JPH0153665B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active mandelonitrile, and more particularly to a method for producing optically active mandelonitrile, which is characterized by reacting benzaldehyde with hydrogen cyanide in the presence of cyclo(L-phenylalanyl-L-histidine). It relates to a method for producing delonitrile. The optically active mandelonitrile obtained by the present invention is an important intermediate for producing optically active mandelic acid, and the known method of hydrolyzing optically active mandelonitrile with hydrochloric acid ( L. Rosenthaler,
Biochem.Z., 14 , 238 (1908), etc.) can easily lead to optically active mandelic acid. Optically active mandelic acid is a raw material for pharmaceuticals (e.g.
D-mandelic acid is the raw material for the semi-synthetic cephalosporin cefamandole. ), is widely used as an optical resolution agent, etc. When considering the production of optically active mandelic acid, if optically active mandelonitrile can be obtained in high yield and high optical purity by a method using an asymmetric catalyst, it is possible to produce optically active mandelonitrile using a method currently used industrially, such as DL. -Mandelic acid is converted into an optically active amine, such as optically active α-
It is far more advantageous than optical resolution using phenylethylamine. Therefore, attempts have been made for a long time to synthesize optically active mandelonitrile from benzaldehyde and hydrogen cyanide using asymmetric catalysts. For example, a method performed in the presence of emulsin, a β-glycosidase enzyme (L. Rosenthaler,
Biochem.Z., 14 , 238 (1908), 19 , 186 (1909)),
Method carried out in the presence of quinine alkaloids (V.
Prelog and M.Wilhelm, Helv.Chim.Acta, 37 ,
1634 (1954)), a method using synthetic optically active polymers including optically active s-isobutylethyleneimine polymer (S.Tsuboyama, Bull.Chem.Soc.
Japan, 35 , 1004 (1962)). However, with these methods, the optical purity is at most about 20%, which is by no means a satisfactory result. The present inventors previously reported that cyclo(L-
By using alanyl-L-histidine) and cyclo(D-alanyl-L-histidine), D
-Mandelonitrile has an optical purity of 9.9%,
reported that it could be obtained at 7.5% (J.Oku, N.Ito
and S. Inoue, Makromol.Chem., 180 , 1089
(1979)), as a result of further research, discovered that extremely good optical purity could be obtained by using cyclo(L-phenylalanyl-L-histidine), and completed the present invention. To explain the present invention in more detail, the reaction of the present invention is carried out in a solvent with cyclo(L-phenylalanyl-L-
It is carried out by reacting hydrogen cyanide with benzaldehyde in the presence of (histidine). Cyclo(L-phenylalanyl-L-histidine) can be used not only in unsolvated form but also in solvated form without any problems.
In some cases, even better results are obtained when the compound is solvated. The amount of cyclo(L-phenylalanyl-L-histidine) is not particularly limited, but is preferably 0.1 to 10 mol% relative to benzaldehyde or hydrogen cyanide. The amounts of benzaldehyde and hydrogen cyanide are not particularly limited, but preferably 0.5 to 2 moles of hydrogen cyanide to 1 mole of benzaldehyde, or 0.5 to 2 moles of benzaldehyde to 1 mole of hydrogen cyanide. The solvent used in the present invention is not particularly limited as long as it can even slightly dissolve the cyclic dipeptide, benzaldehyde, and hydrogen cyanide that are the catalysts.
Aromatic hydrocarbons are preferred, and benzene and toluene are particularly preferred. The reaction temperature can be selected over a wide range from room temperature to the boiling point of the solvent, but since the optically active mandelonitrile produced tends to be racemized, it should be set at a temperature that allows the reaction to proceed and is difficult to racemize, i.e. 20 to 50°C.
Particularly preferred is 30 to 40°C. Since the optically active mandelonitrile produced racemizes over time, it is preferable to terminate the reaction within several hours. The progress of the reaction can be easily estimated by taking out a portion of the reaction solution and examining the absorption intensity at 2735 cm ^-1 in the infrared absorption spectrum. The optically active mandelonitrile produced from the reaction solution can be isolated by a known method, for example, the following method. That is, the reaction solution is concentrated under reduced pressure to remove hydrogen cyanide and benzene. Next, ether is added to the concentrated solution, and the ether layer containing the target product is separated. Repeat this operation several times,
Combine the separated ether layers, separate the insoluble matter,
Concentrate the liquid under reduced pressure to obtain a viscous yellow liquid. By applying this liquid to a silica gel column using ethyl acetate as a solvent and concentrating the eluate containing the target product under reduced pressure, it is possible to isolate an oily substance of optically active mandelonitrile containing unreacted benzaldehyde. The present invention will be specifically explained in Examples below. Example 1 5.30 g (50 mmol) of benzaldehyde, 1.35 g (50 mmol) of hydrogen cyanide and 0.28 g of cyclo(L-phenylalanyl-L-histidine)
(0.97 mmol) was added to 20 ml of benzene, and the mixture was reacted at 35±1°C with stirring under a nitrogen atmosphere. The reaction solution is non-uniform at the beginning of the reaction, but becomes a homogeneous solution approximately 30 minutes after the start of the reaction. The conversion rate reaches 40% 30 minutes after the start of the reaction, so
At this point, the reaction is stopped and the reaction solution is concentrated under reduced pressure. Next, add 20 ml of ether to the oily residue, stir well, and separate the ether layer. Repeat this operation three times. Combine the separated ether layers, separate the insoluble matter,
Concentrate the liquid under reduced pressure. The resulting yellow viscous liquid was dissolved in a small amount of ethyl acetate and subjected to silica gel chromatography using ethyl acetate, and the eluate containing mandelonitrile was concentrated under reduced pressure to remove D-mandelonitrile containing unreacted benzaldehyde. 4.4 g of oil is obtained. The specific rotation of this oil is [α] ²⁵ _D = +23.8° (c =
4.6, benzene). Further, from the results of the NMR spectrum, the molar ratio of mandelonitrile and benzaldehyde in the oil obtained in this example was 55:44. Therefore, the purity of mandelonitrile in the obtained oil is 55 x 133/55 x 133 + 44 x 106 x 100 = 61 (%), and the amount of mandelonitrile in 4.4 g of oil is:
4.4×0.61=2.7 (g) (20 mmol). From the above results, when the specific rotation of the above oil is corrected as mandelonitrile, it becomes [α] ²⁵ _D +39.4° (c = 2.8, benzene), while the optical purity is 100
The specific rotation of D-mandelonitrile in % is [α] ²⁵ _D
Since it is +43.75° (c = 5.0, benzene),
It was found that the mandelonitrile obtained in this example was in the D form, and its optical purity was +39.4/+43.75×100=90 (%). In the following examples as well, the conversion rate of benzaldehyde to mandelonitrile and the optical purity of mandelonitrile were calculated in the same manner as above. Examples 2 to 5 The results shown in Table 1 can be obtained by carrying out the same procedure as in Example 1 except for extending the reaction time. 【table】

Claims (1)

[Claims] 1. A method for producing optically active mandelonitrile, which comprises reacting benzaldehyde and hydrogen cyanide in the presence of cyclo(L-phenylalanyl-L-histidine).