JPH0548222B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel method for producing sulfide derivatives. More specifically, the present invention relates to sulfide derivatives useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, other physiologically active substances, ferroelectric liquid crystal materials, etc., and particularly to optically active compounds thereof, and methods for producing the same. (Prior Art and Problems) In recent years, the usefulness of optically active substances has been increasing in the fields of medicines, agricultural chemicals, other physiologically active substances, and new materials such as ferroelectric liquid crystal materials. As such optically active substances, for example, matsutake alcohol and sulcatol are known to be useful substances, the former as a fragrance and the latter as an insect pheromone, and these substances do not exist in racemic form in nature. be. It is extremely important to obtain not only the optically active matsutake alcohol or sulcatol but also those with high optical purity, and the problem is how to obtain highly pure substances that serve as raw materials for these. (Means for Solving the Problem) The present applicant has previously proposed a method for producing optically active epichlorohydrin with high optical purity (Japanese Patent Application Laid-open Nos. 132196/1982 and 6697/1987). The present inventors attempted to synthesize a compound using the above-mentioned optically active epichlorohydrin as a raw material, and as a result,
We have succeeded in obtaining an extremely highly purified optically active compound that can be used as a raw material for the new material mentioned above. The present invention is based on the following formula () (However, in the above formula (), R ¹ is a hydrogen atom,
Represents an atom or group selected from straight-chain alkyl, branched alkyl, alkenyl, and aralkyl each having 1 to 22 carbon atoms, and ph represents a phenyl group)
In the method for producing a sulfide derivative represented by
Epichlorohydrin in the presence of a hydrogen nucleophile consisting of a metal hydride or a monovalent copper compound catalyst
R ² M (R ² represents the same group as R ¹ excluding the hydrogen atom of formula (), M represents an alkali metal or alkaline earth metal) and R ² MgX (R ² represents the hydrogen atom of formula ()) This is a method for producing sulfide derivatives, which is characterized by reacting with a carbon nucleophile selected from R ¹ (X represents the same group as R 1 excluding R 1 and X represents a halogen atom), and then reacting with thiophenol. The manufacturing method will be explained in detail below. In addition,
In the present invention, racemic sulfide derivatives can of course be obtained when racemic epichlorohydrin is used; however, an example using optically active epichlorohydrin will be explained below. The optically active sulfide derivative represented by the above formula () of the present invention can be produced by the method (A) below. Method (A) Method (A) is a method in which a compound of formula () is produced by reacting optically active epichlorohydrin () with a hydrogen nucleophile or a carbon nucleophile, and the target product is obtained by reacting this with thiophenol. This two-step reaction can be carried out in one pot, and the target optically active sulfide derivative can be obtained without isolating the intermediate compound of formula ().
According to this method, when the (R) form is used as the raw material epichlorohydrin, an (R)-sulfide derivative can be synthesized. In the method (A) above, a metal hydride, a metal compound represented by R ² M or R ² MgX is used as the hydrogen nucleophile or carbon nucleophile. Hydrogen nucleophiles, ie, metal hydrides, include sodium borohydride, lithium aluminum hydride, sodium hydride, lithium hydride, and the like. In carbon nucleophiles, namely R ² M and R ² MgX, R ² represents the same group as R ¹ in the above formula () excluding the hydrogen atom, and M is an alkali metal such as lithium, sodium, potassium, or magnesium, calcium. X represents a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, etc., respectively. ^R2
Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,
n-heptyl, n-octyl, n-nonyl, n-
Decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-
Octadecyl, n-nonadecyl, n-icosyl,
Carbon number is 1 such as n-henicosyl, n-docosyl, etc.
~22 straight chain alkyl groups, isopropyl, isobutyl, neobutyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethyl Propyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl , 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, etc. Branched alkyl group having 1 to 22 carbon atoms, vinyl, allyl, 1-propenyl, 1-methylethynyl, 2
-Methyl-1-propenyl, 1-methyl-1-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, prenyl, geranyl, farnesyl, etc. Examples include alkenyl groups having 1 to 22 carbon atoms and aralkyl groups having 1 to 22 carbon atoms, such as benzyl groups substituted with 1 to 5 methyl or methoxyl groups at the ortho, meta, and para positions. In the reaction (A) above, when reacting with a hydrogen nucleophile or a carbon nucleophile, these nucleophiles are used in an amount of 1.5 to 10 equivalents based on the starting material epichlorohydrin. Further, it is preferable to use a monovalent copper compound such as copper iodide or copper cyanide as a catalyst in the reaction with a carbon nucleophile, since the yield can be significantly improved. The appropriate amount to be used is 0.05 to 1.2 equivalents based on the raw material epichlorohydrin. In the reaction (A), the sulfidation reaction is preferably carried out in an amount of 1 to 2 equivalents of thiophenol based on the starting material epichlorohydrin. In method (A), the reaction is carried out at a temperature of -78
It is preferably carried out at a temperature of -30°C, and the reaction system is carried out in the presence of an organic solvent. Such organic solvents include tetrahydrofuran, diethyl ether,
Ether solvents such as ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, or mixed solvents thereof are preferred. The optically active sulfide derivative () obtained by the present invention can be further oxidized and alkylated to convert it into allyl alcohols with an optical purity of 94% or more, such as matsutake alcohol. In addition, the above sulfide derivative () can be further reduced to obtain optical purity of 94%, such as sulfatol.
% or more of secondary alcohols.

