JP3229658B2 - Method for producing N-acetyl-DL-tryptophan - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an improved process for obtaining N-acetyl-DL-tryptophan from L-tryptophan and acetic anhydride in an aqueous solution of an alkali metal hydroxide.

[0002]

2. Description of the Related Art N-acetyl-DL using acetic anhydride in an aqueous solution of an alkali metal hydroxide is used for L-tryptophan.
-Method for producing tryptophan [The Journal of
Biological Chemistry Vol. XCVI N
o. 2 P511-517 (The Journal
of Biological Chemistry)]
Is known. In this method, L-tryptophan is dissolved in an aqueous caustic soda solution having a molar ratio of about 2 times L-tryptophan, and acetic anhydride having a molar ratio of about 6 times L-tryptophan is added in several portions with vigorous stirring. Thereafter, when the temperature of the solution is maintained at 35 to 40 ° C. for 3 hours, crystals precipitate. Therefore, the mixture is cooled, the crystals are separated, and post-treatments such as washing with water are performed to obtain the desired product. However, the yield by this method was as low as 75% at most, and improvement was desired.

[0003]

SUMMARY OF THE INVENTION The present invention overcomes the drawbacks of the conventional method in that the yield is low, and can be carried out with simple operation and industrially advantageously.
An object of the present invention is to provide a method for producing tryptophan.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, the pH at the time of acetylation has been improved.
Is controlled to 11 or more, and the reaction solution at the time of racemization is performed in a uniform state, so that N-acetyl-DL-
They have found that tryptophan can be produced, and have completed the present invention.

That is, the present invention relates to the reaction of N-acetyl-DL by reacting L-tryptophan with acetic anhydride in an aqueous alkaline solution.
In a method for producing tryptophan, acetic anhydride and alkali metal hydroxide are added to an aqueous solution of L-tryptophan and an alkali metal hydroxide in an equimolar amount to L-tryptophan while maintaining the pH of the aqueous solution at 11 or more. A method for producing N-acetyl-DL-tryptophan, characterized by simultaneously adding an aqueous solution of the compound and performing acetylation, and subsequently treating the aqueous solution with acetic anhydride while heating. The L-tryptophan used in the method of the present invention may be one produced by any of a synthetic method, an enzymatic method and a fermentation method.

[0006] alkali metal hydroxide used in the method of the present invention, for example potassium hydroxide, sodium hydroxide and the like, etc. <br/> molar amount with respect to adjustment of L- tryptophan solution is used. If less than equimolar, impurities are by-produced,
And the racemization rate decreases. If used in an equimolar amount, after racemization, a large amount of mineral acid is required for the precipitation of N-acetyl-DL-tryptophan, which is unfavorable because it causes a decrease in quality and yield.

In the method of the present invention, first, an acetylation reaction is carried out as a first step, and then a racemization is carried out to obtain an intended product. The acetylation is performed while intermittently or continuously adding acetic anhydride to an aqueous solution of an alkali metal hydroxide of L-tryptophan. It is not preferable to add acetic anhydride at one time because the yield of acetylation decreases. Further, the amount of acetic anhydride used for acetylation is 1 to L-tryptophan.
２2 moles, preferably 1 mole. When acetic anhydride is added, the pH of the reaction solution is 11 or more, preferably pH 1
It is carried out while maintaining the range of 1 to 13. If the pH of the reaction solution is less than 11, impurities are produced as by-products and the purity is reduced.

In order to control the pH of the reaction solution at the time of acetylation to 11 or more, the pH of the reaction solution is constantly measured with a pH controller or a pH meter, and the pH of the alkali metal hydroxide is kept at 11 or more. This is achieved by adding an aqueous solution. The reaction temperature at the time of acetylation is 0 to 50 ° C., preferably 20 to 40 ° C., the addition time of acetic anhydride at the time of acetylation is 1 to 5 hours, preferably 2 to 3 hours, and the acetylation ripening time is 1 to 5 hours. Two hours is enough.

When the acetylation is completed, the racemization is subsequently performed. For racemization, the acetylation reaction solution is 60-100
C., preferably 70-80 ° C., dissolving the crystals precipitated in the reaction solution to make it uniform, and at that temperature, add acetic anhydride at a temperature 2-5 times mol of L-tryptophan;
It is preferably carried out by adding 3 to 4 times mol. The addition time of acetic anhydride during the racemization is 1 to 4 hours, preferably 2 to 3 hours.
Time. After the racemization reaction aging, the reaction solution is cooled, acid precipitated, and the crystals are separated, followed by ordinary post-treatments such as washing with water to obtain the desired product.

