JPS6115878A - Production of optically active 3-methyl-4-butanolide - Google Patents

Abstract

PURPOSE:A specific compound with optical activity is allowed to react with NaCN and others, then hydrolyzed and deprotected whereby the titled compound of high optical purity which is used as a starting material for synthesizing optically active terpenes is obtained in high efficiency. CONSTITUTION:The reaction of an optically active alcohol of formula I (X is protected OH) with a compound of formula II (R<1> is lower alkyl, phenyl; Hal is halogen) in an aprotonic solvent gives a compound of formula III. The product is used as a starting substance with optical activity to effect reaction with NaCN or KCN in a solvent containing at least one from dimethyl sulfoxide, N-methylpyrrolidone, dimethylformamide and so on to form an optically active nitrile of formula IV. Then, the product is hydrolyzed in an alcoholic solvent in the presence of NaOH, deprotected, when needed, dehydrated in the presence of an acidic catalyst to give the objective compound in a practical scale. EFFECT:The reaction operations are simple.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing optically active 3-methyl-4-butanolide represented by the formula. Optically active 3-methyl-4-butanolide is particularly useful as a raw material for the synthesis of naturally occurring optically active terpene compounds such as vitamin E1 and dolichol, and these optically active terpene compounds are used as pharmaceuticals. It is also an important substance as a nutritional supplement.

Prior Art C, B, Chapleo et al., J. Chem, S.
oc, , Perkin I.

1977, pp. 1211-1218, four reaction steps starting from methyl hydrogen (+)-3-methylglutarate, consisting of synthesis of iodide (1odo-eater) by photochemical reaction, acetic acid decomposition, hydrolysis, and cyclization. After 5
(-)-(38)-3-methyl-4- with a yield below 0-
It is reported that butanolide was obtained. Also, T,
According to Mukaiyama et al.
3B>-6-:c'y-vdan-3,4-dimethyl-2
-phenylperhydro-1,4-oxazepine-5,7
-The following method using dione as a starting material is disclosed. In addition, in the following, Ph, Ac and Me represent a phenyl group, an acetyl group and a methyl group, respectively, and DM
F means dimethylformamide and THF means tetrahydrofuran.

(Chemistry Letters, 1979, pp. 1207-1210) (90%) (Chemistry Letters, 1980 + pp. 635-638) In addition to these synthetic methods, ethyl-trans-4,4-diphthoky-3-methyl -Octonato is added to beer yeast (Saccharomycea c
erevislae) to microbiologically convert it into (S)-dihydro-4-methyl-2-(5H)-furanone (JP-A-52-136102).

Problems to be Solved by the Invention The method of Chaplao et al.
-) -(S)- type compounds can only be synthesized and photochemical reactions are used, (-)-(38)-3-
Problems include the need to use iodine 5.3 and silver acetate 4,2 to synthesize 1kli of methyl-4-butanolide, making it difficult to adopt this method as an industrial production process. Unfortunately, the method of Mukaiyama et al. is extremely difficult to synthesize on a large scale because the starting material has an extremely complex chemical structure, and at least at present it cannot be used as a large-scale industrial production process. . Furthermore, in addition to the expensive raw materials used in the microbiological method, the conversion rate to the target compound can only reach around 50% even in long-term reactions, and the specificity of the fermentation reaction is limited. It has the problem that it is effective only for the production of (S)-type compounds based on -9=.

Therefore, the object of the present invention is to make it possible to produce optically active 3-methyl-4-butanolide in good yield starting from easily obtained raw materials and by selecting the starting materials (S)-3 -Methyl-4-butanolide as well as (R
) It is an object of the present invention to provide a method suitable for industrial scale operation, which also makes it possible to produce -3-methyl-4-butanolide.

Means for Solving the Problems According to the present invention, the above object is basically achieved by the general formula (wherein X represents a protected hydroxyl group and R1 is a lower alkyl group or ) Substituted and stuttering phenyl group. ) is cyanated in one or more solvents selected from the group consisting of dimethyl sulfoxide, N-methylpyrrolidone, dimethylformamide and dimethylacetamide -10 = reacted with thorium or potassium cyanide to form the general formula An optically active nitrile represented by the formula % ([[) (wherein Optical activity 3 represented by the formula, characterized in that the hydrolysis product is subjected to a membrane-retaining group reaction, and if necessary, further subjected to a dehydration reaction in the presence of an acidic catalyst. -Achieved by a method for producing methyl-4-butanolide.

In the general formulas (old and (Ill)), X represents a protected hydroxyl group, preferably a group as exemplified below.

(]) Hydroxyl groups secured by ether-type bonds -0CHa, -0C2H3, -0CaH7, -0C4H
o, -0CH2C6H4CH3 (2) Hydroxyl group protected by acetal type bond -0CH20CH3, -0CH2OC2H5, -0CH
z0CaHy, and R in the general formula (If) represents a lower alkyl group or a phenyl group which may be substituted with a lower alkyl group, preferably a methyl group, an ethyl group, a propyl group, a phenyl group, or a tolyl group. etc.

The reaction of the compound of general formula (II) with sodium cyanide or potassium cyanide can be performed using dimethyl sulfoxide, N-
The process is preferably carried out in one or more solvents selected from the group consisting of methylpyrrolidone, dimethylformamide and dimethylacedoamide. Although the amount of the solvent used is not critical, it is usually 5 to 500 parts by weight, preferably 5 to 50 parts by weight per 1 part by weight of the compound of general formula (II). The reaction is carried out by adding the compound of general formula (II) and sodium cyanide or potassium cyanide to the above solvent and stirring the mixture. The amount of sodium cyanide or potassium cyanide used is not critical;
0 mol is preferred. During the reaction, the reaction system can be cooled or heated as necessary. The reaction is suitably carried out at a temperature within the range of 0<0>C to 100<0>C. In order to complete the reaction, it generally takes 1 minute to 24 minutes under the above reaction conditions.
It is desirable to stir the reaction system for a period of time, preferably from 10 minutes to 10 hours.

