JPH0569818B2 - - Google Patents

Description

[Detailed Description of the Invention] (Industrial Application Field) The present invention is a pharmaceutical product (R)-carnitine and (R)-
The present invention relates to a method for producing (R)-4-chloro-3-hydroxybutyronitrile, which is useful as an intermediate for synthesizing 4-amino-3-hydroxybutyric acid.

(Prior art and its problems) (R)-4-Amino-3-hydroxybutyric acid has medicinal effects such as improving cerebral metabolism, increasing cerebral blood flow,
It has antihypertensive and sedative effects. Although the racemic form is currently used, it is the (R) form that exhibits biological activity, so it is important to obtain only the (R) form in high purity. Also, (R)-carnitine is a vitamin B _T
Due to its excellent biological activity, it is attracting attention as a nutritional supplement and medicine.

To obtain (R)-carnitine, (R)-4-chlor-
As a method via 3-hydroxybutyronitrile, there is a method using d-mannitol as a starting material (Japanese Patent Application Laid-Open No. 16532/1983). According to this method, the desired intermediate (R)-4-chloro-3-
It takes seven steps to reach hydroxybutyronitrile, and the total yield is low, making it unsuitable for industrial production.

Another method is to simultaneously add a sodium potassium cyanide aqueous solution and an acetic acid aqueous solution to epichlorohydrin and react under neutral conditions to obtain 4-chloro-3-hydroxynitrile, but the yield is 65.5%.
and low yield (J.Chem.Soc, p. 3123 (1950)).

Also (R)-carnitine and (R)-4-amino-3-
The methods for producing hydroxybutyric acid that have been reported to date are as follows.

(i) A method using L-ascorbic acid as a starting material (J.Am.Chem.Soc, Vol. 102, p. 6304 (1980)).

(ii) A method using L-arabinose as a starting material (Acta.Chem.Scand.B, Vol. 37, p. 344 (1983)).

(iii) A method of asymmetric synthesis by shear press oxidation (J.Org.Chem., Vol. 49, p. 3707 (1984)).

(iv) Methods using enzymes and microorganisms (Tetrahed
-ron Lett, Volume 25, Page 5235 (1984),
Tetrahedron Lett, Volume 26, Page 101 (1985),
J.Bull.Soc.Chem: Fr, 103 pages (1980), J.Am.
Chem.Soc, vol. 105, p. 5925 (1983),
Angew.Chem.Int.Ed.Engl, vol. 23, p. 151 (1984), J.Am.Chem.Soc, vol. 107, p. 4028 (1985)).

(v) A method using (2S,4R)-N-acetyl-4-hydroxyproline as a starting material (Synthesis424
(1986)).

(vi) Method by resolution of carnitine and 4-amino-3-hydroxybutyric acid derivatives (Special Publication 1973-
3891, Special Publication No. 43-8248, Special Publication No. 43-26849, Special Publication No. 43-26850, Special Publication No. 47-6609, No. 51- Publication of Special Publication
100026, JP-A-52-133920, JP-A-52-
133933, JP-A-55-13299, JP-A-59-
199666).

Among the above methods, (i) and (ii) have a large number of steps;
(iii) is low optical purity of the product; (iv) is low reaction concentration or low optical purity of the product;
(v) is that the starting materials are expensive; (vi) is that the highest yield is
However, problems remain in that 50% of the obtained substance is lost.

(Means for Solving the Problems) The present inventor has completed the present invention as a result of various studies to solve the above problems.

That is, the present invention uses epichlorohydrin at pH 8.0.
This is a method for producing 4-chloro-3-hydroxybutyronitrile, which is characterized by reacting it with an alkali metal cyanide salt under weak basic conditions of ~10.0%.

(R)-4-chloro- obtained by the method of the present invention
3-Hydroxybutyronitrile is reacted with trimethylamine and then converted to highly pure (R) by oxidative water decomposition.
- Can be converted to carnitine, and can also be purified with high purity by acid hydrolysis after reacting with ammonia.
It is a useful intermediate because it can be converted to (R)-4-amino-3-hydroxybutyric acid.

In the method of the present invention, it is also possible to obtain 4-chloro-3-hydroxybutyronitrile in a ceramide form using epichlorohydrin in a ceramic form, but it is possible to obtain an optically active product using a raw material for an optically active substance as described above. It is particularly useful for a number of reasons.

(R)-4-chloro- from (R)-epichlorohydrin
The reaction for synthesizing 3-hydroxybutyronitrile is an addition reaction of hydrocyanic acid. As for the reaction conditions, the adjustment of pH has a great influence on the yield of the target product, and the reaction must be carried out under weak basicity, and the optimal pH is 8.0 ~
It is 10.0. The solvent is preferably a mixed solvent of water and alcohol. Potassium cyanide and sodium cyanide are preferred as the alkali metal cyanide salt, and acetic acid is preferred as the acid for pH adjustment. The reaction temperature is 20
~25°C is optimal, and the reaction is complete in 1.5 to 4 hours. After the reaction, the solution was extracted with ether, the ether layer was washed and dried, the solvent was distilled off, and the resulting residue was distilled under reduced pressure to obtain (R)-4-chloro-3 as a colorless oil.
-Hydroxybutyronitrile is obtained.

Example The optically active epichlorohydrin used in this Example is
-132196 and Japanese Patent Publication No. 1-55879.

(R)-Epichlorohydrin (9.25g100mmol)
was dissolved in ethanol (21 ml), and while stirring at room temperature, potassium cyanide aqueous solution (9.90 g, 150 ml) was added.
mol, H ₂ O (35 ml) and a 2.5 N acetic acid aqueous solution were simultaneously added dropwise for 15 minutes, at a pH of 8.0 to 10.0 and a temperature of 24
It was kept below ℃. Stirring was continued for an additional 2 hours. The reaction solution was extracted with ether, and the ether layer was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was distilled under reduced pressure (139-141° C./13 mmHg) to obtain 9.37 g of (R)-4-chloro-3-hydroxybutyronitrile as a colorless oil (yield 78.4%).

[α] _D +17.25° (C, 1.02, MeOH) H-NMR (CDCl ₃ ) δ 2.70 (2H, d, J = 6.OHz, -CH ₂ -CH) 3.20-3.45 (1H, br, exchangeable with _D20 ,
-OH ) 3.62 (2H, d, J=5.4Hz, -CH2 _- Cl 3.95~4.30 (1H, m, -CH (OH)-) IRνmax (cm ^-1 ): 3432 (OH), 2260 (CN) (Effect of the invention) (R)-4-chloro-3- obtained by the present invention
Hydroxybutyronitrile is highly purified (R)-carnitine or (R)-4-amino-3 as mentioned above.
- Can be converted to hydroxybutyric acid. Compared to the conventional method in which a similar reaction is carried out under neutral conditions, the method of the present invention yields highly purified (R)-4-chloro-3-hydroxybutyronitrile with a yield of 75 to 80%. Therefore, it is possible to improve the yield by more than 10%.

Claims (1)

[Scope of Claims] 1. A method for producing 4-chloro-3-hydroxybutyronitrile, which comprises reacting epichlorohydrin with an alkali metal cyanide under weakly basic conditions of pH 8.0 to 10.0. 2. The manufacturing method according to claim 1, wherein epichlorohydrin and 4-chloro-3-hydroxybutyronitrile are optically active substances. 3. The production method according to claim 1 or 2, wherein the alkali metal cyanide salt is potassium cyanide or sodium cyanide.