【formula】

【formula】 (n-Bu: n-butyl group) Sulcatol matsutake alcohol (Example) Example 1 By method (A)

Method for producing [Formula] 1.16 g (12.97 mmol) of copper cyanide and 10 ml of tetrahydrofuran were placed in a reaction vessel, and 16.65 ml (95.04 mmol) of n-butyllithium was heated at -78°C under an argon stream.
After dropping a 15% hexane solution of
0.845 ml of (R)-epichlorohydrin with optical purity of 99% obtained by the method described in Publication No. 62-6697
(10.81 mmol) was added dropwise. After stirring at the same temperature for 3 hours, 2.22 ml of thiophenol (21.62 m
mol) and n-butyllithium, 13.88 ml (21.62
After stirring for 15 minutes, add saturated ammonium chloride aqueous solution, filter through Celite, dilute with ether, and wash sequentially with 10% by weight sodium hydroxide, 10% by weight hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine. After that, it was dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude sulfide compound as a yellow oil. This was subjected to column chromatography using 60 g of silica gel, and 1.71 g (yield: 70.6%) of a colorless oily sulfide was obtained from a methylene chloride:hexane=1:4 (volume) fraction. The properties of the obtained sulfide compound were as follows. [α] ²⁵ _D = −34.07° (c = 1.538, CHCl ₃ ) bp = 124°C to 135°C (0.35 mmHg, Kugelrohr) IR νmaxcm ^-1 (neat) 3400 (OH) NMR (CDCl ₃ ) δ: 0.877 ( 3H, m) 1.21 to 1.62 (8H, m) 2.42 (1H, d, J = 3.17Hz) 2.70 to 3.69 (2H, m) 3.52 to 3.69 (1H, m) 7.21 to 7.41 (5H, m) MS (m /e), 101 (M ⁺ −phS ⁺ = CH ₂ ) 82 (100
%) Elemental analysis C ₁₃ H ₂₀ OS C H S Theoretical value (%) 69.59 8.99 14.29 Measured value (%) 68.12 9.02 14.21 Example 2 (R)-(-)-6-methyl-2-hydroxy-5-
Production method of heptyl phenyl sulfide

[Formula] A suspension of 572 mg (3 mmol) of cuprous iodide in 10 ml of tetrahydrofuran was placed in a reaction vessel, and prenyl chloride was added to it at -30°C under an argon stream.
3.14g (30mmol) and magnesium 0.92g (40mmol)
mol) in 25 ml of tetrahydrofuran was added and stirred for 30 minutes. Next, at the same temperature, a solution of 1.85 g (20 mmol) of (R)-epichlorohydrin with an optical purity of 99% as in Example 1 in 5 ml of tetrahydrofuran was added and stirred for 3 hours, then gradually returned to room temperature and stirred for an additional 10 hours. After the reaction is complete, add 15ml of saturated ammonium chloride water and add ether.
After diluting with 50 ml, it was filtered through Celite. The organic layer was separated and removed, and the aqueous layer was extracted with 2×50 ml of ether.
The organic layers were combined, washed with 40 ml of saturated brine, and dried over magnesium sulfate. The crude product obtained after distilling off the solvent at 40°C or lower under reduced pressure was subjected to column chromatography using 70 g of silica gel, and a colorless liquid with the following structure was obtained from the hexane:ether = 6:1 (volume) flow. 1.438g of chlorohydrin (yield 44.2%)
I got it.