[0010]

The present invention will be described below in more detail with reference to Examples and Comparative Examples. Example 1 102.1 g (0.5 mol) of L-tryptophan and 44.4 g (0.5 mol) of 45% NaO in 300 g of water
H aqueous solution was added, and 53.1 g (0.5
2 mol) of acetic anhydride and 53.5 g (0.6 mol) of 45
% NaOH are reacted simultaneously and added continuously. The pH of the solution during the reaction period was maintained at 11-13, and the addition of the two solutions was completed in 2.5 hours. When this reaction solution was analyzed by liquid chromatography, 123.1 g of N-acetyl-L-tryptophan was obtained.
(100% of the acetylation selectivity). The reaction solution was heated to 70 ° C., 153.1 g (1.5 mol) of acetic anhydride was added over 2.5 hours, cooled to 5 ° C., and concentrated hydrochloric acid was added at 10 ° C.
2.4 g was dropped, filtered, washed with water and dried to obtain 115.7 g of N-acetyl-DL-tryptophan (L-
94 mol% based on tryptophan). (Specific rotation ±
0.0 (measuring temperature 20 ° C)]

Comparative Example 1 102.1 g (0.5 mol) of L-tryptophan and 97.9 g (1.1 mol) of 45% NaO in 300 g of water
53.1 g (0.52 mol) was added to the solution to which the H aqueous solution was added.
Acetic anhydride was added, and the reaction temperature was kept at 40 ° C., and the acetylation reaction was completed in 2.5 hours. When this reaction solution was analyzed by liquid chromatography, N-acetyl-L-tryptophan was 98.
4 g (80% of the acetylation selectivity). The reaction solution was cooled to 5 ° C., 120.5 g of concentrated hydrochloric acid was added dropwise, filtered, washed with water and dried to obtain 91.6 g of N-acetyl-L-tryptophan. (74 to L-tryptophan).
4 mol%).

Comparative Example 2 N-acetyl-L-tryptophan obtained in Comparative Example 1 was mixed with 250 g of water and 72.7 g (0.82 mol) of 45%
An aqueous NaOH solution was added, and at a reaction temperature of 40 ° C., 114.0.
g (1.1 mol) of acetic anhydride in 2.5 hours
After cooling to 0 ° C., 81.1 g of concentrated hydrochloric acid was added dropwise, followed by filtration, washing with water and drying, to obtain 86.1 g of N-acetyl-DL-tryptophan (69.9 g with respect to L-tryptophan).
Mol%) [specific optical rotation + 4.3 (measuring temperature 20 ° C)].

Comparative Example 3 40 g (0.195 mol) of L-tryptophan was added to 1N
Dissolved in 400 ml of NaOH aqueous solution, 130 g of acetic anhydride
Was added dropwise in six portions and stirred vigorously. Thereafter, the reaction solution was kept at 35 to 40 ° C and stirred at the same temperature for 3 hours. After a while, the reaction solution in which crystals precipitated was cooled to 5 ° C., and the crystals were separated by filtration. The obtained crystals were washed with water, diluted hydrochloric acid and water in this order. After drying, 36 g of N-acetyl-DL-tryptophan was obtained (75 mol% based on L-tryptophan). mp 204-205 ° C

[0014]

According to the method of the present invention, by-products of impurities are suppressed, the reaction rate of acetylation is improved, and N is produced with high quality and high yield.
-Acetyl-L-tryptophan is obtained and subsequently racemized in a uniform state, whereby the desired product can be obtained in high quality and high yield, which is an industrially useful method.

Claims (2)

(57) [Claims] 1. A L- tryptophan In the process for producing N- acetyl -DL- tryptophan is reacted with acetic anhydride in an alkaline aqueous solution, L- tryptophan and L- tryptophan alkali metal hydroxide equimolar amount to The acetylation is performed by simultaneously adding acetic anhydride and an aqueous solution of an alkali metal hydroxide to the aqueous solution of the product while maintaining the pH of the aqueous solution at 11 or more, followed by further treating the aqueous solution with acetic anhydride while heating. N-acetyl-DL
-A method for producing tryptophan. 2. The heating temperature after acetylation is 60 to 100.
The method according to claim 1, wherein the amount of acetic anhydride used is 2 to 5 times mol of L-tryptophan.