JPS62209049A - Extraction and separation of optically active glycerol derivative - Google Patents

Abstract

PURPOSE:To extract and separate the titled compound, by adding an aqueous solution of trimethylamine hydrochloride to a mixture containing an optically active ester and halogenomethyloxirane under specific condition, selectively converting only one thereof into an alcohol derivative and extracting and separating the titled compound with a hydrophobic organic solvent. CONSTITUTION:An aqueous solution of trimethylamine hydrochloride is added to a mixture containing an optically active ester expressed by formula I (X is halogen; R is 1-8C aliphatic hydrocarbon; R' is aromatic hydrocarbon) and an optically active halogenmethyloxirane expressed by formula III to selectively react only the compound expressed by formula II and form a compound expressed by formula III. After completing the reaction, the compound expressed by formula I is extracted and compound expressed by formula I and the compound expressed by formula III with a hydrophobic organic solvent, e.g. methylene chloride, and the organic solvent layer is concentrated to collect the compound expressed by formula I. The other aqueous layer is then concentrated to collect the compound, expressed by formula III and useful as an important intermediate for synthesizing l-carnitine.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a method for producing C1) a synthetic intermediate of carnitine.

Since carnitine (8-hydroxy-γ-trimethylaminobutyric acid) has one asymmetric center, it exists in two types of optical isomers, the (R) and (8) forms. Cl>-Runithin is known as vitamin B'T, is widely distributed in living organisms, and is an important compound as a carrier of long-chain fatty acids.

Carnitine deficiency has traditionally been treated with (dI) lunitine, but in recent years (1) it has become clear that using only the carnitine alone is much more effective therapeutically.
) - The importance of lunithin has been attracting attention. More specifically, the present invention provides an optical compound represented by the general formula (R)-1 (wherein or a halogen group, d is an aliphatic hydrocarbon group of 01 to C8, and d is an aromatic hydrocarbon group). Active ester (R)-1 and general formula (8)
-2 (wherein, X is the same as above), an aqueous solution of trimethylamine hydrochloride is added to a mixture containing optically active halogenomethyloxirane (8) -2, and (8) -2
Optically active 8-halogeno-2 represented by general formula (8) (wherein, X is the same as above)
-Hydroxypropyltrimethylammonium chloride (8) -8 is produced, and after the reaction is completed, unreacted (R)
(R) -1 and (8) -8 are extracted and separated from a suspension containing -1 and product (8) -8 using a hydrophobic organic solvent, and the organic solvent layer is concentrated to produce (R) This invention relates to a patented method for extracting and separating guxerol derivatives, which is characterized in that -1 is collected and one water side is rm-condensed to collect (8)-8.

(8)-f3 kl: C1)-It is an important intermediate in the synthesis of lunithin, and therefore, separation of (R)-1 and (8)-2 and utilization of (8)-2-E (J)- The reason for this is that L in the final method is also used as a % dispersant for the synthesis of lunitine. In addition, (R)-1 can be induced into (J)-runithine by changing the order of addition of the reaction agents, as well as (8)-β-
It can be used separately as a starting material for blockers, insect pheromones, etc.

(Prior Art and Problems) The present inventors have already published Japanese Patent Application No. 18881/1983.
-53188, general formula (R8)-1 (wherein,
Using the ester racemate (R8)-1 represented by
An optically active unreacted ester (R)-1 and an optically active ice-melting alcohol (8)-4 represented by the general formula (8)-4 (wherein X and R are the same as above) are produced. let me,
By slow silica gel column chromatography, (R
)-1 and (8)-4 can be isolated in isolation.
are doing.

However, silica gel column chromatography has poor operability and is unsuitable as a production method on an industrial scale. Therefore, we conducted studies to establish a simple separation method for (R)-1 and (8)-4, and in Japanese Patent Application No. 60-298481, we applied alkali treatment to the mixture of (R)-1 and (8)-4. When applied, (R)-1 is stable, but (8)-4 is rapidly epoxidized and converted to (S)-2, and further converted to (R)-2.
)-1 and (8)-2 could be easily separated by distillation, and their optical purity was found to be extremely high.

