JPS62158250A - Separation of optically active glycerol derivative - Google Patents

Abstract

PURPOSE:To separate an optically active glycerol derivative into epoxy compound and ester compound, by treating a mixture of an optically active ester compound and an optically active alcohol compound with a base and distilling the treated product. CONSTITUTION:A mixture of an optically active ester compound of formula I (X is halogen; R is 1-8C aliphatic hydrocarbon group; R' is aromatic hydrocarbon group) and an optically active alcohol compound of formula II is added with an alkaline aqueous solution and maintained at 10-18pH to effect the base treatment. The alcohol compound of formula II is selectively converted to the optically active epoxy compound of formula III to obtain a mixture of the compounds of formula I and formula III. The epoxy compound of formula III is separated from the mixture by distillation and the ester compound of formula I is separated from the distillation residue. USE:Starting raw material for l-carnitine, (S)-beta-blocker, insect pheromone, etc.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula 1" (wherein, ) (in the formula, X,
A mixture of optically active alcohols 2 represented by (R is the same as above) is treated under basic conditions to selectively convert alcohol 2 to optically active epoxys r represented by the general formula and The present invention relates to a method for separating optically active glycerol derivatives, which is characterized by separating the epoxy residue by distillation from a mixture of the ester ↓ and the epoxy compound r, and then collecting the ester from the residue. Esther (
This is an effective method for separating alcohol and ester forms after asymmetric (asymmetric) hydrolysis.

The ester ↓ was reacted with Alcolade, and both were l-lunitine and (S)-β-blocker.
1. It is an extremely versatile compound that can be used as a starting material for insect pheromone, etc.

[Conventional technology and problems]

The present inventors have already filed Japanese Patent Application No. 60-18881 and No. 60-18881.
No. 51188, using (R,S)-1 as a substrate, a lipase having stereoselectivity is activated to selectively hydrolyze the (S) form, thereby producing an optically active unreacted ester form [(R)- 1] and ice-melting alcohol [(S)-mi)
It has been revealed that it can be collected. However, 1,2
Both are lipophilic and difficult to completely separate using organic solvents alone, so silica gel column chromatography has been used for separation and purification. 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, Japanese Patent Application No. 60-18881 and No. 60-5818
Citing No. 8, an example is shown below.

Mixture (conventional separation method) Isolation of (R)-1 and (S)-1 Silica gel column chromatography separation (new separation method) Mixture or basic treatment (R)-1 and (S)-1 (mother) -↓, (S)-See Isolation Distillation separation [Means and effects for solving the problem] We have been conducting studies to establish a simple separation method between the ester form and the coal form. As a result, the ester form is stable even under strongly basic conditions of pH 12 or higher, while the alcohol form is easily rx under basic conditions of pH 11 or higher. Upon application, a mixture containing 1 and 8 is obtained.

By the way, the product obtained by separation can be easily converted to 8 by reacting it with alcoholade, and furthermore, highly pure 8 can be obtained by distillation.

The present invention will be explained in detail below.

Examples of combinations include the following.

Examples of X include halogen groups such as chlorine and bromine.

Examples of R include a C1 to C8 aliphatic hydrocarbon group. Examples of R include aromatic hydrocarbon groups such as tolyl, phenyl, and naphthyl.

As shown in the optically active alcohol and the general formula %, when lipase is extracted with a hydrophobic organic solvent such as methylene chloride after asymmetric deicing, approximately equimolar amounts of the ester [(R )−↓] and alcohol [(S)−
4] is obtained. The reverse combination, ie, a mixture of the ester [(S)-↓] and the alcohol [(R)-23], can also be subjected to the reaction.

These extracts can be used as they are in the next reaction. For example, in the methylene chloride extract obtained above, N
An aqueous alkaline solution such as aOH or Ca(OH)2 is added in excess (approximately 1.1 to 8.0 times the molar equivalent) relative to the alcohol content. At this time, make sure that the pH does not become too high.
It is gradually added dropwise to maintain the range of 10 to 13, preferably around 12. The same method may be used when the organic solvent is distilled off and a solvent-free concentrate is used.

The reaction temperature can range from room temperature to the boiling point of the solvent. The end point of the reaction was determined by high performance liquid chromatography (I
(PLC), thin layer chromatography (TLC), (
It can be easily determined by the disappearance of the grass peak in analysis using Uv or 12 detection).

After the reaction, the organic solvent layer is dehydrated with sodium sulfate, etc., and then distilled under reduced pressure to collect the distilled fraction of epoxy compound 8. On the other hand, the residue in the pot is washed with an aqueous NaOH solution, dehydrated with sodium sulfate, concentrated under reduced pressure, and crystallized using an appropriate mixed solvent such as ethyl acetate, ether, hexane, etc. to obtain a highly pure ester ↓ is obtained. Furthermore, instead of using an alkaline solution, the epoxy compound can be selectively converted into an epoxy compound in the same manner by treating it with a basic compound in an organic solvent.