After the reaction is complete, the reaction mixture is brought into contact with a large amount of water.

General formula (III) is obtained by extracting and purifying the organic layer.
can be obtained. The organic layer can be extracted by adding an organic solvent that is not easily miscible with water and is generally used as an extraction solvent, such as hexane, benzene, chloroform, methylene chloride, or diethyl ether. Purification of the compound of general formula (1■) is usually carried out using the organic compound 'Int
The method can be carried out according to the method used for manufacturing, and chromatography and/or distillation methods are particularly preferably used. Examples of adsorbents used in chromatography include silica gel, alumina, activated carbon, and cellulose. Among them, silica gel is preferably used.

As the JIFIi medium, a solvent prepared by mixing an appropriate amount of a polar solvent such as diethyl ether, ethyl acetate, tetrahydrofuran, or acetone with a bulk hydrocarbon solvent such as hexane or benzene is preferably used.

The hydrolysis reaction of the ano group of the compound of general formula (II) obtained as described above is carried out in an alcohol solvent in the presence of sodium hydroxide, potassium hydroxide or barium hydroxide. The following alcohol solvents are preferably used: methanol, ethanol, propatool, butanol,
2-methoxyethanol, 2-ethoxyethanol, 2
-Propoxyethanol, 2-methoxyethanol, ethylene glycol, propylene glycol, tetramethylene glycol, diethylene glycol, triethylene glycol.

For these alcoholic solvents, a small amount (e.g. about 1 to
It is also suitable to mix 50% by weight of water in order to smoothly proceed with hydrolysis. The amount of solvent used is not critical, but it is usually 5 to 500 parts by weight, preferably 5 to 50 parts by weight per part by weight of the compound of general formula (1).

The amount of sodium hydroxide, potassium hydroxide or barium hydroxide used is preferably 1 to 50 mol, particularly 1 to 10 mol, per mol of the compound of general formula (III).

When carrying out the reaction, it is possible to cool or heat the reaction system as necessary, and the temperature is usually -30°C to +100°C.
, preferably a temperature within the range of 0°C to 80°C. In order to complete the reaction, it is desirable to continue the reaction under stirring at the above temperature for usually about 1 minute to 24 hours, preferably 10 minutes to 10 hours.

After the completion of the above hydrolysis reaction, when the reaction mixture is made acidic to pH 1 ~ 3, the hydroxyl group protected by the acetal bond is deprotected to form a compound represented by the formula % formula % (), and the acidic conditions at that time Depending on the strength of the formula (fV), part or most of the compound is subsequently lactonized in situ to form the optically active 3-methyl-4-butanolide of the formula (1).

Deprotection of the hydroxyl group protected by a benzyl ether type bond was carried out by the action of lithium in liquid ammonia or liquid ethylamine.
Deprotection of a hydroxyl group protected by an alkyl ether type bond is carried out by treatment with iodotrimethylsilane in a rhodanized hydrocarbon solvent such as chloroform or methylene chloride.

The compound represented by the general formula (IV) and/or the compound represented by the general formula (1) obtained as described above is extracted from the reaction system, and if necessary, the compound is silactonized by stirring under acidic conditions. After the reaction is completed, the compound of general formula (1) can be obtained by purification. The above extraction is carried out using a reaction mixture containing the compound of general formula (IV) and/or the compound of general formula (1) as an extraction solvent such as hexane, benzene, chloroform, methylene chloride, diethyl ether, ethyl acetate, methyl acetate, etc. This can be carried out by adding the solvent used.

In particular, since the compound of general formula (IV) has a high affinity for water, it is desirable to repeat the extraction operation sufficiently. It is possible to purify the compound of general formula (IV) in the extract in advance and then subject it to the lactonization reaction, but this purification step is omitted and the compound of general formula (1) is directly subjected to the lactonization reaction. It is convenient and preferable to purify at this stage.

The lactonization reaction is carried out in the presence of a common medium.

Examples of suitable solvents include hexane, benzene, toluene, xylene, chloroform, and dichloroethane. Although the amount of the solvent used is not critical, it is usually 5 to 500 parts by weight, preferably 10 to 200 parts by weight per 1 part by weight of the compound of general formula (IV). In order to allow the lactonization reaction to proceed suitably, it is desirable to carry out the reaction in the presence of an acidic catalyst.

Suitably used catalysts include benzenesulfonic acid, halatoluenesulfonic acid, phosphoric acid, acetic acid, and phosphoric acid, preferably 0.0001 to 0.01 mol.

The reaction can be carried out under cooling or heating as required, and is preferably carried out under reflux conditions of the solvent used. In addition, in order for the reaction to proceed smoothly, it is desirable to remove water that is produced as a by-product during the reaction, and a method of distilling off the solvent and water in an azeotropic state is convenient for this purpose. , is suitable.

After the lactonization reaction is completed, the acidic catalyst is removed by washing with water, if necessary, and then the solvent is distilled off to obtain the compound of general formula (I). Distillation is a simple method for purifying this product; for example, distillation under reduced pressure using a water aspirator or a vacuum pump is preferred.

According to the present invention, the optically active compound of the general formula (n) is an optically active alcohol represented by the general formula % (in which X is as defined above). Easily produced in large quantities by reacting with a compound represented by the general formula % (in the formula, R is as defined above, and Hal represents a halogen atom) in the presence of a solvent. I can do it. Here, the following compounds are exemplified as compounds of general formula (■) that can be suitably used.

CH3SO2α, C2H5SO2α, C2H5SO
2α, C6H5802α, CHsCgH4SOzCg,
CHaSOaBr%C2H55O2Br.

