JP2001122841A - Method for producing (r)-4-cyano-3-hydroxybutyric acid lower alkyl ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing the subject compound in high purity. SOLUTION: This method for producing a (R)-4-cyano-3-hydroxybutyric acid lower alkyl ester comprises the following process: the objective reaction product is extracted several times using an organic solvent from a reaction liquid after cyanation of the corresponding (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester; wherein the extraction phases resulted from the 2nd extraction operation and thereafter are used as extraction solvent for other production lot(s).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a lower alkyl (R) -4-cyano-3-hydroxybutyrate. More specifically, the present invention relates to a method for producing (R) -4-cyano-3-hydroxybutyric acid lower alkyl ester by cyanating (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester. The (R) -4-cyano-3-hydroxybutyric acid lower alkyl ester obtained by the present invention is useful as various pharmaceutical intermediates, for example, 3-hydroxy-3-methylglutaryl coenzyme A
Reductase (usually abbreviated as "HMG-CoA")
[R- (R *, R *)]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) Carbonyl] -1H-pyrrole-1-heptanoic acid calcium salt (2: 1) can be used as an important intermediate.

[0002]

2. Description of the Related Art As a method for synthesizing lower alkyl (R) -4-cyano-3-hydroxybutyrate, calcium L-threonine obtained by reacting L-ascorbic acid with hydrogen peroxide and calcium carbonate is used. Hydrate (Car
bohydrate, Res. , 72 , 301 (197
9)) or a dibromo compound obtained by reacting L-arabinose with hydrogen bromide to form a bromohydrin, and (S) -4-bromo-3
-Hydroxybutyric acid methyl ester (Acta
Chem. Scand. B37, 341 (198
3)) a method of protecting a hydroxyl group with a protecting group such as tetrahydropyranyl, trialkylsilyl, or alkyl, and then reacting sodium hydrocyanate in dimethyl sulfoxide (US Pat. No. 4,611,067); The asymmetric hydrogenation reaction was performed on the 4-halogenoacetoacetic acid t-butyl ester obtained from the above using a ruthenium-optically active phosphine complex to obtain (S) -4-halogeno-3-hydroxybutyric acid t-butyl ester (particularly, Kaihei 1-2115
No. 51) and a method of performing a reaction with a cyanating agent in an aprotic polar solvent (Japanese Patent Application Laid-Open No. 5-331128) and the like.

Of the above reported examples, the former method uses an optically active substance as a raw material and requires a step of protecting and deprotecting a hydroxyl group after a plurality of reactions. It can not be said. In the latter method, the raw material obtained by the asymmetric hydrogenation reaction has an optical purity of about 92% e.
In order to use as a pharmaceutical intermediate requiring high optical purity, the product is extracted from the cyanation reaction solution with an organic solvent, washed with water, and the solvent is distilled off. It is necessary to improve the optical purity by recrystallization with an organic solvent.

[0004] Apart from these methods, the lower alkyl ester of 4-halogenoacetoacetic acid obtained from diketene is subjected to an asymmetric reduction reaction using a microorganism to give (S) -4.
Many examples of obtaining lower alkyl esters of -halogeno-3-hydroxybutyric acid have been reported. Initially, the optical purity in the asymmetric reduction reaction was inadequate at 92 to 95% ee (Japanese Patent Laid-Open No. 61-146191), but the discovery of excellent microorganisms resulted in an optical purity of 98 to 99% ee. (Japanese Patent Application Laid-Open No. 8-336393). As a general method when a reaction is performed by a microorganism, (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester produced after the reaction is subjected to eradication by centrifugation or the like.
After extraction from the reaction solution with an organic solvent such as ethyl acetate, methylene chloride, toluene, diethyl ether and the like, the organic solvent is distilled off and the product can be isolated as a pure product by an operation such as column chromatography or distillation. The isolated (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester can be obtained by protecting the hydroxyl group and subjecting it to a cyanation reaction in dimethyl sulfoxide or directly using an aproton as described in the cyanation reaction example described above. (R) -4-cyano-3-hydroxybutyric acid by carrying out a cyanation reaction in a neutral solvent or by carrying out a cyanation reaction as it is in another solvent (Japanese Patent Application Laid-Open No. 7-500105). A lower alkyl ester is obtained. Then, in order to isolate a high-purity (R) -4-cyano-3-hydroxybutyric acid lower alkyl ester from these cyanation reaction solutions, usually, extraction with an appropriate solvent is performed, followed by concentration and distillation under reduced pressure. Purification was performed.

[0005]

However, according to the additional test of the present inventors, it was found that (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester was subjected to a cyanation reaction in an aqueous solvent. In order to recover the water-soluble (R) -4-cyano-3-hydroxybutyric acid lower alkyl ester from the reaction solution at a high extraction rate, it is necessary to perform a plurality of extraction operations using a large amount of an organic solvent. there were. As a result, in order to obtain a crude concentrated solution of (R) -4-cyano-3-hydroxybutyric acid lower alkyl ester from the extracted organic solvent phase, it is necessary to concentrate a large amount of the organic solvent under heating under reduced pressure. However, it takes a lot of time and energy, so that there is a problem that productivity is remarkably reduced in industrial scale production.

