JPH0819071B2 - 3-Amino-2-acyloxy-butyronitrile derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] (In the formula, R ¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 8 carbon atoms, R ² represents a linear or branched alkanoyl group having 1 to 4 carbon atoms, Represents an aroyl group optionally substituted with a chlorine atom or a methoxy group, a linear or branched alkoxycarbonyl group having 1 to 5 carbon atoms, or an aralkoxycarbonyl group optionally substituted with a chlorine atom or a methoxy group. , R ³ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a chlorine atom or an aryl group which may be substituted with a methoxy group). The present invention relates to a butyronitrile derivative and a method for producing the same.

The 3-amino-2-acyloxy-butyronitrile derivative represented by the general formula (I) of the present invention has use as a synthetic raw material for pharmaceuticals. For example, in the general formula (I), a compound in which R ¹ is a cyclohexyl group, a 2-position asymmetric carbon is (R) -configuration and a 3-position asymmetric carbon is (S) -configuration is
Optical activity (2R, 3S), which is an intermediate for the production of amino acid derivatives useful as therapeutic agents for hypertension due to human renin inhibitory action
It can be used as a starting material for the synthesis of -3-amino-4-cyclohexyl-2-hydroxybutyric acid (see JP-A-62-234071, Japanese Pharmacy Society 108th Annual Meeting Abstracts, page 39, (1988) and Reference Examples).

[Conventional technology]

Optical activity (2R, 3S), which is a useful intermediate for the production of pharmaceuticals
-3-Acyl-4-cyclohexyl-2-hydroxybutyric acid has the general formula (In the formula, R ¹ and R ² have the same meanings as described above), an aldehyde derivative represented by the above, or a sodium sulfite adduct thereof, sodium cyanide, potassium cyanide, or another cyanide salt in the presence of dilute hydrochloric acid, or sodium cyanide, A general formula obtained by directly reacting a cyanide salt such as potassium cyanide It was obtained exclusively by hydrolyzing a 3-amino-2-hydroxy-butyronitrile derivative represented by the formula (wherein R ¹ and R ² have the same meanings as described above) under acidic conditions (JP-A-62-62). -234071).

In the production process, when the aldehyde derivative represented by the general formula (II) having the (S) -configuration is used, the 3-amino-2-hydroxy-butyronitrile derivative represented by the general formula (III) is at the 2-position. The asymmetric carbon of (R)-
It is obtained as a mixture of two diastereomers having the configuration and the (S) -configuration, but its stereoselectivity has hitherto been very low (see JP-A-62-33141).

Separation of the 3-amino-2-hydroxy-butyronitrile derivative represented by the general formula (III) obtained with such low stereoselectivity is very complicated (see JP-A-62-33141). When something is hydrolyzed under acidic conditions,
The resulting 3-amino-2-hydroxybutyric acid derivative also becomes a mixture of two diastereomers with low stereoselectivity,
Separation of the desired (2R, 3S) -3-amino-2-hydroxybutyric acid derivative from this was also accompanied by great difficulty (see JP-A-62-234071).

[Problems to be solved by the invention]

The present inventors have found that 3-amino-
A method for producing a 2-hydroxybutyric acid derivative from an aldehyde derivative represented by the general formula (II) in a highly stereoselective manner, that is, from an aldehyde derivative represented by the general formula (II) having a (S) -configuration (2R As a result of searching for a method for producing a (3,3S) -3-amino-2-hydroxybutyric acid derivative with high stereoselectivity, the compound of the present invention and a method for producing the same were found, and the present invention was completed.

[Means for solving problems]

Novel 3-amino-2-represented by the general formula (I)
The acyloxy-butyronitrile derivative can be produced according to the following reaction formula.

(In the formula, R ¹ , R ² , and R ³ have the same meanings as described above, and R ⁵ represents a linear or branched lower alkyl group having 1 to 4 carbon atoms.) (First Step) This step is generally After introducing a protecting group for an amino group into the 2-amino-propionic acid ester derivative represented by the formula (IV), the ester group is reduced, and further, if necessary, the 3-position phenyl group or the like is reduced to give ) To produce a 2-amino-propanol derivative (see Reference Example).