However, when (R)-1 is induced into (7)-lunithine, it is not necessarily necessary to isolate (R)-1 and (8)-2 by distillation. For example, trimethylamine hydrochloride and (8)-2 react rapidly under conditions in which (8)-1 is stable, and a mixture (R)-1 and (
8) If -8 can be separated by a hydrophobic organic solvent extraction operation, the synthesis reaction from (8) -2 to lunitin can be advanced one step and at the same time separation of (R) -1 and (8) -2 can be achieved. This is possible, and the benefits are considered to be great.

Citing Japanese Patent Application Nos. 60-18881, 1988-58188, and 1982-298481, a synthetic route to lunitin using (IL8)-1 as a starting material is shown below.

(New manufacturing method) (Means and effects for solving the problems) The present inventors have developed (几)-1 and (8) for the purpose of simplifying the manufacturing process.
We investigated a method of converting (S)-2 to (8)-8 without separating -2. As a result, by using an appropriate concentration and molar ratio of trimethylamine hydrochloride aqueous solution and setting an appropriate reaction temperature and time, (R)-1 was hardly decomposed. selectively and promptly only (8)-2 without receiving (8)-
The resulting suspension containing (R)-1 and (8)-8 was extracted and separated using a hydrophobic organic solvent. ) -8 was found to be easily separated.

The present invention will be explained in detail below.

The raw material (8)-halogenomethyloxirane can be obtained by the following method.

Patent application No. 6 o-taaat, No. 60-58188, No. 60
-298481, the general formula (R8
)−1 υsuυru
-1 (in the formula, x, n, i are the same as above) using the ester racemate (R8)-1 as a substrate, (S
) is reacted with a lipase having the ability to stereoselectively hydrolyze the ice-melting product (
8)-Alcohol is produced, (R)-1 and (8)
By subjecting the mixture of -4 to an alkali treatment, it is also possible to easily separate the mixture using a black cloth.

(R,8)-1, (R)-1 and (8) of the above starting materials
) Examples of the combinations of substituents X, R, and R in -4 include the following. Examples of X include halogen groups such as chlorine and bromine. Examples of R include 01 to C8 aliphatic hydrocarbon groups. Examples of aromatic hydrocarbon groups include hatryl, phenyl, and naphthyl.

Examples of the lipase that selectively hydrolyzes the (8) body using (R8)-1 as a substrate include enzymes derived from microorganisms such as Riverze Amano P (manufactured by Amano Pharmaceutical Co., Ltd.) and Riverzemru 6;
Alternatively, enzymes derived from animal organs or microorganisms (such as Aspergillus niger) may be used.
iger) ), etc., patent application No. 18881-1981, No. 60-18881.
-58188 may be used. After hydrolysis reaction, methylene chloride, ethyl acetate, butyl acetate.

(R)-1 and (8)-4 are extracted with methyl isobutyl ketone, benzene, toluene, or xylene, and the pH is adjusted to an alkaline side with, for example, NaOH, preferably 10.
If the reaction is carried out while keeping the temperature at ~18, (8)-4 becomes (8)
-2, resulting in a mixture of (R) -1 and (8) -2. The conversion reaction may be followed by high performance liquid chromatography, thin layer chromatography, or the like. (8) −
2 can be isolated by dehydrating with sodium sulfate or the like and drying under reduced pressure.

This hydrophobic organic solvent solution containing approximately equimolar amounts of (R)-1 and (8)-2 can be directly subjected to a reaction with an aqueous trimethylamine hydrochloride solution without being concentrated.

However, the reaction rate tends to be slower than when the reaction is carried out after distilling off the hydrophobic organic solvent.

Therefore, it is highly recommended to conduct the reaction using a concentrate obtained by once distilling off the hydrophobic organic solvent, or to proceed with the reaction while distilling off the organic solvent at a temperature higher than the boiling point of the organic solvent.

Although the reaction proceeds even if the concentration of the other reaction reagent, trimethylamine hydrochloride, in the aqueous solution is low, the reaction proceeds more smoothly if the concentration is as high as possible. Considering the extraction and separation after the reaction, the concentration is 6-60% (W/
V ) range is appropriate. Further, the amount of trimethylamine hydrochloride used may be 1.0 to 2.0 times the molar amount of (8)-2.

Even if 2.0 times the mole or more is used, there is no problem with the reaction, but an excessive amount of trimethylamine hydrochloride remains in the suiseki after the reaction, making subsequent purification difficult.

