JPH0566940B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to general formulas 1 to ^*

[Formula] (In the formula, X represents a halogen group, R represents a C ₁ to C ₈ aliphatic hydrocarbon group, and R' represents an aromatic hydrocarbon group)
Optically active esters 1~ ^* and general formula 2~ ^* represented by

[Formula] ( ^{wherein ,} ~ ^*

[Conventional technology and problems]

The present inventors have already filed Japanese Patent Application No. 60-18881,
No. 53188, using (R,S)-1 as a substrate,
Applying lipase having stereoselectivity, (S)
It has been revealed that the unreacted ester form [(R)-1~] and the hydrolyzate alcohol form [(S)-2~], which are optically active forms, can be collected by selectively hydrolyzing the body. However, since both 1- and 2- are lipophilic, it is difficult to completely separate them using only organic solvents, and separation and purification has been performed using silica gel column chromatography. However, this separation method is unsuitable for industrial-scale production, and there has been a desire to develop a simple method for separating the ester and alcohol forms. Specifically, referring to Japanese Patent Application Nos. 60-13881 and 60-53188, an example is shown as follows.

【table】
~

as well as

【table】
(R)−3

~
[Means and effects for solving the problem] The present inventors

【formula】 An ester body represented by

Studies have been carried out to establish a simple separation method for the alcohol compound represented by the formula. As a result, the ester form is stable even under strong basic conditions with a pH of 12 or higher, while the alcohol form is easily stabilized under basic conditions with a pH of 11 or higher.

It was found that the compound was converted into an epoxy compound represented by the following formula. Therefore, when a mixture of 1- ^* and 2- ^* is treated with a base, a mixture containing 1- ^* and 3- ^* is obtained. When this mixture is distilled, only 3~ ^* are recovered,
Furthermore, it was found that 1 to ^* could be recovered from the residue. Note that 1- ^* obtained by separation can be easily converted to 3- ^* by reacting with an alcoholate, and further, highly purified 3- ^* can be obtained by distillation. The present invention will be explained in detail below. general formula

Examples of the combinations of substituents X, R, and R' of the optically active esters 1 to ^* represented by the formula are as follows. Examples of X include halogen groups such as chlorine and bromine. Examples of R include a _C1 to _C3 aliphatic hydrocarbon group. R′ is, for example, tolyl, phenyl,
Examples include aromatic hydrocarbon groups such as naphthyl. general formula An optically active alcohol represented by 2~ ^* or the general formula

〔Example〕

The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples. (Reference example 1) Asymmetric hydrolysis by lipase Substrate (R,S)-3-chloro-2-acetoxypropyl-p-toluenesulfonate 1 to a ₁

[Formula] 30.7g, Pseudomonas aeruginosa
A reaction solution containing 0.3 g of commercially available lipase "Amano P" (manufactured by Amano Pharmaceutical Co., Ltd.) originating from osa) and 150 ml of water was heated at a temperature of 40 ml.
°C, while maintaining the pH at 7.2 with a 5N-NaOH aqueous solution.
Perform asymmetric hydrolysis. The reaction was completed in about 4 hours, and after cooling, extraction was performed twice with 150 ml of methylene chloride.
When the methylene chloride layer is dehydrated with sodium sulfate,
(R)-3-chloro-2-acetoxypropyl-p
-Toluenesulfonate 1- _{a 1} and (S)-3-chloro-2-hydroxypropyl-p-toluenesulfonate 2-a

A methylene chloride solution containing approximately equimolar amounts of [Formula] is obtained. (Reference Example 2) (R,S)-3-chloro-2 instead of substrate 1-a ₁
-butanoyloxypropyl-p-toluenesulfonate 1-a ₂

