JPH059164A - Production of optically active mandelonitrile derivative - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a production raw material, an intermediate, etc., for ferroelectric liquid crystal, agricultural chemicals and madicines in high yield and in high optical purity by reacting a benzaldehyde derivative with hydrogen cyanide under a specific condition. CONSTITUTION:A benzaldehyde derivative shown by formula I (X is H, F or chlorine; Y is H or F) is allowed to react with hydrogen cyanide to give a compound shown by formula II (* is asymmetric carbon). In the reaction, racemized cyclo[(R)-phenylalanyl-(R)-histidyl] or cyclo[(S)-phenylalanyl-(S)- histidyl] is preserved as a catalyst and >=0.5 equivalent based on 1 equivalent of the catalyst of a mandelonitrile shown by formula II with absolute steric configuration rich in (S) or (R) is made to exist. The reaction is carried out in a solvent (e.g. toluene) at -20 to -25 deg.C for 0.5-20 hours.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an optically active mandelonitrile derivative.

[0002]

2. Description of the Related Art Conventional methods for producing an optically active mandelonitrile derivative include, for example, JP-A-59-116256 and JP-A-60-.
The methods described in JP 42359 and JP 60-97052 A are known. However, in these methods, the optical purity of the optically active mandelonitrile derivative of interest depends on the optical purity of the dipeptide catalyst used. Of high optical purity as cyclo [(R)-
Phenylalanyl- (R) -histidyl] and the like. Therefore, when recovering and reusing the catalyst, not only the operation and equipment for preventing the decrease in optical purity due to racemization but also the equipment can be used. Strict quality control of the catalyst itself is required, which is industrially disadvantageous. Therefore, the present inventors have conducted intensive studies on a method capable of producing an optically active mandelonitrile derivative with high optical purity regardless of the optical purity of the dipeptide catalyst used, and as a result, have completed the method of the present invention.

[0003]

That is, according to the present invention, benzaldehyde whose benzene ring may be substituted with one or two aprotic substituents and hydrogen cyanide are combined with cyclo [(R) -phenylalanyl In the presence of — (R) -histidyl] or in the presence of cyclo [(S) -phenylalanyl- (S) -histidyl] to give each absolute configuration enriched in (S) or (R) Rich,
In the method for producing mandelonitrile in which the benzene ring may be substituted with one or two aprotic substituents, cyclo [(R) -phenylalanyl- (previously partially or completely racemized) is used. R) -histidyl] 1 equivalent or 1 equivalent of partially or completely racemized cyclo [(S) -phenylalanyl- (S) -histidyl] (hereinafter referred to as cyclo (Phe-His)). Mandelonitrile (abbreviated as follows) in which the absolute configuration is (S) -rich or (R) -rich, and the benzene ring may be substituted with one or two aprotic substituents.
It is described as (S) / (R) mandelonitrile derivative. Is present in an amount of 0.5 equivalent or more, and a method for producing an optically active mandelonitrile derivative (hereinafter, referred to as the method of the present invention) is provided. In other words, according to the present invention, benzaldehyde whose benzene ring may be substituted with one or two aprotic substituents and hydrogen cyanide are combined with cyclo [(R) -phenylalanyl- (R) -histidyl]. In the method for producing mandelonitrile in which the absolute configuration is rich in (S) and the benzene ring may be substituted with one or two aprotic substituents, Alternatively, relative to 1 equivalent of completely racemized cyclo [(R) -phenylalanyl- (R) -histidyl], the absolute configuration is rich in (S),
A method for producing an optically active mandelonitrile derivative, characterized in that 0.5 equivalents or more of mandelonitrile optionally substituted on the benzene ring with an aprotic substituent is present, and a benzene ring Benzaldehyde optionally substituted with one or two aprotic substituents and hydrogen cyanide are reacted in the presence of cyclo [(S) -phenylalanyl- (S) -histidyl] to give an absolute configuration In a method for producing a mandelonitrile rich in (R), which may have one or two benzene rings substituted with aprotic substituents, cyclo [(S)] partially or completely racemized in advance. −
Phenylalanyl- (S) -histidyl] per 1 equivalent of mandelonitrile in which the absolute configuration is rich in (R) and the benzene ring may be substituted with 1 or 2 aprotic substituents. Provided is a method for producing an optically active mandelonitrile derivative, characterized in that it is present in an amount of 5 equivalents or more.