Examples of organic solvents include benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, methylene chloride, chloroform, hexane, ethyl acetate, and DMF.
Solvents such as can be used. However, it is preferable to use a solvent whose boiling point is significantly different from that of the epoxy substance 8. The basic compound is selected from metal salts of alcohols, amines, and inorganic bases, and these may be added in an amount of 1.1 to 2.0 times the theoretical molar amount. The reaction is carried out at a temperature ranging from -80°C to the boiling point of the solvent used. Post-treatment after the reaction may be carried out in accordance with the method for alkaline solution treatment.

[Examples] The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these Examples.

(Reference Example 1) Asymmetric ice-melting substrate (R, 5) by lipase
-8-Chloro-2-acetoxypropyl-p-toluenesulfonate 1a1 Pseudo
commercially available lipase originating from Monas aerugin-OSa [Amano PJ (manufactured by Ohno Pharmaceutical Co., Ltd.) 0.8f and water 1
Asymmetric ice thawing is performed on the reaction solution containing 50°C while maintaining the pH at 7.2 with a 5N-NaOH aqueous solution at a temperature of 40°C. 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)-8-chloro-2-acetoxypropyl-p-toluenesulfonate 1a1 and (S)
A methylene chloride solution containing -8-chloro-2-hydroxypropyl-p'-toluenesulfonate 2a is obtained.

(Reference Example 2) (R,5)-8-chloro-2-~butanoyloxyprobyl-p-)luenesulfonate 1 instead of substrate 1a1
a2 According to Reference Example 1, (R)-1a2 and (S)-2a are -
A methylene chloride solution containing approximately equimolar amounts was prepared.

Example 1 (R)-ester lal and (S) obtained in Reference Example 1
-Alcohol 2a 100 πl of water is added to 800 ml of a methylene chloride solution containing about 0.06 mol of each alcohol, and while maintaining the temperature at 80°C, a 5N-NaOH aqueous solution is added dropwise with strong stirring. Adjust the dropping of the alkaline solution so that the pH is 12.0.

The reaction completely disappeared in about 4 hours when the peak of (S)-2a in the methylene chloride layer was followed by HPLC.

Methylene chloride J? After dehydrating IA with sodium sulfate, (S
)-chloromethyloxiraneography (GC), it was determined to be 8.981 (0
, 0425 mol, reaction production rate 85%). Furthermore, 2.54 IC of syrup of (S)-8a was obtained by distillation under reduced pressure.
55% of the theoretical yield) was recovered.

]16+82.8° (c=2.0.methanol) Literature value; Y, Kawakami et al.
Journal of Organic Chemistry
try (Journal of Organic Chemistry), 47.8581-8585 (1982), (
R) -8a α] -82,8~ D (c=2.0.methanol), estimated optical purity from specific optical rotation value 100% e, e, , 1HNMR (90M)
h, CDC15) a (ppm): 2.8
(2H.

d, -CH2CjI), 1118(LH,m, -CH
-).

8.6 (2H, d, -CH2-) On the other hand, the residue in the pot was washed twice with 100 g of 1N-NaOH aqueous solution, dissolved once in 50 g of ether, and 200 g of hexane was added, (R)- 10.7 N (70% of theoretical yield) of 1 at white powder was obtained.

mp41-42℃, [α) 8.7 (c=2.0
.

chloroform), 'HNMR (90M output, CDCl8)
δ (ppm): 2.44 (8H,s, CH8-Ar).

2.98 (IH, broad, OH), 8.5
0-4.12 (5H1m, CH2CH(OH)CH2
), 7.80.

7.75 (each 2H, 2d, J=8.7H
zzAr-H) optically active column (ChiralCEL
The optical purity was determined by HPLC using QC and JASCO Corporation (manufactured by M) and was 99% e.

Example 2 (R)-ester 1a2 and (S) obtained in Reference Example 2
-7/I/: I-/L/23 Using 800 tsl' of methylene chloride solution containing approximately 0.05 mole each, Example 1
It was prepared according to.

(S)-Chloromethyloxirane (8a)"=48% of theoretical yield [α1"+82.5° (c=2.0.methanol).

D 99%e, e.

(R)-8-chloro-2-butanoyloxyprovir-p
-) Luenesulfonate (1a2); theoretical yield of 7
8%, shape syrup 1. ．． 12G-6,6° (c=2
．． 0°chloroform), 'HNMR (90M ratio, CDC
1g) δ (ppm): 0.98 (8H, t,
J=6.8H! .

CH3CH2CH2-), 1.45-1.78
(2H, m.

CH3CH2CH2-), 2.26 (2H, t
, J=7.8 ratio, CH8CH2CH2-), 2.48
(8H, s.

CHs Ar), 8-58 (2H, d-J
~6.7'a.