C5HrSO2Br, C5HsSO2Br, CH
aCsH4SO2Br0 Also, suitable aprotic solvents include ether solvents such as diethyl ether, diimpropyl ether, and tetrahydrofuran, hydrocarbon solvents such as hexane, benzene, and toluene, and carbonized halides such as chloroform and methylene chloride. Examples include hydrogen-based solvents. The amount of solvent used is not critical, but is usually 5 parts by weight of the compound of general formula (v).
-500 parts by weight, preferably 10-100 parts by weight.

The reaction is carried out by adding the compound of general formula (M) or a liquid obtained by dissolving or dispersing it in the above solvent into a solution of the compound of general formula (■) in the above solvent all at once or in small portions several times. This is carried out by adding the mixture and stirring for an appropriate period of time. The amount of the compound of general formula (■) used is not critical, but preferably 0
．． The amount is 5 to 50 mol, preferably 1.0 to 5.0 mol. During the reaction, the reaction system can be cooled or heated as necessary. The reaction is preferably carried out at -10°C
It is carried out at a temperature in the range +50°C. In order to make the reaction proceed smoothly, it is preferable to add an amine compound such as pyridine or triethylamine to the reaction system to capture hydrogen halide produced as a by-product. The amount of the amine compound used is not critical, but 0.1 to 50 mol per mol of the compound of general formula (■), preferably ii:0
．． 5 to 5 mol is suitable.

In order to complete the reaction, it takes about 1 minute to 2 minutes under the above reaction conditions.
It is desirable to leave the reaction system under stirring for 4 hours, preferably 10 minutes to 10 hours. After the reaction is completed, the reaction mixture is brought into contact with water to decompose the unreacted compound of general formula (M), and the organic layer is extracted and purified to obtain general formula (If
) can be obtained. Extraction of organic layer with hexane, benzene, chloroform, methylene chloride%
This can be carried out using a solvent commonly used as an extraction solvent, such as diethyl ether.

Purification of the compound of the general formula (former formula) can be carried out according to the methods normally used for the purification of organic compounds, and chromatography is particularly preferably used.

The chromatography in this case is performed using the general formula (1
) is carried out under conditions similar to those for the compound.

According to the present invention, the compound of general formula (V) used in the above reaction is an optically active compound represented by the general formula (wherein X is as defined above, and R represents a lower alkyl group) (2) (wherein R represents a lower alkyl group and n represents a lower alkyl group and n represents an integer from 1 to 4. It can be easily produced in large quantities by reduction with a lithium borohydride compound shown in (.).

Here, the following are exemplified as specific examples of the lithium aluminum hydride compound of general formula (■-1).

LiAtH4, I-1AzHa (OCHa),
LiAtHa(OC2Ha), LiAtH2(OC
H3)2, LiAtH2(OC*Hs)2, Li
AtH(OCH3)a, LiAtH(OC2H5)3, while the following are exemplified as specific examples of the lithium borohydride compound of general formula (■-2): 0LiBH4, Li
BH(CHa)3, LiBH(CzHs)3, LiB
H(CHtCH(CHs)2)3, LIBH[CH(
CHs)CH*CHs]3 This reduction reaction is usually carried out in an organic solvent that is stable towards the reducing agent. Examples of suitably used solvents include ether solvents such as diethyl ether, diimpropyl ether, dioxane, tetrahydrofuran, dimethoxyethane, and diglyme. Other than these may be used as long as they allow the reaction to proceed smoothly.

The amount of solvent used is not critical, but it is 95 to 500 parts by weight, preferably 10 to 500 parts by weight, per 1 part by weight of the compound of general formula (■).
A 100-ply part is appropriate.

This reduction reaction is carried out by the general formula (■-1) or the general formula (■-
Add the reducing agent represented by 2) to the above solvent, and add the compound of general formula (■) or a solution obtained by diluting it with the above solvent under stirring, either all at once or in small portions several times,
Alternatively, it can be carried out by adding by dropwise addition and then stirring for an appropriate period of time. If necessary, it is also possible to add the reducing agent to the compound of general formula (■) or its solution all at once or in small portions in several portions. The amount of reducing agent used is not critical, but it is 0.25 to 50 mol, preferably 1 to 1 mol, per 1 mol of the compound of general formula (■).
0 mole is good. During the reaction, the reaction system can be cooled or heated as necessary. The reaction is preferably -3
It is carried out at temperatures in the range 0°C to +50°C. In order to complete the reaction, it is desirable to continue the reaction at the above temperature for about 1 minute to 24 hours, preferably 10 minutes to 10 hours while stirring the reaction system.

After the reaction is completed, the reaction mixture is reacted with water, and then the organic layer is extracted and filled to obtain the compound of general formula (V). It is also preferable in terms of reaction operation to add methyl acetate, ethyl acetate, or the like to decompose most of the reducing agent in advance before reacting the reaction mixture with water.

The organic layer can also be extracted by adding a solvent commonly used as an extraction solvent such as hexane, benzene, chloroform, methylene chloride, diethyl ether, etc.

The compound of general formula (V) can be purified according to methods generally used for the purification of organic compounds, and it is particularly convenient to use chromatography and/or distillation. The conditions used for chromatography are similar to those for the compound of general formula (ul) described above. The distillation is preferably carried out under reduced pressure using a water aspirator or a vacuum pump.

In general formula (V), when X is a hydroxyl group protected by an acetal bond, this tortoise is reacted with an alkylating agent or a benzylating agent in the presence of a basic compound in a suitable solvent. An optically active compound represented by the formula (wherein X represents a hydroxyl group protected by an acetal bond, and X2 represents a hydroxyl group protected by an ether bond) is prepared, and then this is prepared under acidic conditions. By treatment, the protecting group can be removed from the X1 group to obtain the optically reversed configuration represented by the general formula (wherein X'1 is as defined above). here,
Examples of solvents that can be used when synthesizing the compound of general formula (K) include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. . Although the amount of the solvent used is not critical, it is preferably 10 to 50 parts by weight per 1 part of the general formula (■).