In the method of the present invention, the aprotic substituent may be, for example, a phenoxy group (which may be substituted with a halogen atom) or a phenyl group (which may be substituted with a C ₁ -C ₁₀ alkyl group). A phenyl group may be substituted), a C _{1 to} C ₁₀ alkoxy group, a C _{1 to} C ₁₀ alkyl group, an acetoxy group, a benzyloxy group, a benzoyloxy group (a C _{1 to} C ₁₀ alkoxy group, C ₁ ~ C ₁₀
And optionally substituted with a phenyl group) and a halogen atom. Here, examples of the halogen atom include a fluorine atom, a chloro atom, a bromo atom, and an iodine atom. From the standpoint of product isolation, the mandelonitrile substituent which may be substituted in the benzene ring used in the method of the present invention with one or two aprotic substituents has a benzene ring which is aprotic. It is preferably the same as the substituent of benzaldehyde which may be substituted with one or two substituents. As one embodiment of the method of the present invention, the general formula

[Chemical 3] [In the formula, X and Y are the same or different, X represents a hydrogen atom, a fluorine atom or a chloro atom, and Y represents a hydrogen atom or a fluorine atom. ] The benzaldehyde derivative shown by these, and hydrogen cyanide are cyclo [(R)-
[Phenylalanyl- (R) -histidyl] to give a compound of the general formula

[Chemical 4] [In the formula, X and Y have the same meanings as described above, and * represents an asymmetric carbon atom. ] In a method for producing a mandelonitrile derivative having an absolute configuration of (S) -rich, a partially or completely racemized cyclo [(R) -phenylalanyl- (R) -histidyl] A method for producing an optically active mandelonitrile derivative, characterized in that 0.5 equivalent or more of a mandelonitrile derivative having an absolute configuration represented by the general formula 4 and rich in (S) is present in an amount of 1 equivalent. Can be given.

In the method of the present invention, the reaction is usually carried out in a solvent, the reaction temperature range is usually -20 to 25 ° C, preferably -5 to 10 ° C, and the reaction time range is the reaction temperature and the cyclo ( Although it depends on the amount of Phe-His), it is usually 0.5 to 20 hours, preferably 4 to 10 hours. The amount of the reagent used in the reaction is usually 1 to 5 for cyclo (Phe-His) with respect to 1 mol of benzaldehyde whose benzene ring may be substituted with one or two aprotic substituents.
Mol% and the (S) / (R) mandelonitrile derivative may be at least 0.5 mol%, but
0.5 to 20 mol% (however, at least 0.5 mol per 1 mol of cyclo (Phe-His)), hydrogen cyanide is usually 1 to 5
It is a mole. Examples of the solvent used include aprotic solvents such as ethyl ether, isopropyl ether, benzene and toluene. The reaction solution after completion of the reaction is treated with an inorganic acid such as dilute hydrochloric acid, and then subjected to ordinary post-treatment such as removal of excess hydrogen cyanide and solvent under reduced pressure to give the desired optically active mandelonitrile derivative. Obtainable. If necessary, it can be purified by an operation such as chromatography.