CH2) , 4.92 5.20 (IH, m,
CH).

7.81.7.74 (4H, 2d, J ~8.7
) h, Ar-H) Example 8 (R)-ester la1 obtained in Reference Example 1 and (S)-
A methylene chloride solution containing approximately 0.06 mol of each alcohol is concentrated under reduced pressure, and the methylene chloride is distilled off to obtain a concentrate. Next, reaction and distillation separation operations were performed according to Example 1.

(S)-Chloromethyloxirane (8a) +52% of theoretical yield, (al +82.8' (c=2.0
, methanol), 100% e, e.

(R)-ゝ8-chloro-2-acetoxypropyl-p-
Toluenesulfone) (lat)i 74% of theoretical yield.

[α] -8,7 (c ~2.0.chloroform),
Example 4 In NaH (0.05 mol) suspended in 50 ml of benzene, (R)-ester lal and (51-alcohol 2
a. A benzene (Sowt) solution of a mixture consisting of about 0.05 mol each is added dropwise with stirring. The reaction is HPLC.

Follow up with GC and TLC. After reacting at room temperature for 12 hours, only the (S)-alcohol core disappeared on HPLC and TLC, and a peak associated with (S)-chloromethyloxirane was observed on GC (GC yield 90%).

The reaction was stopped by adding water under water cooling, washed with water, dried, and dried under reduced pressure (first ~10 mmHg - then <1 mHg).
mHg) The mixture of benzene and 8a was distilled off and then rectified to yield 2.7'1 (60%) of (S)-chloromethyloxirane 8a. tα]” =+ a 2
．． 8° (c=2.0°~
D methanol). On the other hand, the residue was treated in the same manner as in Example 1,
9.66 (68%) of (R)-ester la1 was obtained as a white powder. [α]”=-8,4° (c=~
D2,0,CHC#,”).

Example 5-10 The results of base treatment in an organic solvent in the same manner as in Example 4 are shown.

Note: THF stands for tetrahydrofuran and tBuOK stands for potassium butoxide.

Patent applicant Makoto Asano, agent of Kanebuchi Chemical Industry Co., Ltd. - Procedural amendment (
March 1985 t) Day 1985 x'Irt'4 Request g298481 No. 2
, Title of the invention: 尤翿二＜+1 くふ t 郎 １４C
Ai's 1°3 Mr. 7 Rigana Naturalized 2-1 Nakanoshima 3-chome, Kita-ku, Osaka π1 INt (Name) (ON> Kanebuchi Chemical Industry [Shishikaihi Representative: Masato Niino 4, Agent Name (693 Patent Attorneys) Makoto Asano-5, Date of amendment order (1) Page 14 of the specification, line 6 “Chloroform”
” and MHNMRJO, insert the following sentence.

rlHNMR (90MHz, CDCJ'l) δ(p
pm): 2.01 (8H, s, CH3C0-), 2.
45 (3H.

s,' CH3-Ar-), 3.61 (2H,
d.

-CH2-), 4.20 (2H, d, -CH2-).

4.93-5.18 (IH, m, -CH-),
7.33°7.75 (each 2H, d, Ar-H
) Take 8.06 g of the obtained (R1-1al),
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 d of saturated sodium bicarbonate water, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain a syrup-like (R )-1-chloro-
2-hydroxypropyl-p-toluenesulfone)2
a20' (α] +4.2 (c=2.0.chloroform).
(2) Same page 14, line 10 reach 2H, 2d, J=8.7HzJ as “ea
ch2H, d, J = 8.7 yen”.

(3) On page 14, line 11, "optically active column" is corrected to "optically active column using this 2a."

Claims (5)

[Claims] (1) General formula■^* ▲Mathematical formulas, chemical formulas, tables, etc.▼...■^* (In the formula, X is a halogen group, R is an aliphatic hydrocarbon group of C_1 to C_8, and R is an aromatic carbonized An optically active ester compound represented by the hydrogen group ■^* and the general formula ■^
* ▲There are mathematical formulas, chemical formulas, tables, etc.▼...■^* (In the formula, X and R are the same as above) A mixture of optically active alcohols ■^* represented by is treated under basic conditions. , an optically active epoxy compound represented by the general formula ■^* ▲Mathematical formulas, chemical formulas, tables, etc.▼...■ (wherein, X is the same as above) The epoxy body ■^* is fractionated by distillation from the resulting mixture of the ester body ■^* and the epoxy body ■^*, and then the ester body ■^* is collected from the residue. Method for separating optically active glycerol derivatives. (2) The optically active ester body ■^* is (R)-■, and the optically active alcohol body ■^* and epoxy body ■^*
The separation method according to claim 1, wherein is (S)-■ or (S)-■. (3) The separation method according to claim 1, wherein X is chlorine and R is a tolyl group. (4) The separation 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 18. Method. (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 nonaqueous solvent.