As 2-amino-propionic acid ester hydrochloride,
2-Amino-methyl propionate hydrochloride, 2-amino-
Examples include ethyl propionate hydrochloride, isopropyl 2-amino-propionate hydrochloride, and these can be produced by known methods (Chem.Pharm.Bull., 13 , 99).
5 (1965)., And SR Sandler and W. Karo, “Function
al Group Preparations ", Academic Press, New York, 196
8, pp245-265.).

As the amino group-protecting group introduced into 2-amino-propionate hydrochloride, any group can be used as long as it can be removed by hydrolysis under acidic conditions, but preferably a formyl group, an acetyl group, 1 to 1 carbon atoms such as propionyl group, butyryl group, isobutyryl group
4 straight or branched alkanoyl group, benzoyl group,
Unsubstituted or substituted aroyl group such as p-chlorobenzoyl group and p-methoxybenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, t-butyloxycarbonyl group and the like having 1 to 1 carbon atoms
An unsubstituted or substituted aralkoxycarbonyl group such as a straight chain or branched alkoxycarbonyl group of 5, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group and a p-methoxybenzyloxycarbonyl group is used. These protecting groups can be introduced by a known method (TW Greene, “Protective Groups in Organic Sy
nthesis ", John-Wiley & Sons, New York, 1980, pp218-28
7.).

The reduction of the ester group of the amino group-protected 2-amino-propionic acid ester is carried out using an appropriate reducing agent, for example, sodium borohydride in the presence of lithium chloride or lithium bromide (see Reference Example).

When the 2-amino-propanol derivative represented by the general formula (V) has a phenyl group at the 3-position, it is hydrogenated in the presence of a suitable catalyst, for example, 5% rhodium-alumina to give cyclohexyl at the 3-position. It is also possible to obtain a 2-amino-propanol derivative having a group (see Reference Example).

In this step, in the general formula (IV) having the (S) -configuration,
When the 2-amino-propionic acid ester hydrochloride represented by is used, the 2-amino-propanol derivative represented by the general formula (V) having the (S) -configuration is obtained without racemization. .

(Second Step) In this step, the 2-amino-propanol derivative represented by the general formula (V) is oxidized to produce the 2-amino-propanal derivative represented by the general formula (II). As a preferable oxidation method, a method using sulfur trioxide in dimethyl sulfoxide-pyridine complex-triethylamine can be exemplified (see Reference Example).

In this step, the general formula (V) having the (S) -configuration is shown.
When the 2-amino-propanol derivative represented by is used, the 2-amino-propanal derivative represented by the general formula (II) having the (S) -configuration is obtained without racemization.

(Third Step) In this step, the 2-amino-propanal derivative represented by the general formula (II) is represented by the general formula R ³ COOCOR ⁴ (VI) (wherein R ³ and R ⁴ are each independently, Hydrogen atom, carbon number 1
4 represents a linear or branched alkyl group of 4 or an aryl group which may be substituted with a chlorine atom or a methoxy group) and a carboxylic acid anhydride, and a quaternary ammonium salt, a quaternary ammonium salt, and a tertiary amine. , Or a quaternary ammonium salt and a tertiary amine in the presence of the compound of the general formula (I)
To produce an amino-2-acyloxy-butyronitrolyl derivative.

