JP2535436B2 - Process for producing 3,4-dihydroxybutyronitrile - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing 3,4-dihydroxybutyronitrile, which is a compound useful as an intermediate for synthesizing pharmaceuticals.

[Prior Art] As a method for producing 3,4-dihydroxybutyronitrile, the following methods are known.

(1) KCN in water with 3-chloro-1,2-propanediol
3,4-dihydroxybutyronitrile is prepared by reaction with or subsequently with NaOH and HCl.
To convert to S-butyro cratone derivative (Comptes Rendus Heb
domadaires des Seances De l'Academie des Scienc
e), 238, p. 1231 (1954)).

(2) 3-chloro-1,2-propanediol in water
After reacting with N, a method of purifying using an ion exchange resin (Journal of American Chemical Society (J. Am. Chem. Soc.), 107, 7008 (1985)
Year))).

(3) A method in which R-3-chloro-1,2-propanediol is reacted with a cyanating agent using trimethylamine in methanol to convert it into S-3,4-dihydroxybutyronitrile (JP-A-2-42050). See the bulletin).

[Problems to be Solved by the Invention] In any of the above methods, 3,4-dihydroxybutyric acid amide, 3,4-dihydroxybutyric acid, and the like are easily produced as by-products, and as a practical production method of 3,4-dihydroxybutyronitrile, There are various problems to be solved in its reaction selectivity, reaction yield and product purity.

[Means for Solving the Problems] In view of the above circumstances, the inventors of the present invention have earnestly studied to establish an industrial manufacturing method of 3,4-dihydroxybutyronitrile, which has excellent economical efficiency and is simple and efficient. As a result, 3
-Chloro-1,2-propanediol is reacted with a cyanating agent such as NaCN or KCN in an amide solvent or a mixed solvent of an amide solvent and an alcohol to give 3,4-dihydroxybutyronitrile in high yield and high yield. The present invention has been completed by finding a method for producing with a purity.

That is, the present invention has the general formula (I): The general formula (II) is characterized in that 3-chloro-1,2-propanediol represented by the formula (II) is reacted with a cyanating agent in an amide solvent or a mixed solvent of an amide solvent and an alcohol. And a method for producing 3,4-dihydroxybutyronitrile represented by

From 3-chloro-1,2-propanediol (I), 3,4
In the reaction for obtaining dihydroxybutyronitrile (II), an amide solvent such as dimethylformamide, diethylformamide and dimethylacetamide can be used alone or as a mixture with an alcohol such as methanol or ethanol. , 4-
Minimizes by-products such as dihydroxybutyric acid amide,
In order to increase the selectivity of the production of dihydroxybutyronitrile, it is preferable to carry out the reaction in dimethylformamide or a mixed solvent of dimethylformamide and alcohol, preferably methanol. Examples of the cyanating agent include NaCN, KCN, Mg (CN) ₂ , AgCN, CuCN, etc., but alkali metal cyanides such as NaCN, KCN, etc. are preferable in terms of yield and economy. The amount of the cyanating agent used here is 1 to 2 times equivalent, preferably 1 to 1.2 times equivalent to the compound (I). The temperature in the range of 20 to 100 ° C. is suitable for this reaction, but the higher the temperature, the faster the disappearance of the starting material 3-chloro-1,2-propanediol, but the selectivity of the reaction tends to decrease.
In order to selectively obtain 3,4-dihydroxybutyronitrile, it is preferable to stir at 40 to 60 ° C. for 2 to 20 hours until the raw materials almost disappear. For isolation and purification, mineral acid is added to neutralize the reaction solution, which is then concentrated, acetone is added to remove insoluble inorganic salts by filtration, and the solvent is distilled off.
An oily substance containing 4-dihydroxybutyronitrile is obtained. For further purification, the purpose can be achieved by ordinary column chromatography or the like. However, the reaction and isolation operation are not necessarily limited to these methods, and various methods can be used.

Further, by using (R) and (S) -3-chloro-1,2-propanediol, the corresponding optically active (S) and (R) -3,4-dihydroxybutyronitrile are synthesized. It is also possible to do so.

[Examples] Hereinafter, the present invention will be described in more detail with reference to the present invention, but the present invention is not limited thereto.

