KR820001161B1 - Synthesis of the carbocysteine - Google Patents

Abstract

Title compd. (I), useful for treatment of a disease of the respiratory organs, was prepd. by the reduction of cysteine in a alkali soln. of monochloroacetic acid. Thus, 50 ml aq. 30% NaOH soln. was added in a mixed soln. of 30 g cysteine, 60 g monochloroacetic acid and 200 ml H2O, and heated to 30≰C. 20 g Zn powder was added in the soln., and stirred at 25-30≰C for 100 min to give 33.5 g carbocysteine (m.p. 198-202≰C).

Description

Synthesis of Carbocysteine

Unlike general antibiotics, the present invention is useful as a therapeutic agent for respiratory diseases such as colds, flu, bronchitis, expectorants and nasal mucosa infections without causing side effects such as habituality, allergic reactions, and resistance (I) A more efficient, inexpensive, and medicinal component of S-carboxy methyl-L-cysteine (hereinafter referred to as "carbocysteine") is obtained in a reasonable purity.

Background Art Conventionally, a method for producing carbocysteine has been known which uses cysteine hydrochloride as a starting material.

[Reference, Fr 1,288,907 (1962)]

However, cysteine hydrochloride is easily oxidized and requires the use of an inert gas in the reaction, and because cysteine hydrochloride itself has a high solubility in water, blocking of air (oxygen) and concentration of solvent in its separation process from the production of cystine The process requires a lot of synthesis equipment and energy, and the yield does not exceed 65% (see US Patent No. 2,376,186 (1945)), US Patent No. 2,412,303 (1947), and German Patent No. 804,808. (1949) and US Pat. No. 2,907,703 (1959)], the synthesis of carbocysteine from this, the yield was a disadvantage that does not exceed 55% from cystine.

In addition, there have been attempts of reduction and carboxy methylation in alkaline solutions from cystine (see US Patent No. 2,460,785 (1949)).

Since cystine or cysteine is unstable in alkaline solution, the reaction temperature must be kept low, and the purity of the obtained product is very low [melting point: 188-91 ° (decomposition)]. Recrystallization revealed that the purified yield was less than 60%.

In the present invention, it is possible to improve the purity and yield by making the cysteine produced by reduction into a more stable carbocysteine. The carbocysteine formation reaction could be promoted by increasing the concentration of monochloroacetic acid soda, especially as the reaction was completed and the effect was relatively greater.

Sodium monochloroacetic acid can yield maximum yields when about two times the method of US Pat. No. 2,460,785 is used.

By using monochloroacetic acid in the form of neutralized soda salt, the amount of caustic soda is not only reduced, but also the loss of heat of reaction generated during acid neutralization is avoided.

At this time, the amount of zinc was reduced as much as possible, so that 1/3 of the previous method was used to reduce not only the waste of zinc but also the decrease in yield due to the amount of products lost by precipitation of zinc compounds and side reactions such as desulfurization. In the present invention, a mixture of 1 part of cystine and 1.2-2.5 parts of monochloroacetic acid and water is adjusted to pH 11.5-12 with a 30% aqueous solution of sodium hydroxide, and then 2 equivalents of zinc is added thereto at 30 ° C or lower. At 20-30 ° C., the cysteine is stirred until no longer detected by nitrofurside, then the precipitated zinc compound is removed and concentrated sulfuric acid is added to precipitate the carbocysteine in acid.

EXAMPLE

Synthesis of Carbocysteine

To a mixture of 30 g of cystine, 60 g of monochloroacetic acid, and 200 ml of water, 50 ml of caustic soda 30% solution was slowly added dropwise, and 20 g of zinc powder was added while maintaining the temperature of the reaction below 30 ° C., and nitropurside at 25-30 ° C. Stir until no more cysteine is detected (1 hour 40 minutes).

The precipitated zinc compound residue was filtered off and the filtrate and washings were acidified with 18 ml of concentrated sulfuric acid below 30 ° C., and the product was crystallized at 10-15 ° C.

The obtained primary product was dissolved in 120 ml of 5 mol aqueous hydrochloric acid solution and then adjusted to pH 2-2.5 with 5 mol ammonia water to reprecipitate and purify the product.

Filtration, washing and drying to give 33.5 g of purified carbocysteine.

Yield: 75%, melting point 198-202 ° C (decomposition) cysteine 0.05% or less, cystine 0.1 or less

Yield Variation with Sodium Monochloroacetic Acid

Claims (1)

A method for synthesizing carbocysteine, which can be used for pure medicaments, characterized in that 4 moles of monochloroacetic acid is used per mole of cystine in synthesizing carbocysteine by reducing cystine to an alkaline aqueous solution of monochlorosodium acetate.