As the carboxylic acid anhydride represented by the general formula (VI),
Formic acid acetic anhydride, acetic anhydride, propionic anhydride, isobutyric anhydride, benzoic anhydride, p-chlorobenzoic anhydride, p-methoxybenzoic anhydride and the like can be exemplified, but acetic anhydride or benzoic anhydride is preferably used. To be The carboxylic acid anhydride used is used in an amount of 1.0 to 20 equivalents based on the 2-amino-propanal derivative, but preferable results are obtained when used in 2.5 to 7.0 equivalents. Examples of the quaternary ammonium salt include tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltributylammonium chloride, benzyltributylammonium bromide and methyltrioctyl chloride. Examples include ammonium, N-benzylquinidinium chloride, N-benzylquininium chloride, N-benzylcinchonidinium chloride, N-benzylcinchoninium chloride, N-benzyl-N-methylephedrinium chloride and the like. The quaternary ammonium salt is
0.005-0.20 relative to 2-amino-propanal derivative
It is used in equivalent amounts, but preferable results are obtained when 0.01 to 0.07 equivalents are used. As the tertiary amine, trimethylamine, triethylamine, ethyldiisopropylamine, tributylamine, N, N-tetramethylethylenediamine, N-methylpyrrolidine, N-ethylpyrrolidine, N-benzylpyrrolidine, N-methylmorpholine,
N-ethylmorpholine, N-benzylmorpholine, 1,4
-Diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,8-diazabicyclo [5,4,0] undec-7-ene, pyridine, 2 -Methylpyridine, 2,4,5-trimethylpyridine, 4-dimethylaminopyridine, quinoline and the like can be exemplified, but pyridine and 4-dimethylaminopyridine are preferably used. The tertiary amine is used in an amount of 0.001 to 0.10 equivalent to the 2-amino-propanal derivative, preferably 0.005 to
Used in 0.02 equivalents.

Examples of the cyanide salt used in this reaction include alkali metal cyanide salts such as sodium cyanide and potassium cyanide. The hydrocyanic acid salt is used in an amount of 1.0 to 10 equivalents relative to the 2-amino-propanal derivative, but favorable results are obtained when used in an amount of 1.5 to 6.0 equivalents.

This reaction is carried out in an organic solvent, more preferably a two-layer system of water and an organic solvent. The organic solvent used is dichloromethane, chloroform, carbon tetrachloride, 1,2
-Dichloroethane, halogenated hydrocarbon solvents such as 1,1,1-trichloroethane, ethyl acetate, acetic acid esters such as isoamyl acetate, toluene, hydrocarbon solvents such as xylene, which are immiscible with water, can be exemplified. Dichloromethane, chloroform and 1,2-dichloroethane are preferably used. When the reaction is carried out in a two-layer system of water and an organic solvent, the composition ratio is not particularly limited, but a composition ratio of 1: 1 gives the most preferable result.

This reaction is carried out at -10 to 50 ° C, but when the reaction is carried out in a two-layer system of water and an organic solvent, the most preferable result is obtained at 0 to 5 ° C.

When a 2-amino-propanal derivative having a (S) -configuration is used in this reaction, a 3-amino-2-acyloxy-butyronitrile derivative having a (2R, 3S) -configuration is converted into a (2S, 3S) -configuration. It is highly selective (up to 7: 1) for 3-amino-2-acyloxy-butyronitrile derivatives having

When this reaction is carried out in the absence of carboxylic acid anhydride, a 2-amino-propanal derivative having a (S) -configuration is used to form 3-amino-of the formula (III).
The 2-hydroxy-butyronitrile derivative is obtained as an equal mixture of two diastereomers (see Comparative Examples 1 and 2).

The 3-amino-2-acyloxy-butyronitrile derivative represented by the general formula (I) obtained by the above synthesis step is subjected to a hydrolysis reaction under acidic conditions to simultaneously hydrolyze the nitrile group and the 3-position. Deprotection of amino group and 2-position hydroxyl group at the same time 3-amino-2-hydroxybutyric acid hydrochloride useful as a pharmaceutical synthesis intermediate represented by the formula (wherein R ¹ has the same meaning as described above) was obtained. This hydrolysis reaction is (2R, 3S) -3
When a sample containing -amino-2-acyloxy-4-cyclohexyl-butyronitrile in a ratio of 7: 1 to its (2S, 3S) -form was used, it was treated as a therapeutic agent for hypertension due to its human renin inhibitory effect. Optical activity used as an intermediate for the production of useful amino acid derivatives (2R, 3
S) -3-Amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride was obtained highly stereoselectively.

Hereinafter, the content of the present invention will be described in detail with reference to Examples, Reference Examples and Comparative Examples, but the present invention is not limited to these.

Reference Example 1 (s) -Phenylalanine methyl ester hydrochloride 20.0
g (93 mmol) was suspended in 100 ml of anhydrous tetrahydrofuran,
Under ice cooling, 27.1 ml (194 mmol) of triethylamine and 12.5 ml (110 mmol) of isopropyl chlorocarbonate were simultaneously added dropwise over 30 minutes. After stirring for 1 hour under ice cooling, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with 1M hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate, and saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 24.0 g (98%) of N- (isopropoxycarbonyl)-(S) -phenylalanine methyl ester as a white solid.

