JP2002088047A - Method for producing n-substituted cyanoglycine alkyl ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an N-substituted cyanoglycine alkyl ester represented by the general formula (III) and improved so that the N-substituted cyanoglycine alkyl ester is obtained in a high yield. SOLUTION: This method for producing the N-substituted cyanoglycine alkyl ester represented by the general formula (III) (R1 is a 1 to 6C linear or branched alkyl or a cyclic alkyl; R2 is benzyl or t-butyl), characterized by dissolving an oxime derivative represented by the general formula (I) in an alkali aqueous solution, reducing the oxime derivative with sodium dithionate to obtain the amine derivative the general formula (II), and then reacting the amine derivative with benzyloxycarbonyl chloride or t-butoxycarbonyl chloride in the presence of a base without isolating the amine derivative from the alkali aqueous solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an N-substituted cyanoglycine alkyl ester. N
Substituted cyanoglycine alkyl esters are useful as raw materials for pharmaceutical intermediates.

[0002]

2. Description of the Related Art Generally, a free cyanoglycine alkyl ester is unstable, and is used in a synthesis reaction with an amino group protected by a protecting group. As a method for producing an N-substituted cyanoglycine alkyl ester in which an amino group is protected, there is known a method in which a raw material oxime derivative is reduced and the generated amino group is reacted with a carbamate-forming agent.
Benzyloxycarbonyl chloride or t-butoxycarbonyl chloride, which is chemically stable and easily removed, is often used as a carbamate.

Various reducing agents for oxime derivatives are known, but a sodium hypothionite reduction method using no heavy metal is industrially advantageous. By the way, the reduction reaction with sodium dithionite is performed under alkaline conditions to enhance the reducing power. Specifically, the oxime derivative is dissolved in an aqueous alkali solution and reduced with sodium dithionite. Thereafter, the mixture is extracted with an organic solvent, and the solvent is distilled off under reduced pressure to obtain an amine derivative (cyanoglycine alkyl ester). Then, the generated amine derivative is reacted with a carbamate-forming agent to convert it into an N-substituted cyanoglycine alkyl ester. However, such a method has a problem that the yield of the N-substituted cyanoglycine alkyl ester is low.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an N-substituted cyanoglycine alkyl which has been improved so as to obtain a higher yield than the conventional method. An object of the present invention is to provide a method for producing an ester.

[0005]

As a result of intensive studies, the present inventors have found that the above-mentioned amine derivative (cyanoglycine alkyl ester) is a substance which is unstable even at room temperature, and is subjected to the above-mentioned complicated steps. It was found that a considerable amount of the amine derivative was decomposed on the way. Further, as a result of further studies, it was found that the reaction between the amine derivative and the carbamate-forming agent proceeds without any problem even in an alkaline aqueous solution following the reduction reaction with sodium dithionite.

The present invention has been accomplished based on the above-mentioned findings, and the gist of the present invention is to dissolve an oxime derivative represented by the following general formula (I) in an aqueous alkali solution and then reduce it with sodium dithionite. Converting into an amine derivative represented by the following general formula (II), and then reacting the amine derivative with benzyloxycarbonyl chloride or t-butoxyoxycarbonyl chloride in the presence of a base without isolation from an aqueous alkaline solution. The method for producing an N-substituted cyanoglycine alkyl ester represented by the following general formula (III) is characterized in that:

[0007]

Embedded image

(In the general formulas (I) to (III), R ¹ represents a linear or branched alkyl group or a cyclic alkyl group having 1 to 6 carbon atoms, and in the general formula (III), R ² represents Represents benzyl or t-butyl.)

[0009]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below. First,
In the present invention, the oxime derivative represented by the general formula (I) is dissolved in an alkaline aqueous solution, and then reduced with sodium dithionite to convert the derivative into the amine derivative represented by the general formula (II). This reaction is known per se.

In the oxime derivative represented by the general formula (I), specific examples of R ¹ include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, and t-butyl. Group, n-pentyl group, n-hexyl group, cyclohexyl group and the like.

The amount of water as a solvent used in the above reduction reaction is usually 5 to 50 parts by weight, preferably 7 to 30 parts by weight, per 1 part by weight of the oxime derivative. As the base,
Baking soda, sodium carbonate, potassium carbonate, pyridine, triethylamine and the like are used. The amount of the base is usually 1 to 3 equivalents, preferably 1 to 1 equivalent to 1 equivalent of the oxime derivative.
1.5 equivalents. The amount of sodium dithionite is usually 1 to 5 equivalents, preferably 2 to 4 equivalents, per equivalent of the oxime derivative. The temperature of the reduction reaction is usually 10 to 4
0 ° C, preferably 20-30 ° C. The time of the reduction reaction is usually 2 to 8 hours, preferably 4 to 6 hours. The reducing agent is generally used every 10 minutes to 2 hours, preferably 10 minutes to
It is added in portions every 30 minutes.