[Formula] The properties of the obtained chlorohydrin compound were as follows. [α] ²⁵ _D = +1.78° (C = 3.37, CHCl ₃ ) bp = 100 to 110°C (18 mmHg, Kugelrohr) IR νmaxcm ^-1 (neat) 3400 NMR (CDCl ₃ ) δ: 1.4 to 1.7 (2H, m) 1.62 (3H, br s) 1.69 (3H, br s) 1.9~2.3 (3H, m, 1H disapeared with D ₂ 0) 3.3~3.6 (2H, m) 3.65~3.95 (1H, m) 5.11 (1H , br t, J=7Hz) MS (m/e), 162 (M ⁺ ), 69, 40 (100%) Elemental analysis C ₈ H ₁₅ OCl C H Cl Theoretical value (%) 59.07 9.30 21.80 Measured value (% ) 58.93 9.56 21.57 Next, 1.0g (25m) of sodium hydride (60%)
A solution of 1.23 ml (12 mmol) of thiophenol in tetrahydrofuran (10 ml) was added dropwise at room temperature under an argon stream and stirred for 30 minutes. ) in tetrahydrofuran (10 ml) was added dropwise under ice cooling, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 15 hours. After the reaction, methanol (2 ml) was added and the mixture was stirred for 15 minutes, diluted with ether (120 ml), washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (75 g of silica, n-hexane:ether = 5:1 volume) to obtain the desired product (R)- (-)
2.00 g (yield: 84.7%) of -6-methyl-2-hydroxy-5-heptyl phenyl sulfide was obtained. The properties of the above target product were as follows. [α] ¹⁸ _D = −27.17° (c = 1.52, CHCl ₃ ) bp = 105 to 115°C (0.07 mmHg, Kugelrohr) IR νmaxcm ^-1 (neat) 3425 NMR (CDCl ₃ ) δ: 1.4 to 1.7 (2H, m) 1.6 (3H, br s) 1.67 (3H, drd, J=1.2Hz) 1.95-2.25 (2H, m) 2.37 (1H, brd disapeared with D ₂ 0) 2.83 (1H, dd, J=13.7, 8.6 Hz) 3.15 (1H, dd, J=13.4, 3.7Hz) 3.5~3.85 (1H, m) 5.09 (1H, br t, J=7.1Hz) 7.15~7.5 (5H, m) MS (m/e) 236 (M ⁺ ), 123 (100%) Optical purity 96% ee (MTPA esterification method) (Effects of the invention) The sulfide derivative of the present invention is useful as an optically active substance for pharmaceuticals, agricultural chemicals, physiologically active substances, and ferroelectric liquid crystals. It is important as an intermediate for obtaining materials, and because of its particularly high optical purity, it is excellent as a raw material for synthesizing high-purity optically active substances.

Claims (1)

[Claims] 1. A sulfide derivative represented by the following formula () (However, in the above formula (), R ¹ is a hydrogen atom,
Each represents an atom or group selected from straight-chain alkyl, branched alkyl, alkenyl, and aralkyl having 1 to 22 carbon atoms, and pH represents a phenyl group). or in the presence of a monovalent copper compound catalyst, R ² M (R ² represents the same group as R ¹ in formula () excluding the hydrogen atom, M represents an alkali metal or alkaline earth metal) and R ² MgX( ^R2
represents the same group as R ¹ excluding the hydrogen atom in formula (), and X represents a halogen atom), and then reacts with thiophenol. manufacturing method. 2. The production method according to claim 1, wherein epichlorohydrin and the sulfide derivative are each optically active substances.