In addition, as basic compounds, hydrogenated) IJum,
Potassium hydride, sodium hydroxide, potassium hydroxide,
Suitable examples include butyllithium, methyllithium, and the like. The amount of this basic compound used is determined by the general formula (V
) is preferably 0.5 to 5.0 mol per mol of the compound. Preferred examples of the alkylating agent include methyl iodide, ethyl iodide, propyl iodide, methyl bromide, ethyl bromide, and propyl bromide. Further, the amount of the benzylating agent or benzylating agent used is preferably 1.0 to 5 mol per mol of the compound of general formula (IX).

The reaction is carried out by adding the compound of general formula (IX) and a basic compound to the above solvent, then adding the above alkylating agent or benzylating agent while stirring, and stirring for an appropriate time. During the reaction, the reaction system can be cooled or heated as necessary. The reaction is preferably -10
It is carried out at temperatures in the range from 0C to +800C. The desired reaction can be completed by stirring under the above conditions for about 10 minutes to 24 hours.

Purification of the compound of general formula (IX) is preferably carried out by chromatography. For this chromatography, conditions similar to those for the compound of general formula (I[I) described above can be employed.

The conversion of the compound of general formula (IX) to the compound of general formula (X) is carried out in a suitable solvent in the presence of an acid catalyst. Examples of suitable solvents include alcoholic solvents such as methanol, ethanol, impropatol, and ethylene glycol. The amount of solvent used is not critical, but p5 to 100 parts by weight per 1 part by weight of the compound of general formula (IX),
Particularly suitable is 10 to 50 parts by weight. Examples of the acid catalyst include phosphoric acid, acetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and preferably 0.01 mol.

The general formula (Purification of the compound of DO is the general formula (V) described above)
This can be carried out in the same manner as for the purification of the compound.

The compound of the general formula (■) used in the present invention can be easily produced by protecting the hydroxyl group of an optically active compound represented by the general formula (wherein R is as defined above). can.

The hydroxyl group retention reaction can be carried out using known methods such as McO.
Written by mio” Protective Groups i
n Organic Chemistry” Chapter 3,
Plenum Press (1973). Furthermore, the optically active compound of the general formula (XI) can be obtained by, for example, the method of microbial conversion of methacrylic acid described in Japanese Patent Publication No. 59-21599;
A method using microbial conversion of inobutyric acid is described in Japanese Patent Publication No. 59-21600, and C. T. Goodhue et al.
iotechnology and bioengineering
earing, Vol. 13, pp. 203-214 (197
It can be easily produced in large quantities by the method described in 2010).

Reduction reaction of a compound of general formula (■) to a compound of general formula (■) according to the present invention, a compound of general formula (■) and a compound of general formula (■) to produce a compound of general formula (II) Synthesis of the compound of general formula (1) by reaction with (conversion of the old compound to compound of general formula ([1)) and hydrolysis of the compound of general formula (Ell) and subsequent reactions is the reaction described above. Under these conditions, the optically active configuration of the starting compound is maintained and a product with the same configuration as the starting compound is obtained.

The production of optically active vitamin E from optically active 3-methyl-4-butanolide of general formula (1) is described in, for example, JP-A-52-136102, and the production of optically active dolichol is described in, for example, JP-A-52-136102. Showa 58-
It is described in Publication No. 83643.

Furthermore, since it is difficult to accurately determine the optical purity of the compound of general formula (1), the method of S. 5uzuki et al. (Tetrahedron Lett, 24.
5103 (1983)).

Example Hereinafter, the present invention will be explained in detail using examples.

In the examples, infrared absorption spectroscopy (IR analysis) was performed using a liquid film for oily substances and KBr tablets for solids, and nuclear magnetic resonance spectroscopy (NMR analysis) was performed using tetramethylsilane as an internal standard and 1- It was measured using FD
-MASS analysis and GC-MASS analysis results are 14
This is a value corrected as N, 160.32S, and 85α.

Example 1 (R) Methyl -2-methyl-3-hydroxypropionate (23,63,!i', 0.2 mol, [α] = -
26.6°, C=2.0. CH30H) and para-toluenesulfonic acid (20 mF) were dissolved in methylene chloride, and dihydrobilane (21,
8 ml, 0.288 mol) was added dropwise, and stirring was continued for an additional 2 hours. The raw material (
R) After confirming the disappearance of methyl-2-methyl-3-hydroxypropionate, add powdered bicarbonate (100
After stirring for 10 minutes, the reaction solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 41.6 g of an oil. As a result of FiIR, NMR and GO-MASS analysis of this product, in the general formula (■), X--o, Q R2=C
It was confirmed to be methyl (R)-2-methyl-3-tetrahydropyranyloxypropionate, which is Ha.

IR analysis'I'max 1735.1250.119
0.1170.1120°1070, 1050.102
5.1010. cm-'pm NMR analysis; δ 1.11 (3H2d + J
=7Hz).

Cα4 1.25-2.0 (6H), 2.62 (IH, q,
J=7Hz).

3.1 to 3.9 (7H) including 3.63 (3H, s)
, 4.50 (1) (, br, s) GC-MASS
Analysis: m/e = 202 Lithium aluminum hydride (LiAtH4, 7.6 g, 0.2 r-L) was added to total anhydrous diethyl ether (200+/) at 0° C. with mechanical starvation stirring as above. Got (R
) - A solution of methyl 2-methyl-3-tetrahydropyranyloxypropionate (41.6 g) dissolved in anhydrous diethyl ether (Zoom) was added dropwise, and after completion of the dropwise addition -
Stirring was continued at room temperature overnight. Then water (7,1), 15
After carefully adding IJium aqueous solution (7,6,1) and water (22,81) in this order little by little and stirring well, the formed precipitate was removed by filtration. The precipitate was thoroughly washed with diethyl ether, all the ether layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and after the solvent was distilled off, a liquid substance of 32.5.9 was obtained. This was subjected to silica gel column chromatography (using a mixture of hexane and diethyl ether as a developing solvent) to obtain 31.3 g of a colorless liquid.This liquid was analyzed by IR, NMR and GC-MASS.
As a result of analysis, the general formula (V) is X-6Ω (8
) -2-methyl-3-tetrahydropyranyloxy-
1- It was confirmed that it was a proper tool.