Example 1 Synthesis of 3,4-dihydroxybutyronitrile 95% NaCN 56.8 g (1.1 eq) and dimethylformamide 500 m
110 g (1M) of 3-chloro-1,2-propanediol was added to a solution consisting of 1 and 50 ml of CH ₃ OH, and the mixture was stirred at a bath temperature of 60 ° C. for 5 hours. The reaction solution was spotted for TLC (silica gel) as it was, butanol: acetic acid: water: ethyl acetate = 1: 1:
After developing at 1:30 as a developing solution, it was detected using phosphomolybdic acid, and it was confirmed that the raw material (3-chloro-1,2-propanediol) was almost disappeared. Reaction solution at 10 ℃
The mixture was cooled to 50 ° C., pH was adjusted to 3 with hydrochloric acid, and the solvent was evaporated under reduced pressure. 200 ml of acetone was added to the obtained concentrate,
The insoluble inorganic salt was suction filtered, and the filtrate was evaporated under reduced pressure to obtain 102.6 g of 3,4-dihydroxybutyronitrile as a crude product. GLC (column: glass column (2m, ID3m
m), Silicone OV-210 (Silicone OV-210)
10%, Uniport HP 80-100
Mesh, carrier gas: Helium (25ml / min),
Injection temperature: 170 ℃, Column temperature: 150 ℃, Detector: FID) As a result, purity is 95.6%, production rate is 97%
Met. The crude product was further subjected to a silica gel column (C20
0, hexane: acetone = 1: 1). ¹ H-NMR (90 MHz, CDCl ₃ + CD ₃ OD): δ2.57 to 2.73 (m, 2
H), 3.62 (d, 2H, J = 5Hz), 3.8 to 4.13 (m, 1H), 4.5
(Bs, 2H) IR (neat) (cm ^-1 ): 3400, 2925, 2250, 1415, 110
0,1042 Example 2 Synthesis of 3,4-dihydroxybutyronitrile 5.15 g (1.0 eq) of 95% NaCN and dimethylformamide 36.7
3-chloro-1,2-propanediol
1 g (100 mM) was added, and the mixture was stirred at a bath temperature of 60 ° C for 5 hours.
Spot the reaction mixture as it is for TLC (silica gel),
After developing with butanol: acetic acid: water: ethyl acetate = 1: 1: 1: 30 as a developing solution, phosphomolybdic acid was used for detection, and the raw material (3-chloro-1,2-propanediol) was almost disappeared. It was confirmed. The reaction vessel was cooled to 10 ° C., pH was adjusted to 3 with hydrochloric acid, and the solvent was evaporated under reduced pressure. Acetone (20 ml) was added to the obtained concentrate, insoluble inorganic salts were suction-filtered, and the crude product obtained by distilling the filtrate under reduced pressure was distilled (140-150 ° C / 3 mmHg) to give 8.95 g.
Obtained 3,4-dihydroxybutyronitrile. Production rate is 89
%Met. ¹ H-NMR and IR were the same as in Example 1.

Example 3 Synthesis of S-3,4-dihydroxybutyronitrile 56.8 g (1.1 eq) of 95% NaCN and 500 m of dimethylformamide
L-3-chloro-1,2 in a solution consisting of 50 ml of CH ₃ OH.
-Propanediol 110g (1M) was added, and the mixture was stirred at a bath temperature of 60 ° C for 5 hours. The reaction solution was spotted for TLC (silica gel) as it was, developed with butanol: acetic acid: water: ethyl acetate = 1: 1: 1: 30 as a developing solution, and then detected using phosphomolybdic acid, and the starting material (R- It was confirmed that (3-chloro-1,2-propanediol) almost disappeared. After cooling the reaction vessel to 10 ° C and adjusting the pH to 3 by adding hydrochloric acid,
The solvent was distilled off under reduced pressure. 200 ml of acetone in the obtained concentrate
Was added, and the insoluble inorganic salt was suction filtered, and the filtrate was evaporated under reduced pressure to obtain 104 g of S-3,4-dihydroxybutyronitrile as a crude product. The crude product was further purified by silica gel column (C200, hexane: acetone = 1: 1). ¹ H-NMR and IR were the same as in Example 1.

▲ [α] ²⁰ _D ▼ = −24.1 ° (C = 1.02, CH ₃ OH) [Effect of the Invention] According to the present invention, 3,4-dihydroxybutyronitrile can be produced economically and effectively. it can.

Claims (6)

(57) [Claims] 1. General formula (I): The general formula (II) is characterized in that 3-chloro-1,2-propanediol represented by the formula (II) is reacted with a cyanating agent in an amide solvent or a mixed solvent of an amide solvent and an alcohol. A method for producing 3,4-dihydroxybutyronitrile represented by: 2. The method according to claim 1, wherein an alkali metal cyanide is used as the cyanating agent. 3. The method according to claim 2, wherein the alkali metal cyanide is NaCN, KCN or a mixture thereof. 4. The method according to claim 1, 2 or 3, wherein the amide solvent is dimethylformamide, diethylformamide, dimethylacetamide or a mixture thereof. 5. The method according to claim 1, 2 or 3, wherein the alcohol is methanol, ethanol or a mixture thereof. 6. The method according to claim 1, 2 or 3, wherein the reaction is carried out in a mixed solvent of dimethylformamide and methanol.