JPH0429657B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing optically active (S)-3-halogeno-2-methylpropanol useful for stereoselective organic synthesis. Optically active 3-halogeno-2-methylpropanol, particularly (S)-3-halogeno-2-methylpropanol, has recently attracted attention as a raw material for the synthesis of optically active useful substances. For example, the synthesis of the optically active side chain of natural vitamin E
74623, Journal of Organic Chemistry, Vol. 41, No. 22 (1976), pp. 3505 et seq.), and
It is also useful in the synthesis of phenothiazine drugs (such as levomepromazine) having optically active side chains. Conventionally, as a method for synthesizing optically active 3-halogeno-2-methylpropanol, the (R) form of 3-halogeno-
For 2-methylpropanol, (RS)-3-
A method (formula 1) obtained by reducing (R)-3-chloro-2-methylpropanoic acid obtained by optical resolution of halogeno-2-methylpropanoic acid is known (Japanese Patent Application Laid-open No. 74623/1983). . On the other hand, as an example of the synthesis of (S)-3-halogeno-2-methylpropanol derivatives, a multi-step process as shown in formula (2) is carried out using (S)-3-hydroxy-2-methylpropanoic acid as a raw material. (Journal of Organic Chemistry, Vol. 41, No. 22 (1976), p. 3505 et seq.) (R: protecting group, X: halogen) The present inventors have discovered a more efficient and economical (S)
The present inventors investigated a new method for synthesizing -3-halogeno-2-methylpropanol, discovered an improved production method shown in Formula 3, and completed the present invention. (R: _C1 - _C4 alkyl group, X: halogen) (That is, the present invention