Melting point: 32-34 ° C Rf: 0.76 (chloroform / methanol = 30/1) IR (KBr): 1735, 1680cm ^-1 NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6Hz), 3.11 (2H , d, J = 6Hz), 3.72 (3
H, s), 4.50-5.20 (2H, m), 4.92 (1H, quintet, J = 6H
z), 7.04 to 7.48 (5H, m) Reference Example 2 12.0 g (45 mmol) of N- (isopropoxycarbonyl)-(S) -phenylalanine methyl ester was dissolved in 145 ml of anhydrous tetrahydrofuran to prepare lithium bromide monohydrate.
9.48g (90mmol), sodium borohydride 3.42g (90mm
ol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added with stirring (pH 2-3), and the precipitated crystals were collected by filtration. After washing with water and drying under reduced pressure, white crystals of N- (isopropoxycarbonyl)-(S) -phenylalaninol
11.1 g was quantitatively obtained.

Melting point: 77 to 79 ° C Rf: 0.72 (chloroform / methanol = 5/1) IR (KBr): 1680cm ^-1 NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6Hz), 1.96 to 2.30 (1H , m), 2.88 (2
H, d, J = 7Hz), 3.44-4.16 (3H, m), 4.65-5.13 (1H, m),
4.92 (1H, quintet, J = 6Hz), 7.05 to 7.47 (5H, m) Reference Example 3 N- (isopropoxycarbonyl)-(S) -phenylalaninol 1.0g (4.2mmol) and 5% rhodium-alumina 50mg 1.5 ml of methanol was added to, and hydrogen pressure (4 kg
/ cm ^{2 to 3} kg / cm ² ). Add benzene to the residue,
Further, it was concentrated under reduced pressure to obtain 0.98 g (96%) of N- (isopropoxycarbonyl- (S) -cyclohexylalaninol as a colorless viscous oil.

Rf: 0.76 (chloroform / methanol = 5/1) IR (neat ): 1680cm -1 NMR (CDCl 3) δ: 1.23 (6H, d, J = 6Hz), 0.71~2.13 (13H, m), 3.36~
4.02 (3H, m), 4.51 ~ 5.15 (1H, m), 4.93 (1H, quintet, J
= 6 Hz) Reference Example 4 N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol 505 mg (2.1 mmol), toluene 1.30
ml, dimethyl sulfoxide 2.55 ml (36 mmol) and triethylamine 1.45 ml (10 mmol) were added with sulfur trioxide-pyridine complex salt 1.66 g (10 mmol), and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, and the mixture was extracted with toluene, and the extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine in that order. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure to give N- (isopropoxycarbonyl)-(S) as a pale yellow oil.
367 mg (73%) of cyclohexylalaninal was obtained.
This product was used for the next production of the 3-amino-2-acyloxybutyrotitril derivative without purification.

Rf: 0.40 (hexane / ethyl acetate = 7/3) NMR (CDCl ₃ ) δ: 0.64 to 1.94 (13H, m), 1.23 (6H, d, J = 7Hz), 4.13 to
4.45 (1H, m), 4.77 to 5.25 (2H, m), 9.61 (1H, s) Example 1 N-obtained from 30.0 mg (0.12 mmol) of N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol −
(Isopropoxycarbonyl)-(S) -cyclohexylalaninal 25.0 mg (0.10 mmol) was added to methylene chloride 1.5 m.
Dissolve in l, acetic anhydride 0.035ml (0.37mmol), benzyltributylammonium chloride 1.9mg (0.006mmol), 0.25M
1.5 ml (0.38 mmol) of an aqueous solution of sodium cyanide was sequentially added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. 50% saturated saline solution was added to the reaction solution, and extracted with methylene chloride.
It was washed successively with saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate 30: 1 → 10: 1) to give a colorless oily (2R, 3S) -2- Acetoxy
4-Cyclohexyl-3-isopropoxycarbonylaminobutyronitrile and its mixture with (2S, 3S) -form 15.7 mg (41%: N- (isopropoxycarbonyl)-
(Total yield from (S) -cyclohexylalaninol)
I got The production ratio of (2R, 3S) -body and (2S, 3S) -body is NM
It was determined to be 6: 1 from the R spectrum (400 MHz).

