JPH1072419A - Production of tertiary-leucine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for medicines and agrochemicals in a short time in high yield by reacting a specific carboxylic acid compound with ammonia at a relatively high reaction temperature. SOLUTION: A 2-halo-3,3-dimethylcarboxylic acid compound of the formula (X is a halogen) is reacted with (B) ammonia at 50-200 deg.C. Preferably, the reaction is carried out in a closed system in a solvent such as toluene or under pressure such as equal to or higher than the vapor pressure of the solvent. After the reaction, the reaction mixture is concentrated and the residue is treated by column chromatography.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing tert-leucine.

[0002]

2. Description of the Related Art Tert-leucine is a compound useful as an intermediate for medical and agricultural chemicals, a raw material for asymmetric synthesis catalysts, and the like. As a conventional method for producing tert-leucine in a single step, for example, a method of reacting 2-bromo-3,3-dimethylbutyric acid and ammonia at 37 ° C. [Z. Physico
l. Chem., 228 , 187 (1934), Arch.Biochem., 3 , 88 (1944)]
However, this method requires a long time, for example, 8 days, and has a problem that the yield is low.

[0003]

SUMMARY OF THE INVENTION Accordingly, the present inventors
As a result of intensive studies to develop a method capable of producing tert-leucine with high yield in a short reaction time, 2-bromo-
By reacting the 3,3-dimethylcarboxylic acid compound and ammonia at a relatively high reaction temperature,
The present inventors have found that t-leucine can be produced in a short time and with good yield, and have reached the present invention.

[0004]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein X represents a halogen atom). Production of tert-leucine, characterized by reacting a 2-halo-3,3-dimethylcarboxylic acid compound represented by the formula (1) with ammonia in a temperature range of 50 to 200C. It provides a method.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The substituent X in a 2-halo-3,3-dimethylcarboxylic acid compound represented by the general formula (1)
As a halogen atom represented by a chlorine atom, a bromine atom,
Examples of the iodine atom and the like include 2-halo-3,3-
As the dimethylcarboxylic acid compound, 2-chloro-3,3
-Dimethylbutyric acid, 2-bromo-3,3-dimethylbutyric acid,
Examples thereof include 2-iodo-3,3-dimethylbutyric acid.

[0006] The reaction is usually carried out in a solvent. Examples of such a solvent include water, hydrophobic solvents such as toluene, benzene, xylene, monochlorobenzene, n-hexane, cyclohexane, heptane, diethyl ether, and ethylene glycol diethyl ether; methanol, ethanol, 2-propanol, tetrahydrofuran, and acetonitrile. And these are used alone or in combination of two or more.
The amount of the solvent to be used is generally 1 to 20 times, preferably 1 to 5 times the weight of 2-halo-3,3-dimethylbutyric acid.

For the reaction, for example, 2-halo-3,3-dimethylbutyric acid and ammonia may be mixed in a solvent. Ammonia may be supplied as ammonia gas, or may be ammonia water when water is used as the solvent.

The amount of ammonia used in the reaction is usually at least 2 times the molar amount of 2-halo-3,3-dimethylbutyric acid.
It is preferably at least 5 mole times. Further, the reaction system may be a closed system that is closed to the outside of the system, or may be an open system that is open to the outside of the system. The reaction is preferably performed in a closed system since ammonia gas and the like do not flow out of the system. In order to carry out the reaction in a closed system, a reaction vessel capable of closing the reaction system, for example, an autoclave may be used.

When the reaction temperature is lower than 50 ° C., the reaction rate is low and the yield is inferior.
ert-leucine has a tendency to degrade,
It must be in the range of 00 ° C., preferably 70 to 13
It is in the range of 0 ° C. When a solvent is used, if the pressure is low, the solvent may completely evaporate depending on the reaction temperature. Therefore, the reaction is preferably performed under pressure, for example, at a pressure higher than the vapor pressure of the solvent.

The reaction proceeds relatively quickly and the desired te
rt-Leucine is produced and can be easily removed from the reaction mixture after the reaction by a conventional method, for example, a method of concentrating the reaction mixture and then subjecting the residue to column chromatography.

[0011]

According to the method of the present invention, tert-leucine can be produced in a short time and with high yield.

[0012]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 6.85 g (35 m) of 2-bromo-3,3-dimethylbutyric acid
mol) and 212.9 g of a 28% aqueous ammonia solution
(3500 mmol of ammonia) was placed in an autoclave, sealed, heated to 100 ° C., and stirred at the same temperature for 6 hours. The internal pressure at this time was in the range of 5 to 8 kg / cm ² . Thereafter, the reaction mixture was concentrated under reduced pressure, and the residue was dried to obtain 8.45 g of crude crystals. The crude crystals were subjected to high-performance liquid chromatography [developing solution: aqueous solution prepared by adding sulfuric acid to a mixed aqueous solution of sodium lauryl sulfate and sodium sulfate (concentration of sodium lauryl sulfate 5 mmol / l, concentration of sodium sulfate 2 mmol / l) to pH 2] As a result, the content of tert-leucine was found to be 3.72 g (yield: 81.6%).

Example 2 A crude crystal (tert-leucine content 3.09) was prepared in the same manner as in Example 1 except that the amount of the 28% aqueous ammonia solution was changed to 21.3 g (350 mmol of ammonia).
g) was obtained (yield: 67.4%).

Example 3 A crude crystal (tert-leucine content 3.31) was prepared in the same manner as in Example 1 except that the amount of the 28% aqueous ammonia solution was changed to 42.6 g (700 mmol of ammonia).
g) was obtained (yield: 72.2%).

Example 4 10.54 g of 2-bromo-3,3-dimethylbutyric acid (54
mmol) in 48 g of toluene and 212.9 g of a 28% aqueous ammonia solution (3500 mmol of ammonia)
And sealed in an autoclave, then 100
C. and the mixture was stirred at the same temperature for 6 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the residue was dried to obtain crude crystals 11.04.
g was obtained. When the crude crystals were analyzed in the same manner as in Example 1, the content of tert-leucine was 5.55 g (yield 78.5%).

Example 5 6.85 g (35 m) of 2-bromo-3,3-dimethylbutyric acid
mol) and "212.9 g of 28% aqueous ammonia solution"
(3500 mmol of ammonia) was placed in an autoclave, sealed, heated to 160 ° C., and stirred at the same temperature for 6 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the residue was dried to obtain 8.01 g of crude crystals. When the crude crystals were analyzed in the same manner as in Example 1, the content of tert-leucine was 3.23 g (yield: 70.4%).

Example 6 A crude crystal was obtained in the same manner as in Example 5, except that the reaction temperature was changed to 60 ° C. The crude crystals (content of tert-leucine: 3.67 g) were obtained (80% yield).

Comparative Example 1 A crude crystal (content of tert-leucine: 0.83 g) was obtained in the same manner as in Example 5 except that the reaction temperature was 40 ° C. and the reaction time was 2 days. Yield 18%).

Claims (4)

[Claims] 1. The general formula (1) (Wherein X represents a halogen atom). Production of tert-leucine, characterized by reacting a 2-halo-3,3-dimethylcarboxylic acid compound represented by the formula (1) with ammonia in a temperature range of 50 to 200 ° C. Method. 2. The method according to claim 1, wherein the reaction is carried out in a closed system. 3. The method according to claim 1, wherein the reaction is carried out in a solvent. 4. The method according to claim 1, wherein the reaction is performed under pressure.