The aldehyde derivative which is the starting material compound in the method of the present invention may be a commercially available one or can be obtained by a known method. Cyclo (Phe-His) used in the method of the present invention can be prepared according to ordinary peptide synthesis. For example, cyclo [(R) -phenylalanyl- (R) -histidyl] is N-benzyloxycarbonyl- (R) -phenylalanine and (R)-.
It is condensed with histidine methyl ester to give N-benzyloxycarbonyl- (R) -phenylalanyl- (R).
-Histidine methyl ester is obtained, which is then subjected to a hydrogenolysis reaction in the presence of palladium-carbon, followed by heating under reflux in methanol to carry out a cyclization reaction. The cyclo (Ph
e-His) can be used as it is, but it is further disclosed in
No. 0-97052 and Synlett, 1991, 1991.
It is preferable to activate according to the method described in 63.
The cyclo (Phe-His) is partially or completely racemized, that is, the optical purity is 90% ee or less, and further 70%.
Since the following ee can be used, the method of the present invention has an advantage that it can be repeatedly used without paying attention to reduction in optical purity during recovery and recycling. (S) / used in the method of the present invention
The (R) mandelonitrile derivative can be obtained by the reaction described in JP-A-59-116256. The (S) / (R)
The mandelonitrile derivative may be used after isolation,
The reaction solution containing it may be used as it is without isolation, but it has a high optical purity, that is, an optical purity of 80%.
It is preferable to use an ee or more. The optically active mandelonitrile derivative produced by the method of the present invention is used as a raw material for producing ferroelectric liquid crystals, pharmaceuticals, agricultural chemicals, intermediates and the like. For example, 4-acetoxy form of optically active mandelonitrile, etc. is used as a raw material for ferroelectric liquid crystals (Proceedings of Spring Meeting of the Chemical Society of Japan, 2015-2017 (1990)),
(R) -Mandelonitrile is an intermediate of cephalosporin antibiotic cefamandole, and (R) -mandelonitrile's 4-methoxy, 4-acetoxy and 4-benzyloxy compounds have cardiac functions. As an intermediate of denopamine which is an improving agent, an optically active mandelonitrile derivative represented by the general formula 4 is useful, for example, as an intermediate of pyrethroid insecticide.

[0007]