Rf: 0.54 (hexane / ethyl acetate = 7/3) IR (nujol): 1755,1690 cm ^-1 NMR (CDCl ₃ ) (2R, 3S) -form; δ0.81 to 1.90 (13H, m), 1.25 (6H , d, J
= 6.1Hz), 2.16 (3H, s), 4.00 to 4.28 (1H, m), 4.37 to 4.
73 (1H, m), 4.83 to 5.08 (1H, m), 5.40 (1H, d, J = 4.5H
z) (2S, 3S) -body; δ 0.81 to 1.90 (13H, m), 1.25 (6H, d, J
= 6.1Hz), 2.14 (3H, s), 4.00 to 4.28 (1H, m), 4.37 to 4.
73 (1H, m), 4.83 to 5.08 (1H, m), 5.43 (1H, d, J = 3.5H
z) MS (m / e): 311 ([M + 1] ⁺ ), 251,212 Example 2 N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol N-obtained from 30.0 mg (0.12 mmol)
25.3 mg (0.10 mmol) of (isopropoxycarbonyl)-(S) -cyclohexylalaninal was added to 1.5 m of methylene chloride.
Dissolve in l, acetic anhydride 0.035 ml (0.37 mmol), 4-dimethylaminopyridine 0.15 mg (0.0012 mmol), 0.25M sodium cyanide aqueous solution 1.5 ml (0.38 mmol) are sequentially added under water cooling and stirred at the same temperature for 1.5 hours. did. The same treatment as in Example 1 was carried out to give colorless oily (2R, 3S) -2-acetoxy-4-.
Cyclohexyl-3-isopropoxycarbonylaminobutyronitrile and its mixture with (2S, 3S) -form 10.
5 mg (27%: N- (isopropoxycarbonyl)-(S)
-Total yield from cyclohexyl alaninol) was obtained. The production ratio of the (2R, 3S) -form and the (2S, 3S) -form was determined to be 6: 1 from the NMR spectrum (400 MHz) as in Example 1.

Example 3 N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol N-obtained from 505 mg (2.1 mmol)
36.7 mg (1.5 mmol) of (isopropoxycarbonyl)-(S) -cyclohexylalaninal was added to 5.0 ml of methylene chloride.
Dissolved in acetic anhydride 0.60 ml (6.4 mmol), 4-dimethylaminopyridine 2.5 mg (0.02 mmol), benzyltributylammonium chloride 32.0 mg (0.10 mmol), water 3.75 ml, 5M
An aqueous solution of sodium cyanide (1.25 ml, 6.3 mmol) was sequentially added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. Treated as in Example 1, colorless oily mixture of (2R, 3S) -2-acetoxy-4-cyclohexyl-3-isopropoxycarbonylaminobutyronitrile and its (2S, 3S) -form 419 mg ( 65%: N- (isopropoxycarbonyl)-
(Total yield from (S) -cyclohexylalaninol)
I got The production ratio of the (2R, 3S) -form and the (2S, 3S) -form was determined to be 6: 1 from the NMR spectrum (400 MHz) as in Example 1.

Example 4 N- obtained from 101 mg (0.42 mmol) of N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol.
82.5 mg (0.34 mmol) of (isopropoxycarbonyl)-(S) -cyclohexylalaninal was added to 1.0 m of methylene chloride.
Dissolve in l, acetic anhydride 0.12 ml (1.3 mmol), 4-dimethylaminopyridine 0.5 mg (0.004 mmol), N-benzylquinidinium chloride 9.2 mg (0.02 mmol), water 0.75 ml and 5M sodium cyanide aqueous solution 0.25 ml (1.3 mmol) was sequentially added under ice cooling, and the mixture was stirred at the same temperature for 3 hours. Treated as in Example 1, colorless oily (2R, 3S) -2-acetoxy-4
-Cyclohexyl-3-isopropoxycarbonylaminobutyronitrile and its mixture with (2S, 3S) -form 7
4.2 mg (57%: N- (isopropoxycarbonyl)-
(Total yield from (S) -cyclohexylalaninol)
I got The production ratio of the (2R, 3S) -form and the (2S, 3S) -form was determined to be 7: 1 from the NMR spectrum (400 MHz) as in Example 1.