The reaction temperature can be carried out in the range of 80 to 100°C, but since (R)-1 begins to decompose as the temperature increases, it is desirable to lower the temperature as much as possible, preferably in the range of 80 to 60°C. Also, regarding the reaction time, if the reaction time is too long (
Since the decomposition of R)-1 cannot be ignored, it is desirable to follow the change over time of the reaction, and upon completion of the reaction, promptly cool the reaction and perform an extraction and separation operation.

Let's take a case as an example. (R)-1a, (8)
-28 were separately reacted with an aqueous solution of trimethylamine salt Vlin.

(R)-1a (0,806,F))! J mail + le y
ton hydrochloride (0,955,9) aqueous solution (in 5 mj, 5
0℃.

When reacting for 2 hours, the decomposition rate of (R)-1a is approximately 2
~8%, and when reacted at 60°C for 2 hours, approximately 4~8%
It was 6%. On the other hand, (8)-2a (0,925,9
) with an aqueous solution (5 m/) of trimethylamine hydrochloride (0,955,f) at 50°C, approximately 9
The reaction was almost completely completed in 1 hour at a rate of 0 to 92%. Therefore, as long as the reaction is carried out at 50°C for 1 hour, (R) -1a
There is no need to disassemble it at any time.

Furthermore, in the case of a two-phase reaction between a hydrophobic organic solvent and water, although the reaction time is longer, there is an advantage that decomposition of (R)-11 can be reduced. Regarding analysis of reaction changes over time, the decomposition of (R)-1 can be monitored by high performance liquid chromatography analysis, and the consumption of (8)-2 can be monitored by gas chromatography.

After the reaction, the mixture is cooled to near room temperature and then extracted and separated using a hydrophobic organic solvent.

If an extraction operation is performed using a hydrophobic organic solvent from a suspension containing (R)-1 and (8)-8, (R)-1 and (8)
)-8 can be easily separated, for example, methylene chloride, ethyl acetate, butyl acetate, methyl isobutyl ketone, benzene, toluene, or xylene can be used as a solvent.

After extraction and separation, the organic solvent layer is concentrated under reduced pressure to collect (R)-1 with high purity. On the other hand, if the aqueous layer is concentrated, it will contain impurities such as trace amounts of decomposed products of (R)-1 and unreacted excess trimethylamine hydrochloride (8)-
8 powder is obtained. If this crude powder is further recrystallized using a solvent such as ethanol, highly pure (8)-8 can be obtained. Further, it is not necessarily necessary to purify at this stage, and the purification operation may be performed after proceeding with the next carcine synthesis reaction.

(Examples) Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.

Reference Example 1 Asymmetric ice-melting substrate by lipase・(R8)-8-chloro-2-acetoxyproeruginosa (Pseudomonas aeruginoa)
a) Originated commercially available IJpase “Amano PJ (Ohno Pharmaceutical ■
The reaction solution containing 0.8 I
℃.

Asymmetric ice thawing is performed while maintaining the pH at 7.2 with a 5N NaOH aqueous solution. The reaction is completed in about 4 hours. After cooling, 1
Two extraction operations are carried out with 50 mj of methylene chloride. When the methylene chloride layer is dehydrated with sodium sulfate, (R)-8-
A methylene chloride solution (approximately 800 m/m) containing equimolar amounts of chloro-2-acetoxypropyl p-)luenesulfone 1a and (8)-8 was obtained.

Reference Example 2 A xylene solution (approximately 800 m/m) containing approximately equimolar amounts of (R)-18 and (8)-41 was obtained by preparing according to Reference Example 1 except that xylene was used as the extraction solvent. Ta.

Reference Example 8 Instead of substrate 1a, (R8)-8-chloro-2-butanoyloxypropyl 1)-)luenesulfonate was prepared according to Reference Example 1, and (R)-1b and (8)-4
A methylene chloride solution containing approximately equimolar amounts of a (approximately 800
ml was prepared.

Reference Example 4 Selective epoxidation of (S)-ester (R)-ester 1a obtained in Reference Example 1 and (S)-
A methylene chloride solution (about 800 mj) containing about 0.06 mol of each alcohol 4a was added to about toomI! After concentrating under reduced pressure to 60ml of water! was added, kept at 80°C, and 5N NaOH aqueous solution was added dropwise while stirring vigorously.