IR analysis Niji max ~3450.1205.1190
．． 1170.1140°1120, 1080.1060
．． 1035.980.910.875°820c1n' 99m NMR analysis: δ 0.83 (3H, d, J=6.
5Hz).

Cl4 1.25-2.0 (7H), 2゜59 (IH, s, -
0H).

3.05-3.90 (6H, m), 4.45 (IH, b
r, s) GC-MASS analysis: m/e=174 Then, the <s>-2-methyl-3-tetrahydropyranyloxy-1-propatol (31,3,9,0
, 18 mol) and pyridine (2o, 6 ml s
0.25 mol) was dissolved in methylene chloride (120 m/), and while stirring at 0°C, para-toluenesulfonic acid chloride (31.5 g, 0.2 mol) was added, and the mixture was stirred for 3 hours at 0°C and carefully stirred. Afterwards, stirring was continued at room temperature overnight. After confirming the disappearance of the raw alcohol by thin layer chromatography analysis, the reaction solution was poured into water, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed twice with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a pale yellow liquid. This product was purified by silica gel column chromatography (using a mixture of hexane and diethyl ether as the developing solvent) to obtain 49.2
g of a colorless liquid was obtained. IR, NMR and FD-M
As a result of ASS analysis, in general formula (II) “”-’-
0-Q5R” --CsH4CHa (R) −2
-Methyl-3-tetrahydropyranyloxyprobyl-p-toluenesulfonate.

IR analysis: νmax 1600.1500.1190
．． 1180.1135°1125, 1100.1075
．． 1065.1035.1020゜980, 960.9
40.820.670 cm-”91m NMR analysis: δ 0.89 (3H, d, J=7
Hz).

C14 1,25-1.75 (6H), 1.99 (IH
, m), 2.40 (3H, s).

2°95~3.7 (4H, m), 8.88 (2) I,
m).

4.37(1)L br, s), 7.25(2H,
d, J=7Hz).

7.70 (2H, d, J-7Hz) FD-MASS analysis: m/e-328 then 4@-(R)-2-methyl-3-tetrahydropyranyloxyprobyl p-)luenesulfonate (49,2
Ns 0-12S mol) and sodium cyanide (1
4,79,0,3 mol) in dimethyl sulfoxide (10
After 1 hour while stirring at 60° to 70°C, disappearance of the raw material sulfonate was confirmed by thin layer chromatography analysis.

The reaction solution was poured into water (300 d) and extracted three times with diethyl ether. The obtained organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a slightly yellow liquid.

This product was purified by silica gel column chromatography (using a mixture of hexane and diethyl ether as a developing solvent) to obtain 23.8 g of a colorless liquid. As a result of IR, NMR and GC-MASS analysis, this product has the general formula (In) with X=-00 (S) -
O IR analysis confirmed to be 3-methyl-4-tetrahydropyranyloxybutyronitrile: ”max 2240.1190.1125
．． 1115.1070°1050, 1025.1015
．． 965.895.860.805 side pm NMR analysis: δ 1.06 (3H, d, J=7H
z).

C1a 1.25-2.2 (7H), 2.2-2.6 (2
H, m) +3.0 to 3.9 (4H, m), 4.5
0(IH, br, s) GC-MASS analysis; m,”
e = isa then this nitrile compound (23,8
g, 0.13 mol) and 50% by weight aqueous sodium hydroxide solution (100 m/) in ethylene glycol (100 m
/), and after reacting overnight at 120-140°C, the reaction mixture was cooled to room temperature, water (100 m) was added, and 3% by weight
Add hydrochloric acid aqueous solution little by little to adjust the pH to 2, and let it rise to 2 at room temperature.
The mixture was stirred for hours, extracted with diethyl ether, the obtained diethyl ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid.

Pour this into a water aspirator under reduced pressure (15mmH9)
10.7 g of a colorless liquid was obtained as a fraction with a boiling point of 90-95°C/15 mlHg. This thing is I
R.

Results of NMR% GC-MASS and optical rotation analysis, (-
)-(38)-3-methyl-4-butanolide.

IR analysis Niji max 1775.11?0.1145.
1015.990°935, 835 cm' 91m NMR analysis: δ 1.10 (3H, d, J=6
．． 5Hz).

Cα4 1-97 (I HT q , J = 9 H3) +
2.40 (IH+d, J = 8Hz) +2-60
(1 meter) + 3-75 (IHldd, J-9H
z + J-7Hz)+4.30 (IH, dd,
J=9Hz, 7Hz) -37= GO-MASS analysis: m/e "' 100 Optical rotation analysis: [α] T=-25,6° (cm4.o, CHsOH) (Optical purity 98%) Example 2 The same operation as in Example 1 was performed except that ethyl vinyl ether (20,7,!i+, 0.288 mol) was used in place of the dihydropyran used in Example 1, and 9.86 g of colorless final product was obtained. A liquid product was obtained. As a result of IR, NMR, optical rotation, and gas chromatography analysis, this product was found to be almost identical to (-)-(38)-3-methyl-4-butanolide obtained in Example 1. It was confirmed that the physical property values of the synthetic intermediate were 9 as shown below.

IR analysis Niji max 1745.1245.1205.
1180.1130°1080, 1065.1040
cm-''91m NMR analysis: δc, 41.0-1.3 (9H).

2.61 (IH, q, J-7Hz).

3.62 (3H, II) included, 3.1 to 3.9 (7H
).

4.66 (IH, q, J=5.5Hz)QC-M
ASS analysis: m/e -190 (i'Ha ■R analysis: vm, x ~ 3400.1130.1110
．． 1065.1050°1020,965 cm-” NMR analysis: 63”:: 0.83 (8H, d,
J-6,5Hz).