Example 5 N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol N-obtained from 30.0 mg (0.12 mmol)
(Isopropoxycarbonyl)-(S) -cyclohexylalaninal 25.0 mg (0.10 mmol) was added to methylene chloride 1.5 m.
Dissolve in l, acetic anhydride 0.035 ml (0.37 mmol), pyridine 0.
03 mg (0.37 mmol), benzyltributylammonium chloride 1.9 mg (0.006 mmol), and 0.25 M sodium cyanide aqueous solution 1.5 ml (0.38 mmol) were sequentially added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. The same treatment as in Example 1 was carried out to give colorless oily (2R, 3S) -2-acetoxy-4-cyclohexyl-3.
18.6 mg (49%: total yield from N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol) of isopropoxycarbonylaminobutyronitrile and its mixture with the (2S, 3S) -form were obtained. . The production ratio of the (2R, 3S) -form and the (2S, 3S) -form was determined to be 6: 1 from the NMR spectrum (400 MHz) as in Example 1.

Examples 6 to 24 Examples 6 to 24 were performed in the same manner as in Example 3 and the following results were obtained. All carboxylic acid anhydrides are acetic anhydride 3.
Performed using 6 equivalents. In addition, the yield is the total yield from N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol, which is the (2R, 3S) -form and the (2S, 3S) -form.
The production ratio with the body was determined from the NMR spectrum (400 MHz).

Example 25 N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol N-obtained from 30.0 mg (0.12 mmol)
(Isopropoxycarbonyl)-(S) -cyclohexylalaninal 25.0 mg (0.10 mmol) was added to methylene chloride 1.5 m.
Dissolve in l, benzoic anhydride 0.07 ml (0.37 mmol), 4-dimethylaminopyridine 0.15 mg (0.0012 mmol), benzyltributylammonium chloride 2.0 mg (0.0066 mmol), 0.2
1.5M aqueous solution of 5M sodium cyanide (0.38mmol) was sequentially added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. The residue obtained by treating in the same manner as in Example 1 was purified by thin layer chromatography (silica gel, hexane-ethyl acetate 3: 1), and colorless oily (2R, 3S) -2-benzoxy-4-cyclohexyl- A mixture of 3-isopropoxycarbonylaminobutyronitrile and its (2S, 3S) -form 27.2 mg (59%: N-
(Isopropoxycarbonyl)-(S) -cyclohexylalaninol was obtained. (2R, 3S)-
The ratio of the (2S, 3S) -form to the NMR spectrum (400MH
z) was determined to be 5: 1.

Rf: 0.69 (hexane / ethyl acetate = 7/3) IR (neat): 1735, 1720, 1690 cm ^-1 NMR (CDCl ₃ ) (2R, 3S) -form; δ 0.82 to 1.94 (19H, m), 4.10 ~ 4.46 (1
H, m), 4.57 to 4.76 (1H, m), 4.82 to 5.10 (1H, m), 5.64
(1H, d, J = 5.0Hz), 7.40 to 7.75 (3H, m), 8.00 to 8.16 (2
H, m) (2S, 3S) -body; δ 0.82 to 1.94 (19H, m), 4.10 to 4.46 (1
H, m), 4.57 to 4.76 (1H, m), 4.82 to 5.10 (1H, m), 5.63
(1H, d, J = 3.7Hz), 7.40 to 7.75 (3H, m), 8.00 to 8.16 (2
H, m) MS (m / e): 313,212 Comparative Example 1 N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol N-obtained from 30.0 mg (0.12 mmol)
(Isopropoxycarbonyl)-(S) -cyclohexylalaninal 25.0 mg (0.10 mmol) was added to methylene chloride 1.5 m.
dissolved in l, benzyltributylammonium chloride 1.9mg
(0.006mmol), 0.25M sodium cyanide aqueous solution 1.5ml
(0.38 mmol) was sequentially added under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. Treated as in Example 1 to give crude (2R, 3S) -4.
-Cyclohexyl-2-hydroxy-3-isopropoxyl carbonylaminobutyronitrile and its (2S, 3
A mixture with S) -form was obtained. 0.25m acetic anhydride to this mixture
l, catalytic amount of 4-dimethylaminopyridine, pyridine 0.5
ml was added, and the mixture was stirred at room temperature for 2 hours. 1M Hydrochloride was added to the reaction solution, which was extracted with ether. The extract was washed successively with saturated saline, saturated copper sulfate aqueous solution, saturated saline, 1M sodium hydroxide aqueous solution, and saturated saline. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, hexane-ethyl acetate 30: 1 → 1).
2: 1 mg of a colorless oily mixture of (2R, 3S) -2-acetoxy-4-cyclohexyl-3-isopropoxycarbonylaminobutyronitrile and its (2S, 3S) -form. 52%: N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol total yield) was obtained. The production ratio of the (2R, 3S) -form and the (2S, 3S) -form was 1: 1 from the NMR spectrum (400 MHz) as in Example 1.
I decided.