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 (8)-4a in the methylene chloride layer was followed by HPLO. When the methylene chloride layer was dehydrated with sodium sulfate, the content was analyzed by gas chromatography (GO) and found to be 8.98.9.
There was a considerable amount.

Furthermore, under normal pressure and a bath temperature of 60°C, methylene chloride was added to the foam (
Concentrate 19.5 containing R)-11 and (8)-21
．． I got a 9.

Note that (8)-28, which corresponds to approximately 0.2 PK, was contained in the foamed methylene chloride solution;
The loss of 2a can be solved by repeatedly using the foamed methylene chloride solution in this step.

Reference Example 5 Using the xylene solution obtained in Reference Example 2, preparation was carried out according to Reference Example 4 to obtain 100me as a xylene solution containing (R)-1a and (8)-21.

Reference Example 6 Using a methylene chloride solution containing (R)-1b and (8)-4a obtained in Reference Example 8, preparation was carried out according to Reference Example 4, and (几)-1b and (8) Concentrate 20.1.9 containing -2a was obtained.

Example 1 20 m7 of an aqueous solution containing 4.7811 of trimethylamine hydrochloride was added at once to 19.5.9 of the concentrate obtained in Reference Example 4, and the reaction was carried out at 50° C. for 1 hour. (8) After confirming by GC that -28 was almost completely consumed, the reaction was terminated and cooled with water. Next, an extraction operation is performed twice with 50 m/m of methylene chloride, and the methylene chloride layer is once dehydrated with sodium sulfate and then concentrated under reduced pressure. This concentrate was combined with ether-hexane-5QmI! : Perform crystallization operation in a 50 m/system,
A white powder of (R)-11 was obtained.

mp 41-42℃, CC1]-8,7°(C-2,0
゜Chloroform).

IHNMR (90MHz, 0DO1a) δ (ppm
):2.01(8H,,8,0Hs00-),2.45
(8H,8゜0H3-Ar-)-8,61(2H,d-
-CH2-) *4.20 (2H, d, -CHg-), 4
．． 98-5.18 (IH'.

m, -0R-), 7.8B, 7.75 (eaCh 2
Hd.

(R)-1H) 8.06% of the obtained (R)-1H. F was taken and refluxed in methanol for 6 hours, then concentrated under reduced pressure.

50rnI of methylene chloride in the concentrate! was added, washed twice with 50 m of saturated sodium bicarbonate water, dehydrated with sodium sulfate, and concentrated under reduced pressure to obtain a syrup-like (R)-8-chloro-2-hydroxypropyl p-loform)' HNMR (90 MHz, ODOIB)
δ (ppm): 2.44 (8E[,8,CH3-mur
-), 2.98 (IH.

broad, OH), 8.50-4.32 (5H, m.

-0H2CII(OII)OH2-), 7.80
, 7.75 (each2nct, human r-H) Optical active column (Chiral 0EDOO, manufactured by Nippon Bunko Banji, developing solvent, hexane-2-propanol 98
．． (R)- by HPLO using 5:1.5)
The optical purity of 41 was determined to be 99%e.

On the other hand, reduce the pressure on the water layer side (8) -8-chloro-2
-Hydroxypropyltrimethylammonyl white coarse powder 7.29% was obtained. Add 7.21 of this coarse powder to 55 mL of ethanol.
Repeat the operation of dissolving in 0 mr and crystallizing twice, filtering,
After drying, highly pure (S)-8a crystal 4.8I was obtained.

Melting point 214-216°C Example 2 Concentrate obtained in Reference Example 4 19.5. ! 20 ml of an aqueous solution containing trimethylamine hydrochloride 7.17.9 in 7! was added all at once, and the reaction was carried out at 40°C for 8 hours. Below, Example 1
(R)-119,3)'.

H2O) was obtained.

Example 8 The methylene chloride solution (about 100 ml) containing (n)-ta and (3)-2a obtained in Reference Example 4 was used as it was. According to Example 1, the reaction was carried out at 50°C for 2 hours while methylene chloride was distilled off at the same time as the reaction. Hereinafter, according to Example 1, (B)-1a and (8) -
! I did tt'A of la.

(IL)-1a 10.8,9. ca:+-
8, f; °C (c=~
D2.0. rioaform) and (8)-814,5
JF.