A methylene chloride solution containing approximately equimolar amounts of (R)-1 to _{a 2} and (S)-2 to a was prepared according to Reference Example 1 except that 33.5 g of the formula was used. Example 1 100 ml of water was added to 800 ml of methylene chloride solution containing about 0.05 mol each of (R)-esters 1 to _{a 1} and (S)-alcohols 2 to a obtained in Reference Example 1, and the mixture was kept at 80°C.
Add the 5N-NaOH aqueous solution dropwise while stirring vigorously. Adjust the dropping of alkaline solution so that the pH is 12.0. The reaction was carried out using HPLC with (S)-2~a in the methylene chloride layer.
When the peak was traced, it completely disappeared in about 4 hours. After dehydrating the methylene chloride layer with sodium sulfate,
(S)-chloromethyloxirane

When the content of [Formula] was measured by gas chromatography (GC), it was found to be 3.93g.
(0.0425 mol, reaction production rate 85%).
Further, by distillation under reduced pressure, the syrup of (S)-3~a 2.54
g (55% of theoretical yield) was recovered. [a] ¹⁵ _D +32.8° (c = 2.0, methanol) Literature value; Y. Kawakami et al., Journal of
Organic Chemistry, 47 , 3581-3585
(1982), (R) −3~a; [a] ¹⁵ _D −32.8° (c
=
2.0, methanol) Estimated optical purity 100%ee from the specific optical rotation value, ^1H NMR (90MHz, CDCl ₃ )
δ (ppm): 2.8 (2H, d-CH ₂ Cl), 3.8 (1H, m,
-CH-), 3.6 (2H, d, -CH ₂ -)
Wash twice with water, dissolve in 50 ml of ether, and then dissolve in hexane.
When adding 200ml, (R)-1 ~ a ₁ white powder 10.7
g (70% of the theoretical yield) was obtained. mp 41-42℃, [a] ^20D _- 8.7° (c=2.0, chloroform), ^1H NMR (90MHz, _CDCl3 ) δ (ppm): 2.01
(3H, s, CH ₃ CO−), 2.45 (3H, s, CH ₃ −Ar
−), 3.61 (2H, d, −CH ₂ −), 4.20 (2H, d, −
CH ₂ −), 4.93−5.18 (1H, m, −CH−), 7.33,
7.75 (each 2H, d, Ar-H) Take 3.06g of the obtained (R)-1~ _a1 ,
After refluxing in methanol for 5 hours, it was concentrated under reduced pressure. To this concentrate was added 50 ml of methylene chloride, washed twice with 50 ml of saturated sodium bicarbonate water, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain a syrup-like (R )-3-chloro-2-hydroxypropyl-p
-Toluenesulfonate 2-a