Comparative Example 2 N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol obtained from 30.0 mg (0.12 mmol) of N-
25.4 mg (0.11 mmol) of (isopropoxycarbonyl)-(S) -cyclohexylalaninal was added to 1.5 m of methylene chloride.
Dissolve in l, 0.25N sodium cyanide aqueous solution 1.5m under ice cooling
l (0.38 mmol) was added, and the mixture was stirred at the same temperature for 1.5 hours. Treatment as in Example 1 gave crude (2R, 3S) -4-cyclohexyl-2-hydroxy-3-isopropoxylcarbonylaminobutyronitrile and its mixture with (2S, 3S) -form. . To this mixture were added acetic anhydride 0.25 ml, pyridine 0.5 ml, and a catalytic amount of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 3 hours. Treated as in Comparative Example 1,
Colorless oily (2R, 3S) -2-acetoxy-4-cyclohexyl-3-isopropoxycarbonylaminobutyronitrile and its mixture with (2S, 3S) -form 20.2 mg
(53%: N- (isopropoxycarbonyl)-(S) -cyclohexylalaninol total yield) was obtained.
The production ratio of the (2R, 3S) -form and the (2S, 3S) -form was determined to be 1: 1 from the NMR spectrum (400 MHz) as in Example 1.

Reference Example 5 (2R, 3S) -2-acetoxy-4-cyclohexyl-
392 mg (1.3 mmol) of a 6: 1 mixture of 3-isopropoxycarbonylaminobutyronitrile and its (2S, 3S) -form was dissolved in 20 ml of ethyl acetate, 5 ml of water and 13 ml of concentrated hydrochloric acid were added, and the reaction mixture was heated to 100 ° C. The mixture was heated to and ethyl acetate was distilled off. Further, 5 ml of concentrated hydrochloric acid was added, and the mixture was heated with stirring at 80 ° C. for 9 hours. The reaction solution was concentrated under reduced pressure to about 1 to 2 ml, allowed to stand overnight, and the precipitated crystals were collected by filtration. After washing with toluene, it was dried under reduced pressure to obtain 111 mg (37%) of white crystals of (2R, 3S) -3-amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride.

Melting point: 190 ° C ▲ [α] ²⁰ _D ▼: -12.4 ° (C = 0.482, 1NHCl) -12.2 ° (C = 2.045, H ₂ O) IR (KBr): 1725cm ^-1 NMR (D ₂ O) δ : 0.86 to 1.78 (13H, m), 3.70 (1H, dt, J = 7.2,3.5Hz),
4.36 (1H, d, J = 3.5Hz) MS (m / e): 202 ([MH-HCl] ⁺ ), 156,126,104 Reference Example 6 (2R, 3S) -2-acetoxy-4-cyclohexyl-
21.6 mg (0.070 mmol) of a 6: 1 mixture of 3-isopropoxycarbonylaminobutyronitrile and its (2S, 3S) -form
Was hydrolyzed in the same manner as in Reference Example 5, the reaction solution was concentrated to dryness under reduced pressure, and crude (2R, 3S) -3-amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride and its (2S, 3
19.3 mg of a 6: 1 mixture with the S) -form was quantitatively obtained.