[0006]

As a result of various studies to solve the above-mentioned problems, it has been found that, in a plurality of extraction operations, the second and subsequent extraction phases are used as extraction solvents for other production lots, so that the actual concentration can be carried out. Reduced organic solvent phase,
The inventors have found that the time and energy required for concentration can be reduced, and have completed the present invention. That is, in the present invention, (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester is cyanated with a cyanating agent such as sodium hydrocyanate in an aqueous solvent, and then extracted multiple times with a suitable organic solvent and concentrated. (R) -4-cyano-3-hydroxybutyric acid lower alkyl ester by using the second or subsequent extraction phase as an extraction solvent for another production lot. The present invention relates to a method for producing a lower alkyl 4-cyano-3-hydroxybutyrate.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The raw material of the present invention, crude (R)-
The 4-cyano-3-hydroxybutyric acid lower alkyl ester is a linear or branched alkyl ester having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms. These can be obtained by subjecting the corresponding (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester to cyanation with a cyanating agent, extracting with a suitable solvent, and, if necessary, concentrating the extract. .

Specifically, (S) -4-halogeno-3-
As a halogen of the hydroxybutyric acid lower alkyl ester, chlorine is preferable, but bromine or iodine may be used. As the cyanating agent, for example, an alkali metal cyanide or an alkaline earth metal cyanide is used. Among them, sodium cyanide (sodium cyanate) and potassium cyanide (potassium cyanate), which are common cyanides, are used, and inexpensive sodium cyanide is preferably used. The solvent for the cyanation reaction is ethanol,
Water, dimethylformamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran, and the like, and a mixture thereof are used. Among them, water is preferable because it is inexpensive and can be extracted with an organic solvent that is hardly soluble in water. The temperature of the cyanation reaction is appropriately selected in consideration of production efficiency in the range of 20 ° C. to the boiling point of the solvent. In the case of an aqueous solvent, the temperature is preferably 50 ° C. to the reflux temperature. A preferred embodiment of the cyanation reaction is that the concentration of (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester is from 5 to 40.
The reaction is carried out by adding water so as to give a weight%, raising the temperature to about 80 ° C., and dropwise adding an aqueous solution of sodium cyanate with stirring. The reaction proceeds relatively quickly, but may be aged in the range of 0 to 10 hours after the completion of dropping depending on the reaction temperature. The conversion of (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester increases as the amount of sodium hydrocyanic acid increases, but when sodium hydrocyanic acid is added until the entire amount is consumed, (R)-produced. Since the lower alkyl ester of 4-cyano-3-hydroxybutyric acid is decomposed to lower the yield,
By adjusting the amount of sodium cyanide used, (S) -4-
It is important that the reaction is terminated in a state where the lower alkylamine-3-hydroxybutyrate has remained to some extent.

In the extraction step, a poor solvent of the solvent used in the reaction is used. However, when the reaction solvent is water, the solvent is poorly soluble in water, and the lower alkyl (R) -4-cyano-3-hydroxybutyrate is used. Use an organic solvent that dissolves well. Specific organic solvents include lower alkyl esters of acetic acid such as ethyl acetate and butyl acetate, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene and benzene, and ketones such as methyl isobutyl ketone. Alternatively, ethers such as dibutyl ether and the like, and a mixture thereof are used. In order to increase the extraction efficiency in the extraction operation, the reaction solution may be concentrated to some extent before adding these extraction solvents, or the extraction efficiency may be improved by salting out. In particular, when the reaction solvent is a mixed solvent such as water and ethyl alcohol, to increase the extraction efficiency,
It is preferred to add the extraction organic solvent after removing the low boiling point ethyl alcohol by evaporation in advance.

The amount of the organic solvent to be used is preferably 10 to 10 times the amount of the cyanation reaction solution in consideration of the extraction rate and industrial productivity.
It is necessary to perform the extraction and liquid separation operations 2 to 6 times, preferably 3 or 4 times, with respect to the same reaction solution, using 0% by weight, preferably 20 to 60% by weight as one addition amount. In the present invention, the second and subsequent extraction phases are used as extraction organic solvents for other production lots. Specifically, when the extraction is performed three times, the extracted phase separated for the third time can be used as the first extracted organic solvent in the next production. In this case, only the extract phase separated in the first and second times is concentrated to obtain a crude concentrate. More specifically, when the extraction is carried out three times, the second extraction phase is used as the first extraction organic solvent in the next production, and the third extraction phase is used in the next production. Can be used as a second extraction organic solvent in the production of.
In this case, only the extract phase separated for the first time is concentrated to obtain a crude concentrate.

