JP3223052B2 - Method for producing S-hydroxypropyl-L-cysteine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an industrially advantageous process for producing S-hydroxypropyl-L-cysteine.

[0002]

2. Description of the Related Art
As a method for producing S-hydroxypropyl-L-cysteine, a method of reacting cysteine with 3-halogeno-1-propanol in the presence of an alkali (condensing agent) [Bio
chem. J. 100 , 362 (1966); Jour
nalof Pharmaceutical Scie
nces 50, 312 (1961)] and a method of reacting a thiol derivative with β-chloroalanine in an aqueous solution having a pH of 10 to 13 (JP-A-60-258159).

[0003] However, in the former method, cystine is produced as a by-product, and the reduction in purity cannot be avoided. On the other hand, the latter method has disadvantages such as a long reaction time and an expensive raw material, and thus cannot be said to be an industrially advantageous method.

Accordingly, an object of the present invention is to provide an industrially advantageous method for producing S-hydroxypropyl-L-cysteine.

[0005]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies and as a result, according to the following raw materials and reaction conditions, S-hydroxypropyl-L-cysteine can be industrially advantageously used. The present inventors have found that they can be manufactured and completed the present invention.

That is, the present invention provides the following three methods for producing S-hydroxypropyl-L-cysteine. (1) A method for producing S-hydroxypropyl-L-cysteine, comprising reacting cysteine or cysteine hydrochloride with allyl alcohol in the presence of a radical initiator. (2) A method for producing S-hydroxypropyl-L-cysteine, which comprises reacting cysteine or cysteine hydrochloride with allyl alcohol in the presence of a radical initiator and a reducing agent. (3) A method for producing S-hydroxypropyl-L-cysteine, which comprises reacting cysteine or cysteine hydrochloride with allyl alcohol under light irradiation. In the present invention, cysteine hydrochloride may be a hydrate.

In the method (1) of the present invention, the amount of allyl alcohol to be used is 1 to 3 in molar ratio with respect to cysteine or cysteine hydrochloride (hereinafter referred to as “cysteine etc.”).
It is preferably about 1.5 times, preferably about 1.5 to 2.5 times, and particularly about 2 times. The radical initiator used here is not particularly limited as long as it has a thiol group of cysteine as a radical, and examples thereof include persulfates such as sodium persulfate, potassium persulfate, and ammonium persulfate. The amount of the radical initiator used is preferably about 10% by weight based on cysteine and the like. The reaction solvent is preferably an aqueous solvent such as water, alcohol, or a mixture thereof. The reaction time varies depending on the temperature, but is usually preferably 5 to 60 minutes. The reaction temperature is preferably from 0 ° C. to room temperature.

The conditions of the method (2) of the present invention are the same as those of (1) except that the reaction is carried out by further adding a reducing agent.
Examples of the reducing agent used here include ferrous chloride and sodium metabisulfite, and the amount used is preferably about 5 to 10% by weight based on cysteine and the like.

In the method (3) of the present invention, the reaction is started by irradiating light. Light irradiation is preferably performed at a wavelength of 250 to 260 nm for about 10 to 60 minutes. Preferred light irradiation lamps include low pressure silver lamps. The molar ratio of the raw materials used other than the light irradiation, the reaction temperature, the reaction time, and the reaction solvent are preferably the same as those in the method (1).

In the process (4) of the present invention, it is preferable to react 2,2-dimethylthiadiazolidine-4-carboxylic acid with about the same mole of 3-halogeno-1-propanol. Examples of the halogen atom of 3-halogeno-1-propanol include a fluorine atom, a bromine atom, a chlorine atom, and an iodine atom. The pH at the time of the reaction is from 8 to 10, preferably about 9. To adjust the pH, it is preferable to use an alkali such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. The reaction can be performed at 0 ° C. to room temperature, and is preferably performed for about 1 hour to 1 day with stirring.

In the method (5) of the present invention, cysteine and the like are reacted with 3-halogeno-1-propanol as exemplified in the method (4), and then a reducing agent is further reacted. Examples of the reducing agent used here include sodium sulfide, hydrosulfide, and the like.
It is preferably about 5% by weight. In these reactions, the pH is preferably set to 8 to 10, particularly about 9, and the reaction temperature is preferably set to about 40 to 70 ° C. The reaction time is preferably about 30 to 60 minutes for the first reaction, and about 4 to 8 hours for the reaction after the addition of the reducing agent.

The method (6) of the present invention is a method in which 3-halogenopropyl-1-acetate is reacted with cysteine and the like in the presence of an alkali. The 3-halogenopropyl-1-acetate used herein is 3-halogenopropyl-1-acetate. Examples are fluoropropyl-1-acetate, 3-chloropropyl-1-acetate, 3-bromopropyl-1-acetate, 3-iodopropyl-1-acetate. 3-halogeno-1-acetate can be obtained by reacting inexpensive dihalogenopropane with acetic anhydride or the like. The 3-halogeno-1-acetate is preferably used in an amount of about 1 to 2 mol based on cysteine and the like. Examples of the alkali used include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. The pH at the time of the reaction is preferably adjusted to about 10 to 12, preferably about 11 by this alkali. The reaction temperature is preferably set to 40 to 70 ° C. The crude product obtained as described above can be washed and purified by a conventional method to obtain highly pure S-hydroxypropyl-L-cysteine.

[0013]

According to the present invention, S-hydroxypropyl-L-cysteine can be industrially advantageously produced.