NMR (D ₂ O) (2R, 3S) -form; δ: 0.86 to 1.78 (13H, m), 3.70 (1H, dt,
J = 7.2,3.5Hz), 4.36 (1H, d, J = 3.5Hz) (2S, 3S) -body; δ: 0.86 to 1.78 (13H, m), 3.76 to 3.84
(1H, m), 4.48 (1H, d, J = 3.2Hz) Reference Example 7 (2R, 3S) -2-Benzoxy-4-cyclohexyl-
13.6 mg (0.037 mmol) of a 5: 1 mixture of 3-isopropoxycarbonylaminobutyronitrile and its (2S, 3S) -form
Was dissolved in 1 ml of ethyl acetate, 1 ml of water and 1 ml of concentrated hydrochloric acid were added, and the reaction solution was heated to 100 ° C. to distill off ethyl acetate. Furthermore, 0.5 ml of concentrated hydrochloric acid was added, and the mixture was heated with stirring at 80 ° C. for 10 hours. The reaction solution was concentrated to dryness under reduced pressure, and (2R, 3S) -3-amino-4
10.4 mg of a 5: 1 mixture of cyclohexyl-2-hydroxybutyric acid hydrochloride and its (2S, 3S) -form were quantitatively obtained.

The NMR spectrum of this product was almost the same as that described in Reference Example 6.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Kunikazu Sakai 4-19-11 Hamadayama, Suginami-ku, Tokyo (72) Inventor Daisuke Tsunemoto 2-24-5 Midorigaoka, Zama City, Kanagawa Prefecture (72) Inventor Satoshi Kamijo 2525 Hirooka, Yoshida, Ojira, Shiojiri City, Nagano Prefecture (72) Inventor Hiroshi Harada 8054, Nakagawa, Shiga-mura, Higashichikuma-gun, Nagano Examiner Reiko Imamura

Claims (6)

[Claims] 1. A general formula (In the formula, R ¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 8 carbon atoms, R ² represents a linear or branched alkanoyl group having 1 to 4 carbon atoms, Represents an aroyl group optionally substituted with a chlorine atom or a methoxy group, a linear or branched alkoxycarbonyl group having 1 to 5 carbon atoms, or an aralkoxycarbonyl group optionally substituted with a chlorine atom or a methoxy group. , R ³ represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, or a chlorine atom or an aryl group which may be substituted with a methoxy group). Butyronitrile derivative. 2. The compound according to claim 1, wherein the 2-position asymmetric carbon has (R) -configuration and the 3-position asymmetric carbon has (S) -configuration. 3. The method according to claim 2, wherein R ¹ is a cyclohexyl group.
A compound as described. 4. A general formula (In the formula, R ¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 5 to 8 carbon atoms, and R ² represents a linear or branched alkanoyl group having 1 to 4 carbon atoms. , An aroyl group which may be substituted with a chlorine atom or a methoxy group, a linear or branched alkoxycarbonyl group having 1 to 5 carbon atoms, or an aralkoxycarbonyl group which may be substituted with a chlorine atom or a methoxy group. Represented by the general formula R ³ COOCOR ⁴ (wherein R ³ and R ⁴ are each independently a hydrogen atom or a carbon number of 1 to 4).
Represents a linear or branched alkyl group, or an aryl group which may be substituted with a chlorine atom or a methoxy group)
A general formula characterized by reacting a carboxylic acid anhydride and hydrocyanic acid salt represented by the following in the presence of a quaternary ammonium salt and / or a tertiary amine: (In the formula, R ¹ , R ² and R ³ have the same meanings as described above.) A method for producing a 3-amino-2-acyloxy-butyronitrile derivative. 5. The method for producing a 3-amino-2-acyloxy-butyronitrile derivative according to claim 4, wherein the 2-position asymmetric carbon has (R) -configuration and the 3-position asymmetric carbon has (S) -configuration. . 6. The method according to claim 5, wherein R ¹ is a cyclohexyl group.
A method for producing the described 3-amino-2-acyloxy-butyronitrile derivative.