Since the impurities dissolved in the reaction solution are precipitated by the addition of the organic solvent and the interface at the time of liquid separation becomes unclear, the filtration is carried out after an appropriate stirring time after the addition of the organic solvent. I do. In order to carry out the filtration efficiently, it is effective to add a filter aid such as diatomaceous earth. The filtered mixture of the aqueous phase and the organic solvent phase shows a clear interface by taking a relatively short standing time, and can be easily separated visually. From the organic solvent phase separated by the above operation, the desired (R)-
A crude concentrate of lower alkyl 4-cyano-3-hydroxybutyrate can be obtained. Further, the organic solvent distilled off during concentration under reduced pressure can be used as it is as an organic solvent for extraction.

[0012]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples. (Example) 150 g of ethyl (S) -4-chloro-3-hydroxybutyrate and 450 g of water were added to a glass reaction vessel connected to a reflux condenser equipped with a cooling device, and the temperature was raised to about 85 ° C with stirring. Thereafter, a solution consisting of 57 g of sodium cyanide and 150 g of water was continuously added over a period of 1 hour in a temperature range of 85 to 90 ° C., and further aged in a temperature range of 85 to 90 ° C. for 1 hour. Cooled down. In this reaction solution,
After adding 300 ml of ethyl acetate (containing 4 g of ethyl (R) -4-cyano-3-hydroxybutyrate) obtained as a third extraction phase in another experiment, commercially available diatomaceous earth (manufactured by Showa Chemical Industry Co., Ltd.) 2 g of Radiolite # 700 (average particle size: 23 μm), and the mixture was stirred for 30 minutes. Filtration was performed under reduced pressure using 5C (retained particle diameter: 1 μm). Next, the filtered mixture of the aqueous phase and the organic solvent phase was allowed to stand for 30 minutes, and separated into an organic phase and an aqueous phase. Ethyl acetate (300 ml) was added to the aqueous phase, and the mixture was stirred for 30 minutes. 340 ml of the first extraction phase (containing 66 g of ethyl (R) -4-cyano-3-hydroxybutyrate) and 310 ml of the second extraction phase (containing 12 g of ethyl (R) -4-cyano-3-hydroxybutyrate) Mix, total amount 650
The ml extracted phase was concentrated under reduced pressure using an evaporator to obtain 97 g of a crude concentrated liquid containing 78 g of ethyl (R) -4-cyano-3-hydroxybutyrate. The concentration conditions are
The degree of pressure reduction was about 100 torr, the bath temperature was about 50 ° C., and the time required for concentration was 1.5 hours. The electrical equipment used was EYELA's rotary evaporator NE-
1 (rated 100V, 12A), EYELA diaphragm type vacuum pump DIVAC 2.2L (rated 100
V, 4A), EYELA vacuum control unit NVC-
1100 (rated 100V, 1A), EYELA cooling water circulator Cool Ace CA-1110 (rated 100
V, 11A), and the estimated required power is 1.7 kWH.

(Comparative Example) A cyanation reaction liquid and an extraction operation were performed in the same manner as in the Example, except that extraction was performed three times using only unused ethyl acetate as an organic solvent for extraction. 1
Second extraction phase 340 ml (containing 62 g of ethyl (R) -4-cyano-3-hydroxybutyrate)
10 ml (containing 12 g of ethyl (R) -4-cyano-3-hydroxybutyrate) and 300 ml of the third extraction phase
(Ethyl (R) -4-cyano-3-hydroxybutyrate
g), and the total of 950 ml of the extracted phase was concentrated under reduced pressure using an evaporator to obtain (R) -4-cyano-
97 g of a crude concentrate containing 78 g of ethyl 3-hydroxybutyrate was obtained. The time required for concentration was 2.2 hours. The estimated required power is 2.5 kWH.

[0014]

According to the present invention, (S) -4-halogeno-3-hydroxybutyric acid lower alkyl ester is cyanated with a cyanating agent such as sodium cyanide in an aqueous solvent and then extracted with an appropriate organic solvent. Then, the crude (R)-
When obtaining lower alkyl 4-cyano-3-hydroxybutyrate, the time and energy required for the concentration operation can be significantly reduced by using the second and subsequent extraction phases as extraction solvents for other production lots. .

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Hidetaka Dozada 1-1 Kurosaki Castle Stone, Yawatanishi-ku, Kitakyushu-shi, Fukuoka F-term (reference) 4K006 AA02 AC54 AD16 BB11 BB12 BB14 BB15 BB16 BB17 BB20 BB21 BB31 QN14

Claims (4)

[Claims] 1. A lower alkyl (R) -4-cyano-3-hydroxybutyrate is produced by subjecting a lower alkyl (S) -4-halogeno-3-hydroxybutyrate to a cyanation reaction in the presence of an aqueous solvent. In the process of extracting the product from the reaction solution after cyanation with an organic solvent a plurality of times, the second or subsequent extraction phase is used as an extraction solvent for another production lot (R) -4. -A method for producing a lower alkyl cyano-3-hydroxybutyrate. 2. The method according to claim 1, wherein the aqueous solvent is water or a mixture of water and a water-soluble organic solvent. 3. The method according to claim 2, wherein the water-soluble organic solvent is an alcohol, an acid amide or a nitrile. 4. The method according to claim 1, wherein the organic solvent is an acetic ester, a halogenated hydrocarbon, an aromatic hydrocarbon, a ketone or an ether. .