1-13 (3H1t, J7Hz) + 1-27
(3H+ d, J -5-5HE) +", 88 (
IH+”)+2.51 (IH, s, OH).

a, 05~3-90 (6H+m)+4.61(
IH1q1t5,5Hz) GO-MASS analysis; m
/e=162H8 IR analysis: vmax2250.1190.1130.
1120.1070°1055, 1025.1015.
965 side-1 NMR analysis"c'oa 1.0~1-
3 (9H) + 2.2~25 (2H9m) +3
．． 0-3.9 (4H), 4.66 (IH, q,
J=5.5Hz) GO-MASS analysis: m/e-1
71 Example 3 Lithium aluminum hydride (7.6 g, 0.2 mol) used as the reducing agent in Example 1 was replaced with lithium trimethoxyaluminum hydride (LiAZH (OC
H3) As 5 i, 2 Ji' s O-4 mole]
1 g of colorless liquid was obtained. As a result of IR, NMR, optical rotation and gas chromatography analysis, it was confirmed that this product was almost the same as (-)-(38)-3-methyl-4-butanolide obtained in Example 1.

Example 4 Lithium borohydride (4.4 g, 0.2 mol) was used in place of the lithium aluminum hydride (7.6 g, 0.2 mol) used as the reducing agent in Example 1, and the reduction reaction The same operation as in Example 1 was carried out, except that anhydrous diethylene glycol dimethyl ether was used as the solvent in place of anhydrous diethyl ether, to obtain a colorless liquid of 9.62p. This product was obtained in Example 1 as a result of IR, NMR, optical rotation, and gas chromatography analysis (-
)-(3S)-3-methyl-4-butanolide.

Example 5 Lithium aluminum hydride (7.6 g, 0.2 mol) K used as a reducing agent in Example 1. Lithium triethylborohydride (42.4 g, 0.2 mol) was used as a reducing agent instead.
The same operation as in Example 1 was carried out, except that anhydrous tetrahydrofuran was used instead of anhydrous diethyl ether as the solvent for the reduction reaction, and 8.831
A colorless liquid of I was obtained. Results of iIR, NMR, optical rotation, and gas chromatography analysis of this Amane, Example 1
It was confirmed that it is almost the same as (-)-(3S)-3-methyl-4-butanolide obtained in .

Example 6 Same as Example 1 except that methanesulfonic acid chloride (22,91s O-2 mol) was used instead of para-toluenesulfonic acid chloride (31,5#, 0.2 mol) used in Example 1. A similar operation was performed to obtain 9.929 colorless liquid. This one is IR, NMR.

Results of optical rotation and gas chromatography analysis, 41
It was confirmed that it was almost the same as (-)-(3S)-3-methyl-4-butanolide obtained in Example 1.

Note that 1 synthetic intermediate X-OQ, R=CH5
The physical properties of the compound of general formula (It) were determined as follows.

IR analysis: l'maX 1195.1190.113
0.1105.1080°10?0.1040.102
5.980 cmpm NMR analysis: δ 0.90 (3H, d, J-7H
z).

Cα4 1.25-1.75 (6H), 2.00 (IH, m)
, 2.73 (3H, 8).

2.95-3.7 (4H, m), 4.00 (2
H, m).

4.36 (IH, br, s) GO-MASS analysis: m/e-252 Example 7 In Example 1, (R)-2-methyl-3-tetrahydropyranyloxypropyl p-toluenesulfonate and sodium cyanide The same operation as in Example 1 was performed except that dimethyl formamide was used instead of dimethyl sulfoxide used as the reaction solvent, and 10.2
g of a colorless liquid was obtained.

This product gave almost the same analytical results as (-)-(38)-3-methyl-4-butanolide obtained in Example 1. Furthermore, almost the same analytical results were obtained when dimethyl acedoazide or N-methylpyrrolidone was used instead of dimethyl sulfoxide.

Example 8 IJum (14 cyanide) used in Example 1
, 7g, 0.3 mol) in place of potassium cyanide (19
, 5 g, 0.3 mol) was used, and 10.8 g of a colorless liquid was obtained. This product gave almost the same analysis results as (-)-(38)-3-methyl-4-butanolide obtained in Example 1. Example 9 As a solvent for the hydrolysis reaction of cyano group in Example 1. Example 1 except that ethyl alcohol (100d) was used instead of the ethylene glycol (100wLl) used.
The same operation as in Example 1 was performed to obtain 10,217 colorless liquids. This is based on the results of various instrumental analyzes (-
)-(3B)-3-methyl-4-butanolide. Furthermore, almost the same results were obtained when inpropatol, 2-methoxyethanol, or diethylene glycol was used instead of ethyl alcohol.

Example 10 Synthesized by the method of Example 1, 7'c(S)-'2-methyl-3-tetrahydropyranyloxy-1-propatol (10.45 g, 0.06 mol) was dissolved in anhydrous tetrahydrofuran (20d). (50% by weight oil-dispersed hydrogenation of the dissolved solution) IJium (5,769,0.12 mol)
The mixture was added dropwise to anhydrous tetrahydrofuran (60 ml) containing 100 ml of anhydrous tetrahydrofuran, stirred for 5 hours at 50°C, and then a solution of benzyl bromide (12,31 L O, 072 mol) dissolved in anhydrous tetrahydrofuran (20 w/) was added dropwise at 50°C. , stirring was continued for an additional 2 hours at the same temperature. The reaction mixture was then cooled to room temperature, poured into water (approximately 200 d), the organic layer was extracted with diethyl ether, the obtained diethyl ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a liquid. Ta. This product was purified by silica gel column chromatography (using a mixture of hexane and diethyl ether as the developing solvent) to yield 15.2,! A colorless liquid of ii' was obtained. As a result of IR%NMR and GC-MAS8 analysis, this product has the general formula (IX) with X''=0
-G;J.

