentyn-2-ol (Compound [(±) -I] R = PM
P: para-methoxyphenyl) synthesis (step a)

[0046]

[Chemical 15]

(DL) -O- (4-methoxyphenyl)
Glycidol [(±) III] 1.1 g (6.1 mmo
l) DMSO (5 mL) solution in lithium acetylide ethylenediamine complex (90%) 920 mg (9 mmo)
1) is slowly added at room temperature and stirred for 9 hours. Brine is added, concentrated hydrochloric acid is added until the reaction solution becomes acidic, the mixture is extracted with diethyl ale, washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on 50 g of silica gel, and a light yellow oily substance (±) -1- (4-methoxyphenyl) was obtained from the ethyl acetate-normal hexane (1: 3, v / v) fraction. Oxy) -4-pentyn-2-ol [(±) -I] 1.2 g (95.5
%) Was obtained. IR (film) ν _max : 3450, 3294 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 2.07 (t, J = 2.7Hz, 1H), 2.52-2.58 (m,
3H → 1H, exchangeable with D ₂ O), 3.77 (s, 3H),
3.94-4.30 (m, 3H), 6.85 (s, 4H) MS (m / z): 206 (M ⁺ ), 124 (100%) Exact mass: Calcd for C ₁₂ H ₁₄ O ₃ 206.0943, Found 206.
0985

Example 1 (Step A) Asymmetric Acylation Reaction (Table 2, Reaction No. 8)

[0049]

[Chemical 16]

12.5 g of the compound [(±) -I] (60.
7 mmol): Lipase PS (Amano Pharmaceutical Co., Ltd.) 6.0 g, toluene 600 mL, vinyl acetate 12 mL (130 mmo)
The mixture of l) is shaken at 27 ° C. for 52 hours. After filtration through Celite, the solvent is evaporated under reduced pressure. The residue is silica gel 50
Subjected to 0 g column chromatography, ethyl acetate-
7.5 g (49.8) of 1- (4-methoxyphenyloxy) -2-acetoxy-4-pentyne [(R) -II] as colorless crystals from the normal hexane (1: 6, v / v) stream.
%), Ethyl acetate-normal hexane (1: 3, v /
v) 1- (4-methoxyphenyloxy) -4-pentyn-2-ol [(S) -I] as a pale yellow oil from the stream.
6 g (44.8%) were obtained. [(R) -II] Optical purity 77.1% ee [CHIRA
LCEL OD (Daicel Industries), isopropanol-
Normal hexane (1:99, v / v)] [(S) -I] Optical purity> 99% ee [CHIRAL
CEL OD, isopropanol-normal hexane (1: 9, v / v)] [α] _D ³⁰ : +19.831 (C 1.012, CHCl ₃ ) The compound [(R) -II] obtained as crude crystals was used in hexane. Optical purity> 9 by repeating recrystallization
5.6 g of a highly pure product with 9% ee was obtained.

Table 2 shows the results of examination of the same operation using various lipases.

[0052]

[Table 2]

Example 2 (Step B) Asymmetric Hydrolysis Reaction (Table 3, Reaction No. 1)

[0054]

[Chemical 17]

Racemic compound [(±) II] 248 mg
(1.0 mmol), Lipase PS 100 mg, 0.1
A mixture of a mixed solution of M phosphate buffer and acetone (9: 1) is shaken at 27 ° C. for 2 days. It is filtered through Celite, the solvent is evaporated under reduced pressure, extracted with diethyl ether, washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on 20 g of silica gel, and ethyl acetate-normal hexane (1: 6, v
/ V) colorless crystalline compound [(S) -II] 114
mg (42%), pale yellow oily compound [(R) -I] 1
Obtained 13 mg (58%).

Table 3 shows the results of the examination of the same procedure using various lipases.

[0057]

[Table 3]

Reference Example 2 Synthesis of (R) -1- (4-methoxyphenyloxy) -4-pentyn-2-ol (Compound [(R) -I]) (Step c)

[0059]

[Chemical 18]

Compound [(R) -II] 230 mg (0.9
3 mmol) in tetrahydrofuran (5 mL) solution, 148 mg (3.7 mmo) of powdered sodium hydroxide
l) is added and stirred overnight at room temperature. The mixture is diluted with water, extracted with diethyl ether, washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and a pale yellow oily compound [(R)-
I] 190 mg (99.2%) were obtained. (Α) _D ³⁰ : -19.769 (C 1.180, CHCl ₃ )

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C12R 1:38) (C12P 41/00 C12R 1:91)

Claims (2)

[Claims] 1. The formula [(±) -I] The secondary hydroxyl group is optically asymmetrically acylated by an enzyme and / or a microorganism having an ability to asymmetrically acylate a hydroxyl group of a racemic compound represented by the formula (R represents a hydroxyl-protecting group). After that, the remaining alcohol [(S)-
I] And the resulting ester [(R) -II] The method for optical resolution of an optically active 4-hydroxy-1-pentyne derivative, characterized in that the compound is separated and purified. 2. The formula [(±) -II] A racemic compound represented by the formula (wherein R represents a hydroxyl-protecting group) is used to optically and selectively convert an acyl group on the secondary hydroxyl group into an optically active group by an enzyme and / or a microorganism having an ability to asymmetrically hydrolyze an acyl group. Ester remaining after asymmetric hydrolysis [(S) -II] And the generated alcohol [(R) -I] The method for optical resolution of an optically active 4-hydroxy-1-pentyne derivative, characterized in that the compound is separated and purified.