EXAMPLES Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples. In the following examples and comparative examples, the optical purity (mirror image) of cyclo [(R) -phenylalanyl- (R) -histidyl] and (S) -2-hydroxy-2- (3′-phenoxyphenyl) acetonitrile Excess rate% e
e) was determined by high performance liquid chromatography (HPLC), and the analysis conditions were as follows: [Column, Ultron
ES-OVM; mobile phase, 20 mM KH ₂ PO ₄ (pH
7.5); Flow rate, 1.0 ml / min; Detection, UV25
4 nm] and [column, Sumipax OA-41
00; mobile phase, hexane / dichloroethane / ethanol / ethyl acetate = 800/200/10/1; flow rate, 1.
0 ml / min; detection, UV 254 nm]. Example 1 12.2% ee cyclo [(R) -phenylalanyl- (R)
-Histidyl] (activated according to the method described in Synlett, 1991, 263, that is, after being dissolved in methanol, the solution is precipitated by pouring into ethyl ether under vigorous stirring, which is filtered and dried. 0.308 g (1.1 mmol), 3-phenoxybenzaldehyde 10.2 g (50 mmol), 92.0% ee of (S) -2-hydroxy-2- (3'-phenoxyphenyl) acetonitrile.
After 1.0 g (4.4 mmol) and 40 ml of toluene were mixed at 5 ° C, the mixture was stirred at the same temperature for 1 hour. After 3.8 ml (99 mmol) of hydrogen cyanide was added dropwise at the same temperature, stirring was continued at the same temperature for 4 hours. Next, 20 ml of 0.5% hydrochloric acid water was added to this reaction solution, and the mixture was stirred for 30 minutes, then liquid separation was performed, and the aqueous layer was further added to 20 minutes.
Extracted twice with ml of toluene. All the organic layers thus obtained are combined, and excess hydrogen cyanide and toluene are distilled off under reduced pressure to obtain the desired optically active (S)-
2-Hydroxy-2- (3'-phenoxyphenyl) acetonitrile was obtained with a chemical yield of 79% and an optical purity of 86.6% ee. Example 2 12.2% ee cyclo [(R) -phenylalanyl- (R)
-Histidyl] 0.308 g (1.1 mmol) was used in place of 2% ee, and the same operation as in Example 1 was carried out. As a result, the desired optically active (S) -2-hydroxy-2-
(3′-phenoxyphenyl) acetonitrile was obtained with a chemical yield of 43% and an optical purity of 81.6% ee. Example 3 12.2% ee cyclo [(R) -phenylalanyl- (R)
-Histidyl] 0.308 g (1.1 mmol) instead of 40% ee
The same operation as in Example 1 was carried out except that it was used, and the desired optically active (S) -2-hydroxy-2-
(3′-phenoxyphenyl) acetonitrile was obtained with a chemical yield of 90% and an optical purity of 90.2% ee. Example 4 12.2% ee cyclo [(R) -phenylalanyl- (R)
-Histidyl] 66.8 instead of 0.308 g (1.1 mmol)
The same operation as in Example 1 was carried out except that that of% ee was used, and the desired optically active (S) -2-hydroxy-
2- (3′-phenoxyphenyl) acetonitrile was obtained with a chemical yield of 89% and an optical purity of 96.0% ee. Example 5 12.2% ee cyclo [(R) -phenylalanyl- (R)
-Histidyl] 84.6% ee instead of 0.308 g (1.1 mmol)
The same operation as in Example 1 was carried out except that it was used, and the optically active (S) -2-hydroxy-2- (3′-
Phenoxyphenyl) acetonitrile has a chemical yield of 96
%, Optical purity 94.8% ee. Example 6 Cyclo (phenylalanyl histidyl) 0.3 with 12.2% ee
Instead of 08 g (1.1 mmol), racemic one was used, and
Example except that 0.25 g (1.1 mmol) of 96% ee was used instead of 1.0 g (4.4 mmol) of (S) -2-hydroxy-2- (3′-phenoxyphenyl) acetonitrile with 92.0% ee. When the same operation as in 1 was performed, the optically active (S) -2-hydroxy-2- (3′-phenoxyphenyl) acetonitrile had a chemical yield of 79% and an optical purity of 80%.
Got with ee.

Comparative Example 1 (S) -2-Hydroxy-2- (3'-phenoxyphenyl) acetonitrile with 92.0% ee 1.0g (4.4 mmol) was added and the same procedure as in Example 1 was carried out. The target optically active (S) -2-hydroxy-2- (3'-phenoxyphenyl) acetonitrile has a chemical yield of 27% and optical purity.
Obtained with 11.0% ee. Comparative Example 2 The same operation as in Example 2 was carried out without adding 1.0 g (4.4 mmol) of (S) -2-hydroxy-2- (3′-phenoxyphenyl) acetonitrile having 92.0% ee, and the desired optical Active (S) -2-hydroxy-2- (3'-phenoxyphenyl) acetonitrile has a chemical yield of 4%, optical purity
Obtained at 3.4% ee. Comparative Example 3 The same operation as in Example 3 was carried out without adding 1.0 g (4.4 mmol) of (S) -2-hydroxy-2- (3′-phenoxyphenyl) acetonitrile with 92.0% ee, and the desired optical Active (S) -2-hydroxy-2- (3'-phenoxyphenyl) acetonitrile has a chemical yield of 62%, optical purity
Obtained at 37.2% ee. Comparative Example 4 The same operation as in Example 4 was carried out without adding 1.0 g (4.4 mmol) of (S) -2-hydroxy-2- (3′-phenoxyphenyl) acetonitrile having 92.0% ee. Active (S) -2-hydroxy-2- (3'-phenoxyphenyl) acetonitrile has a chemical yield of 81%, optical purity
Obtained with 64.6% ee. Comparative Example 5 The same operation as in Example 5 was carried out without adding 1.0 g (4.4 mmol) of (S) -2-hydroxy-2- (3′-phenoxyphenyl) acetonitrile having 92.0% ee. Active (S) -2-hydroxy-2- (3'-phenoxyphenyl) acetonitrile has a chemical yield of 89%, optical purity
It was obtained with 80.0% ee.