X2 = -OCH2C6H5 2 - [(S) -
It was confirmed to be 3-benzyloxy-2-methylpropoxykutetrahydro-2H-bilane.

IR analysis Niji max3050.3020.1600 (W
), 1490(W).

1190, 1110.1090.1065.1050.
1020°1010, 965.895.860.805
．． 725.690 cm-'NMR analysis = δ island 0.91
(3H, d, J-7Hz).

1.3-1.75 (6H), i, 95 (iH, m).

3.0-3.8 (6H, m), 4.40 (2H
,B).

4.43 (IH2br+ 8), 7.23 (5H
,s) GC-MASS analysis: m/e=264 This pyran compound (15.2 g, 0.058 mol) was then dissolved in methanol (300 d) and mixed with no(radruenesulfonic acid (1 g) at 40°C for 1 hour. After stirring and confirming the disappearance of the raw biran compound by thin layer chromatography analysis, the mixture was cooled to room temperature and powdered sodium bicarbonate (2 g
), most of the methanol was distilled off under reduced pressure, and water (
The organic layer was extracted with diethyl ether, the obtained diethyl ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a pale yellow liquid.

This product was distilled using a Kugelrohr type device under reduced pressure with a vacuum pump to obtain 9.9 g of a colorless liquid.

According to the analysis results below, this product is X2 = -0CH2C6
A compound of general formula (X) that is H5, that is, general formula (V)
It was confirmed that it was (R)-3-benzyloxy-2-methyl-1-propatol, where X=-OCH2C6H5.

IR analysis Niji max ~3400.3080* 305
0.1610(w).

1500, 1100.1080.1040.740.7
05 tyn-”19m NMR analysis: δ 0.83 (3H, d, J-7H
z).

Cα4 1.86 (IH, m), 2.47 (IH2OHL3
．． 25-3.55 (4H, m), 4.40 (2H, 8
), 7.23 (5H, s) GC-MASS analysis: m
/e w 180 Optical rotation analysis: [α] = -2,2° (
C-2,0, CHsOH) then (R)-3-benzyloxy-2-methyl-1-propanol (9,4L
O,052 mol) and pyridine (16,8 wl,
0.21 mol) was dissolved in chloroform (200d),
While cooling with ice water, p-toluenesulfonic acid chloride (14,3,9,0,075 mol) was added without stirring, and after stirring for 3 hours under the same temperature conditions, stirring was continued overnight at room temperature. The reaction mixture was poured into 200 at water, the organic layer was washed with diluted hydrochloric acid to remove residual pyridine, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid. Na. This product was purified by silica gel column chromatography (using a mixture of hexane and ethyl acetate as a developing solvent).
A colorless liquid of fi was obtained. According to the following analytical results, this product has the general formula (II) of X--0CH2C6H5,
It was confirmed to be (S)-3-benzyloxy-2-methylpropyl 1)-)luenesulfonate, which is R--C6H4CH3.

IR analysis: vmax3060.3025.1595.
1490.1180°1170, 1090.965.9
35.830.805 cm-”NMR analysis: δg=,
0.86 (3H, d, J = 7Hz).

t, 99 (IH, m), 2.34 (3H, s) + 3.
23 (2H, d, J=6Hz), 3.89 (2H, d,
J=6Hz).

4.29 (2H, s), 7.18 (5H, s).

7.21 (2H, d, J=8Hz), 7.68
(2H, d, J=8Hz) FD-MASS analysis:
m/e = 334 optical rotation analysis; [α] - +7.6
°(C-2,0, CHaOH) then the above sulfone) (15,2p, 0.046 mol) and sodium cyanide (2,729,0,54 mol) were added in dimethyl sulfoxide (100 i+l) and 70 The mixture was stirred at ℃ overnight, and the disappearance of the raw material sulfonate was confirmed by thin layer chromatography analysis. [Then, the reaction solution was cooled to room temperature, poured into 300 m# of water, and the organic layer was extracted with diethyl ether. The diethyl ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid substance. This product was purified by silica gel column chromatography (using a mixture of hexane and ethyl acetate as a developing solvent).8.
0 g of colorless liquid was obtained. According to the analysis results below, this product has the general formula (III) with X=-OCf(2csH5
It was confirmed that it is (R)-4-benzyloxy-3-methylbutyronitrile.

IR analysis; νmax 3100.3080.3050.
2260°1610(w), 1500. ~1100.
740.700 cm-”pln NMR analysis: δ 0.96 (3H,d, J-6
,5Hz).

Around 4 2.00 (II (, m), 2.26 (2H, m),
3.05-3.45 (2H, m).

4.40 (2H, 8), 7.23 (5H, s) GC-
MASS analysis: m/e=189 Optical rotation analysis: [α] - +28.3° (C-3,0,C
HaOH) then the above nitrile (7,9L 0.042
mol) and 50% by weight hydroxide) IJium aqueous solution (
20d) in ethylene glycol (20d) and 1
After confirming the disappearance of the p raw material nitrile by continuous stirring overnight at 30°C, the reaction mixture was cooled to room temperature, and water (20d) was added to give a concentration of 3% by weight.
The mixture was adjusted to I)H2 with an aqueous hydrochloric acid solution, the organic layer was extracted with diethyl ether, the diethyl ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow liquid.

This product was purified by silica gel column chromatography (using a mixture of hexane and ethyl acetate as a developing solvent) to obtain a colorless liquid with a weight of 8.22 fi. Carbon (0,4,!i'), ethanol (50 m/), and the above liquid material (8,22 g) were charged, and the mixture was sufficiently replaced with hydrogen, and then stirred overnight at 50°C under a hydrogen pressure of 50 atm. Continued. The reaction solution was filtered to remove the catalyst, the F solution was concentrated under reduced pressure to distill off most of the ethanol, and the residue was
001 in benzene, para-toluenesulfonic acid (
100 mg) was added thereto, and water in the reaction system was azeotropically removed while heating to reflux conditions.