[Formula] 2.10g was obtained. [a] ²⁰ _D +4.2° (c=2.0, chloroform). ^1H
NMR (90MHz, CDCl ₃ ) δ (ppm): 2.44 (3H, s,
_CH3 -Ar), 2.98 (1H, broad, OH), 3.50-4.32
(5H, m _, -CH2CH (OH) CH2- ) _, 7.30,
7.75 (each2H, d, J = 8.7Hz, Ar-H) Using this 2a, optically active column (Chiral CEL
The optical purity was determined by HPLC using OC (manufactured by Nihonko Co., Ltd.) and was 99% e,e or higher. Example 2 Prepared according to Example 1 using 300 ml of methylene chloride solution containing about 0.05 mol each of (R)-esters 1 to _{a 2} and (S)-alcohols 2 to a obtained in Reference Example 2. I went to (S)-Chloromethyloxirane (3-a); 4.3% of theoretical yield [a] ¹⁵ _D +32.5° (c = 2.0, methanol), 99% e, e. (R)-3-chloro-2 -butanoyloxypropyl-p-toluenesulfonate (1~ _a2 ); 78% of theoretical yield, shape syrup, [a] ²⁰ _D -6.6° (c=
2.0, chloroform), ^1H NMR (90MHz, CDCl ₃ )
δ (ppm): 0.93 (3H, t, J = 6.3Hz, CH ₃ CH _2
CH2- ), 1.45-1.78( _{2H ,} m , _CH3CH2CH2
-), 2.26 (2H, t, J = 7.3Hz, CH ₃ CH ₂ CH ₂
−), 2.43 (3H, s, CH ₃ −Ar), 3.58 (2H, d,
J = 5.7Hz, -CH ₂ -), 4.92-5.20 (1H, m, -CH
-), 7.31, 7.74 (4H, 2d, J = 8.7Hz, Ar-H) Example 3 (R)-esters 1 to _{a 1} and (S)-alcohols 2 to a obtained in Reference Example 1, respectively A methylene chloride solution containing 0.05 mol is concentrated under reduced pressure, and methylene chloride is distilled off to obtain a concentrate. Next, reaction and distillation separation operations were performed according to Example 1. (S)-Chloromethyloxirane (3-a); 52% of theoretical yield, [a] ¹⁵ _D +32.8° (c = 2.0, methanol), 100% ee (R)-3-chloro-2- Acetoxypropyl-p-toluenesulfonate (1-a ₁ ); 74% of theoretical yield, [a] ²⁰ _D -8.7° (c = 2.0, chloroform)
,
99% ee or more Example 4 NaH (0.05 mol) suspended in 50 ml of benzene
, (R)-ester 1~a and (S)-alcohol 2~
a, benzene (50
ml) solution dropwise while stirring. The reaction was performed using HPLC, GC,
Track with TLC. When reacted at room temperature for 12 hours,
Only (S)-alcohol 2~ _{a 1} disappeared by HPLC and TLC, and (S)-chloromethyloxirane 3~a by GC.
peak was observed (GC yield 90%). below freezing,
The reaction was stopped by adding water, washed with water, dried, and the mixture of benzene and 3-a was distilled off under reduced pressure (first ~10 mmHg, then <1 mmHg), then rectified, and 2.77 g
(60%) of (S)-chloromethyloxirane 3-a was obtained. [a] ¹⁵ _D = +32.8° (c = 2.0, methanol). On the other hand, the residue was treated in the same manner as in Example 1 to obtain 9.65 g (63%) of (R)-ester 1-a ₁ as a white powder. [a] ²⁰ _D = -8.4° (c = 2.0,
_CHCl3 ). Example 5-10 The results of base treatment in an organic solvent in the same manner as in Example 4 are shown.

【table】

[Table] Shows ium butoxide.

Claims (1)

[Claims] 1 General formula 1~ ^* [Formula] (wherein, X is a halogen group, R is a C ₁ to _{C 3} aliphatic hydrocarbon group, and R' is an aromatic hydrocarbon group) A mixture of the optically active ester 1- ^* represented by the formula 2-* and the optically active alcohol 2- ^* represented by the general formula 2- ^* [formula] (wherein X and R' are the same as above) was prepared under basic conditions. to selectively convert the alcohol 2- ^* into the optically active epoxy 3- ^* represented by the general formula 3- ^* [Formula] (wherein, X is the same as above),
An optically active glycerol derivative characterized in that epoxy bodies 3- ^{* are fractionated by distillation from the resulting mixture of ester bodies 1-* and epoxy bodies 3-* , and} then ester bodies 1- ^* are collected from the residue. separation method. 2. A patent in which the optically active esters 1~ ^* are (R)-1~, and the optically active alcohols 2~ ^* and epoxy bodies 3~ ^* are (S)-2~, (S)-3~ A separation method according to claim 1. 3. The separation method according to claim 1, wherein X is chlorine and R' is a tolyl group. 4. The separation method according to any one of claims 1 to 3, wherein the treatment under basic conditions is performed by adding an alkaline aqueous solution to the mixture and maintaining the pH in the range of 10 to 13. 5. The separation method according to any one of claims 1 to 3, wherein the treatment under basic conditions is performed with a basic compound in a non-aqueous solvent.