[0009]

EFFECT OF THE INVENTION By using the method of the present invention, the catalyst cyclo [(R) -phenylalanyl- (R) -histidyl] or cyclo [(S) -phenylalanyl- (S)] is used.
-Histidyl], the optically active mandelonitrile derivative can be obtained with high chemical yield and high optical purity.

Claims (4)

[Claims] 1. A benzaldehyde, which may have one or two benzene rings substituted with an aprotic substituent, and hydrogen cyanide are mixed with cyclo [(R) -phenylalanyl-
In the presence of (R) -histidyl] or cyclo [(S)-
[Phenylalanyl- (S) -histidyl] and the benzene ring is an aprotic substituent having an absolute configuration of (S) -rich or (R) -rich, respectively.
Alternatively, in the method for producing an optionally substituted two mandelonitrile, one equivalent or a part of cyclo [(R) -phenylalanyl- (R) -histidyl], which is partially or completely racemized in advance, is used. Alternatively, fully racemized cyclo [(S) -phenylalanyl-
(S) -histidyl] per equivalent of (S) -rich or (R) -absolute configuration, the benzene ring may be substituted with one or two aprotic substituents. A method for producing an optically active mandelonitrile derivative, characterized in that 0.5 equivalent or more of delonitrile is present. 2. Benzaldehyde, which may have one or two benzene rings substituted with aprotic substituents, and hydrogen cyanide are mixed with cyclo [(R) -phenylalanyl-
(R) -histidyl] to produce mandelonitrile which is enriched in (S) in absolute configuration and in which one or two benzene rings may be substituted with aprotic substituents. In advance, the benzene ring is aprotic with an absolute configuration of (S) per 1 equivalent of cyclo [(R) -phenylalanyl- (R) -histidyl] partially or completely racemized in advance. 1 in substituent
Alternatively, a method for producing an optically active mandelonitrile derivative, characterized in that 0.5 equivalents or more of mandelonitrile optionally substituted with 2 is present. 3. Benzaldehyde, which may have one or two benzene rings substituted with aprotic substituents, and hydrogen cyanide are combined with cyclo [(S) -phenylalanyl-
(S) -histidyl] in the presence of (R) to produce a mandelonitrile in which the benzene ring may be substituted with one or two aprotic substituents. In the above, the benzene ring which is rich in absolute configuration (R) is aprotic with respect to 1 equivalent of cyclo [(S) -phenylalanyl- (S) -histidyl] partially or completely racemized in advance. 1 in substituent
Alternatively, a method for producing an optically active mandelonitrile derivative, characterized in that 0.5 equivalents or more of mandelonitrile optionally substituted with 2 is present. 4. A general formula: ## STR1 ## [In the formula, X and Y are the same or different, X represents a hydrogen atom, a fluorine atom or a chloro atom, and Y represents a hydrogen atom or a fluorine atom. ] The benzaldehyde derivative shown by these, and hydrogen cyanide are cyclo [(R)-
[Phenylalanyl- (R) -histidyl] in the presence of a compound of the general formula: [In the formula, X and Y have the same meanings as described above, and * represents an asymmetric carbon atom. ] In a method for producing a mandelonitrile derivative having an absolute configuration of (S) -rich, a partially or completely racemized cyclo [(R) -phenylalanyl- (R) -histidyl] A method for producing an optically active mandelonitrile derivative, characterized in that 0.5 equivalent or more of a mandelonitrile derivative having an absolute configuration represented by the general formula 2 and rich in (S) is present per 1 equivalent. .