After complete water production, the reaction mixture was cooled to room temperature, powdered potassium carbonate (200 mg) was added, and 0.
After washing with a 5% by weight aqueous potassium carbonate solution and drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was distilled using a water aspirator and a Kugelrohr type distiller under reduced pressure.
3.219 of a colorless liquid was obtained. IR of this, NM
The results of R and GC-MASS analysis are shown in Example 1.
, -)-(aS)-S-methyl-4-butanolide.

=50- On the other hand, the optical rotation is (g) F-+ 25,9' (C-2,
8, CHsOH) (optical purity of 98% or more), and it was confirmed that this product was (+)-(3R)-3-methyl-4-butanolide.

Example 11 Benzyl pro-Kando (12,3
methyl iodide (1p, 0.072 mol)
Xw*-0CH in general formula (1) according to the same procedure as in Example 9 except that Xw*-0CH
4.5 g of (R)-4-methoxy-3-methylbutyronitrile, which is s, was obtained. The analysis results of this product are shown below.

IR analysis = νmax 2250.1120.1100.
1080 car-”19m NMR analysis: δ 0.97 (3H, d, J-6
,5Hz).

α right 2.01 (IH, mL 2.27 (2H, m).

3.05 to 3.45 (including 3.27 (3H,s)
5H) GO-MA8S analysis: m/e-113 Next, the above nitrile was hydrolyzed in the same manner as in Example 10, and 4.6 g of the obtained liquid was mixed with 20 iu of chloroform.
K dissolved therein, 10.711% of iodotrimethylsilane was gradually added dropwise at room temperature, and the mixture was stirred overnight.

After pouring the reaction mixture into methanol (5.5 t#), volatile substances were distilled off under reduced pressure, and the residue was dissolved in 2001 benzene. After complete generation of water, the reaction mixture was cooled, powdered potassium carbonate (200 mg) was added, washed with a 0.5% by weight aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was distilled using a Kugelrohr distiller under reduced pressure using a water R aspirator to obtain a colorless liquid of 2.50.li+.IR%NMR, GC-MA of this
The measurement results of SB, gas chromatography analysis, and optical rotation were in good agreement with those of (+)-(3R)-3-methyl-4-butanolide obtained in Example 10.0 Example 12 Used in Example 1 (R) Methyl-2-methyl-3-hydroxypropionate (8)-2-methyl-3-hydroxypropionate (23,63,j
i', 0.2 mol, [α1 richness + 26.5° (C-4,0
, CHaOH) was used, but the same procedure as in Example 1 was carried out to obtain 9.35 g of a colorless liquid as the final product. As a result of IRlNMR, optical rotation, and gas chromatography, this product was found to be the (+)-(3R
)-3-methyl-4-butanolide.

Effects of the Invention According to the method of the present invention, optically active 3-methyl-
Both R-form and 8-form optical isomers can be produced with high optical purity by efficiently using 4-butanolide and by selecting raw materials. Furthermore, the method of the present invention is suitable for industrial-scale production of optically active 3-methyl-4-butanolide because the reactions and other operations used are easy, and raw materials are also easily available.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X represents a protected hydroxyl group, R^1
represents a lower alkyl group or a phenyl group optionally substituted with a lower alkyl group. ) The optically active compound represented by dimethyl sulfoxide, N
- By reacting with sodium cyanide or potassium cyanide in one or more solvents selected from the group consisting of methylpyrrolidone, dimethylformamide, and dimethylacetamide, the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc.▼ (wherein X is (as defined above), the nitrile is hydrolyzed in an alcoholic solvent in the presence of sodium hydroxide, potassium hydroxide or barium hydroxide, and then the hydrolysis product is deprotected. The optically active 3-methyl-4-butanolide represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Production method. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a protected hydroxyl group.) An optically active alcohol represented by the general formula R^1-SO_2 is prepared in the presence of an aprotic solvent. -Hal (In the formula, R^1 represents a lower alkyl group or a phenyl group optionally substituted with a lower alkyl group, and Hal represents a halogen atom.) By reacting with a compound represented by the general formula ▲ formula, There are chemical formulas, tables, etc. ▼ (In the formula, R^1 and The product is reacted with sodium cyanide or potassium cyanide in one or more solvents selected from the group consisting of acetamide to produce the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X is as defined above.) The nitrile is hydrolyzed in an alcoholic solvent in the presence of sodium hydroxide or potassium hydroxide, and then the hydrolyzed product is subjected to a deprotection reaction, and if necessary, an acidic catalyst is added. A method for producing optically active 3-methyl-4-butanolide represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ characterized by subjecting it to a dehydration reaction in the presence of. 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a protected hydroxyl group, and R represents a hydrogen atom or a lower alkyl group.) OR^3)_4_-_n or LiBH
n(R^3)_4_-_n (in the formula, R^3 represents a lower alkyl group, and n represents an integer of 1 to 4) by reduction with a metal hydride compound represented by the general formula ▲ mathematical formula, chemical formula , tables, etc.▼ (In the formula, X is as defined above.) An optically active alcohol represented by
_2-Hal (In the formula, R^1 represents a lower alkyl group or a phenyl group optionally substituted with a lower alkyl group, and Hal represents a halogen atom.) By reacting with a compound represented by the general formula ▲ formula , chemical formulas, tables, etc. ▼ (In the formula, R^1 and It is reacted with sodium cyanide or potassium cyanide in one or more solvents selected from the group consisting of dimethylacetamide to produce the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, X is as defined above). ), the nitrile is hydrolyzed in the presence of sodium hydroxide or potassium hydroxide in an alcoholic solvent, and the hydrolyzed product is then subjected to a deprotecting group reaction, and if necessary, further acidified. A method for producing optically active 3-methyl-4-butanolide represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ characterized by subjecting it to a dehydration reaction in the presence of a catalyst.