JPH04266864A - Production of l-dopa - Google Patents

Abstract

PURPOSE:To obtain L-dopa useful for the therapy of Parkinson's disease by preferential crystallization, with racemization, from DLdopa. CONSTITUTION:L-dopa crystal is inoculated in a supersaturated solution of DL-dopa containing an aromatic aldehyde plus lower fatty acid at the molar ratio >=0.3 based on the DL-dopa to effect crystallization of L-dopa from said solution under the racemization condition for the dissolved D-dopa. With the present method, the desired L-dopa can be obtained in a single step without the need for any troublesome treatments from DL-dopa; therefore, being highly useful from the viewpoint of industry.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing L-dopa useful for the treatment of Parkinson's disease from DL-dopa by preferential crystallization accompanied by racemization.

0002

[Prior Art] Dopa, that is, [3-(3,4-dihydroxyphenyl)alanine], which is generally obtained by a synthetic method, is in the DL-form, so it must be further optically resolved to obtain the L-form. is necessary. Various methods using preferential crystallization have been reported for optical resolution of DL-DOPA. For example, a method in which a 0.3N hydrochloric acid saturated solution of DL-dopa at 45°C is cooled to 32°C and seed crystals of L-dopa are inoculated (U.S. Pat. No. 3,405,159), 50-
A saturated aqueous solution of DL-DOPA at 100°C was heated to 45-9
A method of inoculating seed crystals of L-dopa after cooling to 5°C (Japanese Patent Application Laid-Open No. 47-34246), a method of inoculating needle-like crystals of L-dopa into an aqueous supersaturated solution of DL-dopa at 30°C or lower (Japanese Patent Publication No. 49-31974), a method of inoculating an aqueous supersaturated solution of DL-dopa at a temperature higher than 30°C with needle-like crystals of L-dopa in the presence of tetragonal crystals of L-dopa (Japanese Patent Publication No. 49-31974); 49-31975), DL-Dopa-1
Method of inoculating L-dopa 1/2 hydrochloride crystals into a supersaturated solution of /2 hydrochloride (Japanese Patent Publication No. 7073/1983), D
Add L-dopa and/or L-dopa 1 to an aqueous supersaturated solution containing L-dopa and D-dopa 1/2 hydrochloride.
/2 Method of inoculating hydrochloride crystals (Special Publication No. 50-124)
No. 18, No. 50-12419), a method of crystallizing L-dopa by cooling an aqueous supersaturated solution containing DL-dopa and a small amount of L-dopa (Japanese Patent Publication No. 51-36260, No. 51-124) 36261) and the like are known.

0003

[Problems to be Solved by the Invention] However, although these preferential crystallization methods are industrially advantageous, they still have technical limitations. Since the preferential crystallization method crystallizes only L-dopa in the presence of supersaturated D-dopa, separation and acquisition of crystallized crystals must be carried out in a state where spontaneous crystallization of D-dopa does not occur. There must be. On the other hand, various methods have been reported for racemizing optically active amino acids, one of which is a method of racemizing optically active amino acids in the coexistence of lower fatty acids and aliphatic or aromatic aldehydes (Japanese Patent Application Laid-Open No. 123150/1989). However, there is no known method for producing L-dopa that involves a racemization reaction of D-dopa dissolved from a supersaturated solution of DL-dopa during preferential crystallization of L-dopa.

As a result of intensive studies on this point, the present inventors added aromatic aldehyde at a molar ratio of 0.3 or more to DL-dopa to a supersaturated solution of DL-dopa in which lower fatty acids coexist, and then - When dopa crystals are inoculated, L-dopa preferentially crystallizes from the supersaturated solution, and in parallel, D-dopa dissolved in the supersaturated solution is easily racemized; - Dopa is stable without being racemized even under the racemization conditions of dissolved D-dopa; therefore, under the racemization conditions of D-dopa, the racemization reaction proceeds in parallel with the preferential crystallization of L-dopa. Therefore, the solution during preferential crystallization always contains L-dopa and D
The present invention has been completed by discovering that DL-dopa can be obtained as a solution containing approximately the same amount of -dopa, and as a result, all of the supersaturated DL-dopa can be obtained as L-dopa.

[0005]

[Means for Solving the Problems] The present invention provides for the preferential crystallization of L-dopa from a supersaturated solution of DL-dopa.
In the presence of an aromatic aldehyde and a lower fatty acid in a molar ratio of 0.3 or more to L-dopa, crystals of L-dopa are added to the supersaturated solution, and the supersaturated solution is heated under racemization conditions for the dissolved D-dopa. This is a method for producing L-dopa, which is characterized by preferentially crystallizing L-dopa from.