[0014]

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

Example 1 2.0 g (16.5 mmol) of cysteine was dissolved in 20 ml of water, then 1.95 g (33 mmol) of allyl alcohol was added, and 200 mg of potassium persulfate was added with stirring at room temperature to carry out a reaction for 15 minutes. Was. After completion of the reaction, the solvent was distilled off under reduced pressure, 25% ethanol was added to the residue, and the insoluble matter was removed by filtration. The filtrate was concentrated and the residue was recrystallized from water-ethanol to give colorless crystals of S- (3-hydroxypropyl) -L-.
2.51 g (yield: 85%) of cysteine was obtained.

EXAMPLE 2 2.0 g (16.5 mmol) of cysteine was dissolved in 20 ml of water, then 1.95 g (33 mmol) of allyl alcohol was added, and while stirring at room temperature, 200 mg of ferrous chloride and 200 mg of ammonium persulfate were added. For 15 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure.
Ethanol was added, and insolubles were removed by filtration. The filtrate was concentrated, and the residue was recrystallized from water-ethanol to give colorless crystals of S-.
(3-hydroxypropyl) -L-cysteine 2.3
6 g (yield: 80%) was obtained.

Example 3 2.0 g (16.5 mmol) of cysteine was dissolved in 20 ml of water, then 1.95 g (33 mmol) of allyl alcohol was added, and a low-pressure mercury lamp (250 to 3) was stirred at room temperature.
(10 nm, 10 W) for 30 minutes. After completion of the reaction, the reaction mixture was washed with ethyl acetate, and the aqueous layer was distilled off under reduced pressure.
The residue was recrystallized from water-ethanol to give colorless crystals of S-.
(3-hydroxypropyl) -L-cysteine 2.7
8 g (yield: 94%) was obtained.

Example 4 2,2-Dimethylthiazolidine-4-carboxylic acid 1.6
1 g (10 mmol) was dissolved in 10 ml of water, and the mixture was adjusted to pH 9 by adding 6 ml of a 5% aqueous sodium hydroxide solution under ice-cooling and stirring. 1.53 g (11 mmol) of 3-bromo-1-propanol was added thereto, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was neutralized with 2N hydrochloric acid and the solvent was distilled off under reduced pressure. The residue was subjected to ion exchange chromatography (Dowex-50).
W), fractions eluted with 2N aqueous ammonia were collected and concentrated under reduced pressure. The residue was recrystallized from water-ethanol to obtain 1.36 g (yield: 76%) of colorless crystals of S- (3-hydroxypropyl) -L-cysteine.

Example 5 8.7 g (49.5 mmol) of cysteine hydrochloride hydrate, 4.2 g of sodium hydroxide, 2 g of sodium carbonate (anhydrous) and 5 g of 3-chloro-1-propanol were added to 1 g of water.
5 ml was added and the mixture was stirred at pH 9 at 60 ° C. for 1 hour. Next, 90 mg of sodium sulfide was added to the reaction mixture, and the mixture was stirred at the same temperature for 4 hours while adjusting the pH to 9 with a 2N aqueous sodium hydroxide solution. After the completion of the reaction, the mixture was adjusted to pH 4 with 10% hydrochloric acid, and the reaction mixture was subjected to ion exchange chromatography (Dowex-50).
W), fractions eluted with 2N aqueous ammonia were collected and concentrated under reduced pressure. The residue was recrystallized from water-ethanol to obtain 7.97 g (yield: 90%) of S- (3-hydroxypropyl) -L-cysteine as colorless crystals.

EXAMPLE 6 A mixture of 40 g (254 mmol) of 1-bromo-3-chloropropane, 30 g (306 mmol) of potassium acetate, 0.256 g of triethylamine and 3 ml of acetic anhydride was added to 7
The reaction was performed at 5 ° C. for 9 hours. After the reaction, 45 ml of water was added and the lower layer (aqueous layer) was removed to obtain 29.84 g (yield: 86%) of 3-chloropropyl acetate from the upper layer. Then, L-
9.68 g (80 mmol) of cysteine was suspended in 60 ml of water, and adjusted to pH 11 by adding a 2N aqueous sodium hydroxide solution. The resulting 3-chloropropyl acetate 1
2 g (88 mmol) was added, and the mixture was stirred at 60 ° C. for 5 hours while maintaining the pH at 11 with a 2N aqueous sodium hydroxide solution. After the completion of the reaction, the pH was adjusted to 4 with 10% hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue was subjected to ion exchange chromatography (D
owex-50W), fractions eluted with 2N aqueous ammonia were collected and concentrated under reduced pressure. The residue was recrystallized from water-ethanol to obtain 10.2 g (yield: 71%) of colorless crystals of S- (3-hydroxypropyl) -L-cysteine.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-2-3674 (JP, A) JP-A-60-258159 (JP, A) JP-A-2-272 (JP, A) JP-A-62-267 221663 (JP, A) JP 30-2026 (JP, B1) US Patent 3,892,852 (US, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 323/58 C07C 319/14 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A process for producing S-hydroxypropyl-L-cysteine, which comprises reacting cysteine or cysteine hydrochloride with allyl alcohol in the presence of a radical initiator. 2. S-hydroxypropyl-L characterized by reacting cysteine or cysteine hydrochloride with allyl alcohol in the presence of a radical initiator and a reducing agent.
-A method for producing cysteine. 3. A process for producing S-hydroxypropyl-L-cysteine, which comprises reacting cysteine or cysteine hydrochloride with allyl alcohol under light irradiation.