[α] -28,9° (C! 1.0, H, O)
I got it.

Example 4 The methylene chloride solution (approximately 100 m/ml) containing (R)-1a and (8)-28 obtained in Glue Example 4 was used as it was. According to Example 1, the reaction was carried out at a bath temperature of 50°C,
The reaction was carried out without refluxing the methylene chloride without distilling it off. The reaction between (8)-21 and trimethylamine hydrochloride was completed in less than 12 hours.

Hereinafter, (R)-18 and (8)-81 according to Example 1
was purified.

(R)-1a 10.5.9, I:aa-8,6
°((x~D2
．． 0. (OCfform) and (8)-f3a 4.6.
F.

[α] −29,1° (c −1,0*H2O) was obtained.

Example 5 4.78I of trimethylamine hydrochloride was added to the xylene solution containing (R)-11 and (8)-21 obtained in Reference Example 6.
20mI of an aqueous solution containing! was added all at once, and the reaction was carried out at 50°C for 5 hours. Hereinafter, purification was performed according to Example 1.

(Ill)-1a 10.4Jil, (a)
−B, 6° (c=~
Cram school 2.0. (roroform) and (8)-8a 4
．． 4. y.

[α] −29,2° (C=1.0, H2O)
I got it.

Example 6 Trimethylamine hydrochloride 4 was added to the concentrate 20.1.9 containing (R)-1b and (8)-21 prepared in Reference Example 6.
．． Add 50ml of an aqueous solution containing 78.9 at once and heat at 60℃.
The reaction was carried out for 1 hour. Hereinafter, purification was performed according to Example 1, and syrup-like (R)-1b 18.8I and white powder (S)-aa 4.1. I got p.

20' (R)-1b: (aa-6,6° (c=2.0.ri~D loloform) 'HNMR (90MHz, CD01B) δ:0.9
8 (8H, t, 0H80H2CH, -), 1.45-1
．． 78 (2H, m, 0H8C1[2CH2-), 2.2
6 (2H, t.

OHB OH20H2-) t 2.4 B(8H*
ss OHB -A r-) p8.58 (2H, d,
-0H2-), 4.17 (2H, d.

-0H2-), 4.92~5.20 (IH, m
, -0H-).

7.81, 7.74 (each 2Hd, Ar
-H) (8) -8a: [α] -29,0° (c=
1.0°～D ■20)

Claims (4)

[Claims] (1) General formula (R) -■ ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
(R)-■ (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 hydrocarbon group.) , General formula (R) -■ ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(S)
−■ Optically active halogenomethyloxirane (S
)-■ is added to a mixture containing trimethylamine hydrochloride, and only (S)-■ is selectively reacted, resulting in the general formula (S)-■▲There are mathematical formulas, chemical formulas, tables, etc.▼...
・・・・・・(S)-■ (wherein, The reaction (R)-■ and the product (
(R)-■ and (S)-■ are extracted and separated from the suspension containing S)-■ using a hydrophobic organic solvent, and the organic solvent layer is concentrated to collect (R)-■. Concentrate one aqueous layer (
A method for extracting and separating optically active glycerol derivatives, which comprises collecting S)-■. (2) The separation method according to claim 1, wherein the substituent X is chlorine and R' is a tolyl group. (3) General formula (R) -■ ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(R)
-■ (wherein, X is a halogen group, R is an aliphatic hydrocarbon group of C_1 to C_8, and R' is an aromatic hydrocarbon group); General formula (S) -■ ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(S)
−■ Optically active halogenomethyloxirane (S
) -■ A mixture containing the general formula (RS) -■ ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(RS
)-■ (wherein X, R, and R' are the same as above) The ester racemate (RS)-■ represented by Body (R)-■ and general formula (S)-4 ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・(S)
-■ (wherein, X and R' are the same as above) An optically active alcohol (S)-■ is produced, and (R)-■ and (S)-4 are extracted with a hydrophobic organic solvent. Then, the extract is treated with an alkaline solution to obtain (S)-
(R)-■ obtained by selectively epoxidizing only ■
The separation method according to claim 1, which is a mixture of and (S)-■. (4) The separation method according to claim 1, wherein the hydrophobic organic solvent is methylene chloride, ethyl acetate, butyl acetate, methyl isobutyl ketone, benzene, toluene, or xylene.