[0006] The lower fatty acids used in the present invention have 1 to 3 carbon atoms.
saturated fatty acids, specifically formic acid, acetic acid, and propionic acid, with acetic acid being particularly preferred. The concentration of lower fatty acids is not limited, but is usually 10 v/v% or more, preferably 30 v/v% or more.

The aromatic aldehydes used in the present invention are benzaldehydes with or without hydroxyl groups, such as benzaldehyde, salicylaldehyde, m-hydroxybenzaldehyde, and p-hydroxybenzaldehyde. The amount of these aldehydes used is based on the raw material DL
- a molar ratio of 0.3 or more to dopa;

[0008] In the present invention, the preferential crystallization and racemization can be carried out in parallel in an aqueous solvent or an anhydrous solvent. This operation begins with the solvent, D
By inoculating seed crystals of L-dopa into a supersaturated solution of DL-dopa obtained by mixing L-dopa, lower fatty acids, and aromatic aldehydes in any order, heating, and then cooling or concentrating, and stirring. While L-dopa crystallizes, racemization of D-dopa progresses suitably. This operation can be carried out at a temperature ranging from room temperature to the reflux temperature of the supersaturated solution, but is generally preferably carried out at 50 to 100°C.

[0009] By doing so, substantially all of the supersaturated DL-dopa can be converted into L-dopa. In the present invention, since the supersaturated portion of DL-dopa is the target of the conversion reaction, in order to carry out the reaction more effectively, the supersaturated portion of DL-dopa may be added subsequently.

[0010] The L-dopa thus obtained can be collected by known methods such as filtration and centrifugation.

[0011]

[Examples] Examples of the present invention are shown below, but the present invention is not limited thereto. [Example 1] 22.2 g of DL-dopa was heated at 85° C.
It was dissolved in 360 ml of a 3% aqueous acetic acid solution, 4 ml of salicylaldehyde was added, and after removing excess crystals, the temperature was raised to 92°C. Next, the solution was maintained at 75°C, and 2.2 g of L-dopa was inoculated, and the temperature was lowered to 70°C after 3 hours, to 65°C after 4.5 hours, and stirred until 6 hours later. The precipitated crystals are collected by filtration, washed with a small amount of ethanol, and dried to an optical purity of 100.
% L-dopa (excluding the inoculated amount; the same applies to the following examples) was obtained.

[Example 2] 18.7 g of DL-Dopa was added to 8
It was dissolved in 360 ml of 50% acetic acid aqueous solution at 5°C, 3.6 ml of salicylaldehyde was added, and the temperature was raised to 92°C. Next, the solution was maintained at 90°C, 2.0 g of L-dopa was inoculated, and the temperature was lowered to 70°C after 30 minutes, to 50°C after 2 hours, and stirred until 4 hours later. The precipitated crystals were filtered, washed with a small amount of ethanol, and dried to obtain L with an optical purity of 97.7%.
- Obtained 2.1 g of Dopa.

[Example 3] 15.4 g of DL-dopa and 18 ml of salicylaldehyde were dissolved in a 33% aqueous solution at 85°C, and the temperature was raised to 92°C. Then, the temperature was lowered to 70°C, 2.0 g of L-dopa was inoculated, stirred for 1.5 hours, and after 3 hours the temperature was lowered to 50°C. The precipitated crystals were collected by filtration, washed with a small amount of ethanol, and dried to an optical purity of 98.
．． 4.6 g of 4% L-dopa was obtained.

[0014]

[Effects of the Invention] According to the present invention, the desired L-dopa can be obtained in high yield from DL-dopa in one step without requiring any complicated treatment, which is extremely useful industrially. It is something.

Claims (3)

[Claims] Claim 1: When preferentially crystallizing L-dopa from a supersaturated solution of DL-dopa, in the coexistence of an aromatic aldehyde and a lower fatty acid in a molar ratio of 0.3 or more to DL-dopa,
L-dopa crystals are added to the supersaturated solution, and the dissolved D
- A method for producing L-dopa, which comprises preferentially crystallizing L-dopa from the supersaturated solution under dopa racemization conditions. 2. The method according to claim 1, wherein the lower fatty acid is a saturated fatty acid having 1 to 3 carbon atoms, and the aromatic aldehyde is benzaldehyde with or without a hydroxyl group. 3. The method according to claim 1, wherein the lower fatty acid is acetic acid and the aromatic aldehyde is salicylaldehyde.