[Formula] (R is H or a C ₁ to C ₄ lower alkyl group) (R)-3-hydroxy-2-methylpropanoic acid or its ester is halogenated and then reduced. The present invention relates to a method for producing (S)-3-halogeno-2-methylpropanol. Compared to the conventional method starting from (S)-3-hydroxy-2-methylpropanoic acid, this method does not require the introduction of protecting groups for hydroxyl or carboxyl groups, and achieves the desired goal in just two reaction steps. (S)-3-halogeno-2-methylpropanol can be easily obtained. Optically active (R)-3 which is the starting material of the present invention
-Hydroxy-2-methylpropanoic acid can be easily obtained with good optical purity by stereoselective β-hydroxylation of isobutyric acid by microorganisms as proposed by the present applicant (Japanese Patent Laid-Open No. 56-68394). It can also be easily obtained by esterifying (R)-3-hydroxy-2-methylpropanoic acid with alcohol. As the ester of (R)-3-hydroxy-2-methylpropanoic acid, methyl ester, ethyl ester, n-propyl ester, iSO-propyl ester, n-butyl ester, t-butyl ester, etc. can be applied to this reaction. . The halogenation of (R)-3-hydroxy-2-methylpropanoic acid or its ester is thionyl chloride, phosphorus trichloride, phosphorus pentachloride, triphenylphosphine-carbon tetrachloride, triphenylphosphine-N-chloro When succinimide is used, it is chlorinated, and hydrobromic acid, phosphorus tribromide, triphenylphosphine-bromine, triphenylphosphine-
Bromination can be achieved using N-bromosuccinimide, triphenylphosphine-carbon tetrabromide, or the like. Next, the above (S)-3-halogeno-2-methylpropanoic acid or its ester is reduced, but at this time, the halogen is not reduced and only the carboxylic acid group or ester group is selectively converted to alcohol. It is necessary to choose a method to reduce Reducing agents for this include combinations of Lewis acid catalysts with _NaBH4 , e.g. _NaBH4-
A reducing agent for BF ₃ , LiAlH ₄ , diisobutylaluminum hydride, etc. can be used. The reduction proceeds efficiently when the amount of these reducing agents used is from about 1 molar to 2 times the molar amount of the reaction substrate. The reaction temperature can be selected from mild conditions from -50°C to 50°C. As the solvent, solvents such as tetrahydrocran, dioxane, ethyl ether, toluene, hexane, etc. can be used. After the reaction, the solvent is distilled off, water or an aqueous ammonium chloride solution is added under cooling, and then the target product is extracted with an organic solvent such as ether or ethyl acetate. The extraction solvent is distilled off, and the objective (S)-3-halogeno-2-methylpropanol can be obtained in pure form by distillation. According to the present invention, the configuration of the starting material (R)-3-hydroxy-2-methylpropanoic acid or its ester is maintained, and the target (S)-3-halogeno-2-methylpropanol can be efficiently and economically produced. can be obtained. Also, the ester group is NaBH ₄ −
Another new and improved point is that the hydroxyl group can be converted to a hydroxyl group in good yield using a reducing agent containing a combination of Lewis acids. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 10.4 g of (R)-3-hydroxy-2-methylpropanoic acid was mixed with 24.0 g of thionyl chloride and 0.1 g of imidazole.
g of the mixed solution, and then heated and stirred at 70° C. for 5 hours. Excess thionyl chloride was distilled off under reduced pressure, and 50 ml of water was added to the remaining reaction solution under cooling, followed by stirring for 5 hours. Next, methylene chloride was added for extraction, and after the methylene chloride was distilled off, the mixture was distilled under reduced pressure to obtain 11.0 g of (S)-3-chloro-2-methylpropanoic acid. Boiling point: 91-92℃/9mmHg [α] ²⁵ _D = -13.9゜ (C = 2, MeOH) 6.1g of this (S)-3-chloro-2-methylpropanoic acid and 1.9g of NaBH ₄ were added to 50ml of tetrahydrofuran.
10 ml of a tetrahydrofuran solution containing 8.5 g of BF ₃ -etherate was mixed with the mixture and stirred at room temperature.
was dripped. Then, after stirring for 3 hours, tetrahydrofuran was distilled off under reduced pressure, and the reaction product was added to ice water.
Ethyl ether was added for extraction. After ethyl ether was distilled off, the residue was distilled under reduced pressure to obtain 4.1 g of (S)-3-chloro-2-methylpropanol having a boiling point of 75° C./25 mmHg. [α] ²⁵ _D = 13.6° (C = 5, MeOH) Example 2 (S)-3-chloro-2-methylpropanoic acid synthesized in the same manner as in Example 1 was added in the presence of a catalytic amount of H ₂ SO ₄ . By heating in methanol, 63℃/
(S)-3-chloro-2- with a boiling point of 30 mmHg
Methylpropanoic acid methyl ester {[α] ²⁵ _D = −
16.7° (C=1, MeOH)} was obtained in a yield of 90 mol%. 13.7 g of this (S)-3-chloro-2-methylpropanoic acid methyl ester and 3.8 g of NaBH ₄ were mixed in 100 ml of tetrahydrofuran, and then the reaction temperature was increased.
While maintaining the temperature below 35° C., 20 ml of tetrahydrofuran containing 17 g of BF ₃ -etherate was added dropwise. After the dropwise addition, stirring was continued for 5 hours, and then, after distilling off tetrahydrofuran, the reaction product was added to ice water, and then extracted with ethyl ether. By distilling under reduced pressure, 8.1 g of (S)-3-chloro-2-methylpropanol having a boiling point of 75° C./25 mmHg was obtained. [α] ²⁵ _D = 13.6° (C = 5, MeOH) Example 3 10.4 g of (R)-3-hydroxy-2-methylpropanoic acid, 24.0 g of thionyl chloride, and 0.1 g of imidazole
g, and then heated and stirred at 70°C for 5 hours. Excess thionyl chloride was distilled off under reduced pressure, and 30 ml of methanol was added to the remaining reaction solution under cooling, followed by continued stirring. After removing excess methanol, the residue was distilled under reduced pressure to obtain 12.3 g of (S)-3-chloro-2-methylpropanoic acid methyl ester having a boiling point of 63° C./30 mmHg. 6.9 g of this (S)-3-chloro-2-methylpropanoic acid methyl ester was dissolved in 30 ml of toluene, and 30 ml of a toluene solution containing twice the equivalent of diisobutylaluminum hydride was added dropwise at -50°C. After the dropwise addition, the temperature was raised to room temperature and stirring was continued for 5 hours. Then, 10 ml of methanol and aqueous ammonium chloride were added under cooling. After stirring, the toluene layer was separated, the toluene was distilled off, and the mixture was distilled under reduced pressure.
(S)-3-chloro- with a boiling point of °C/25 mmHg
3.6 g of 2-methylpropanol was obtained. Example 4 (R)-3-hydroxy- obtained by heating (R)-3-hydroxy-2-methylpropanoic acid in methanol in the presence of a catalytic amount of H ₂ SO ₄
2-methylpropanoic acid methyl ester {b・p:
64~66℃/4mmHg, [α] ²⁵ _D = -26.3° (C = 2,
MeOH)} 11.8g and triphenylphosphine 29.5g
g was dissolved in 70 ml of methylene chloride, and 20 g of N-bromosuccinimide was added while maintaining the reaction temperature below 35°C. Then, after stirring at room temperature for 3 hours,
The solvent was evaporated, filtered and the mother liquor was distilled. boiling point
14.4 g of (S)-3-bromo-2-methylpropanoic acid methyl ester at 64-66°C/18 mmHg was obtained. {[α] ²⁵ _D = -19.6° (C = 5.MeBH)} Using 9.0 g of this (S)-3-bromo-2-methylpropanoic acid methyl ester, it was prepared in a tetrahydrofuran solvent in the same manner as in Example 2. NaBH ₄ −BF ₃
Reduction was carried out with an etherate reducing agent. After the reaction, tetrahydrofuran was distilled off, the reaction product was added to ice water, extracted with ethyl ether, and distilled under reduced pressure to obtain 5.5 g of (S)-3-bromo-2-
Methylpropanol was obtained. b・p: 72℃/15mmHg [α] ²⁵ _D = 11.4゜ (C=4, MeOH) Example 5 10.4g of (R)-3-hydroxy-2-methylpropanoic acid was added to triphenylphosphine in acetonitrile. 40 with 29.5g and 33.1g of carbon tetrabromide reactants
Stirring was continued for 8 hours at °C. After the reaction, the solvent was distilled off _, water was added to the reaction mixture under cooling, and after stirring for ₃ hours, it was extracted with ethyl ether. Then, a reduction reaction was carried out in the same manner as in Example 1. After the reaction, (S)-3-bromo-2-methylpropanol having a boiling point of 72°C/15mmHg was distilled under reduced pressure in the same manner as in Example 1.
Obtained 9.0g. [α] ²⁵ _D = 11.5゜ (C = 4, MeOH)

Claims (1)

[Claims] 1 (R)-3-hydroxy-2-methylpropanoic acid or (R)- represented by the general formula [Formula] (R represents H or a C ₁ to C ₄ lower alkyl group) (S)-3-, which is characterized by halogenating an ester of 3-hydroxy-2-methylpropanoic acid and then reducing it, represented by the general formula [Formula] (X represents a halogen)
Method for producing halogeno-2-methylpropanol. 2. The method of claim 1, wherein X is bromine. 3. The method according to claim 1, wherein X is chlorine.