Next, in the present invention, the amine derivative represented by the general formula (II) is reacted with benzyloxycarbonyl chloride or t-butoxyoxycarbonyl chloride in the presence of a base without isolation from an aqueous alkaline solution. .

Specifically, after the above reaction, the reaction solution is cooled if necessary, and benzyloxycarbonyl chloride or t-butoxycarbonyl chloride as a carbamate-forming agent and a base are added and stirred. As the base, the same base as in the above reduction reaction is used. The base promotes the carbamate reaction and traps hydrochloric acid by-produced in the reaction as a salt. The carbamate is preferably used after being dissolved in an organic solvent. At that time, as the organic solvent, ethyl acetate, dichloromethane, diethyl ether and the like are used.

The amount of the base is usually 1 to 5 equivalents, preferably 2 to 3 equivalents, per equivalent of the carbamate-forming agent. The amount of the carbamate is based on 1 equivalent of the oxime derivative.
Usually 0.8 to 3 equivalents, preferably 1 to 2 equivalents. The amount of the solvent for dissolving the carbamate is usually 1 to 10 parts by weight, preferably 3 parts by weight, per part by weight of the carbamate.
-5 parts by weight. The temperature of the carbamate reaction is usually 0 to 30 ° C, preferably 0 to 10 ° C. The carbamate reaction time is usually 0.5 to 3 hours, preferably 1 to 3 hours.
~ 2 hours.

In the carbamate reaction, after stirring,
In about 10 minutes, the N-substituted cyanoglycine alkyl ester represented by the general formula (III) precipitates as a crystal product. The precipitated N-substituted cyanoglycine alkyl ester is washed after filtration, but can be further purified, if necessary, by a method such as recrystallization.

[0016]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist of the present invention. Oxyimino cyanoacetic acid ethyl ester (R ^{1 of the} general formula (I)
= Ethyl group).

Example 1 First, ethyl oxyiminocyanoacetate 24.9
g (0.176 mol), water 640 g, saturated aqueous sodium bicarbonate 16
To a solution consisting of 0 g, 120 g (0.689 mol) of sodium dithionite was added in 10 portions every 15 minutes while stirring at room temperature. Next, the reaction solution was cooled to 10 ° C., and after adding 16 g (0.190 mol) of sodium bicarbonate, 30 g (0.176 mol) of benzyloxycarbonyl chloride was added.
mol) in ethyl acetate. About 10 minutes after the start of the addition, white crystals of the carbamate were precipitated. 1
After stirring for an hour, the crystals were filtered, washed with water and hexane, and then recrystallized from hexane / ethyl acetate to give N-benzyloxycarbonyl cyanoglycine ethyl ester in 2 parts.
4.5 g (yield 53%) was obtained.

Comparative Example 1 Ethyl oxyimino cyanoacetate 24.9 g
(0.176 mol), water 640 g, saturated aqueous sodium bicarbonate 160
g of sodium dithionite (120 g, 0.689 mol) was added to the solution consisting of 4 g every 1 to 2 hours while stirring at room temperature. After completion of the addition, the reaction solution was extracted five times with dichloromethane, and the extract was concentrated. As a result, 7.44 g of crude cyanoglycine ethyl ester was obtained (33% yield).
Obtained.

Benzyloxycarbonyl chloride 1
9 g of crude cyanoglycine ethyl ester (0.07 mol) was added to a solution of 3.95 g (0.082 mol) in ethyl acetate at room temperature.
mol) was added dropwise. After stirring for 10 minutes at room temperature.
The mixture was refluxed for 5 hours. Activated carbon was added to the reaction solution, and the mixture was filtered and concentrated, and the residue was washed with ether. Recrystallization from hexane / ethyl acetate gave 11.74 g of N-benzyloxycarbonyl cyanoglycine ethyl ester (yield 64).
%). The total yield from oxyimino cyanoacetic acid ethyl ester was 21%.

[0020]

According to the present invention described above, an N-substituted cyanoglycine alkyl ester can be produced in a high yield by a simplified method, and the industrial value of the present invention is remarkable.

Claims (1)

[Claims] 1. An oxime derivative represented by the following general formula (I) is dissolved in an aqueous alkali solution, and then reduced with sodium dithionite to convert it into an amine derivative represented by the following general formula (II). N-substituted cyanoglycine represented by the following general formula (III), wherein the amine derivative is reacted with benzyloxycarbonyl chloride or t-butoxycarbonyl chloride in the presence of a base without isolation from an aqueous alkali solution. A method for producing an alkyl ester. Embedded image (In the general formulas (I) to (III), R ¹ represents a linear or branched alkyl group or a cyclic alkyl group having 1 to 6 carbon atoms, and in the general formula (III), R ² represents benzyl or t -Butyl.)