SINGLE CRYSTALLINE DL-CYSTEINE AND PROCESS FOR THEIR PREPARATION

Abstract: Single crystalline DL-cysteine characterized by the X-­ ray diffraction spectrum wherein strong reflection lines ap­ pear at the following latice spacings are novel crystals showing excellent storage stability. ('f' in the column of relative intensity (I) means a strong spectral intensity, and 'ff' an extremely strong intensity). The single crystalline DL-cysteine is prepared by neutralizing an aromatic sulfonate or hydrochloride of DL-cysteine with a base in a mixed solvent composed of water and an organic solvent selected from lower alcohols and cellosolves.

Description: DESCRIPTION SINGLE-CRYSTAL DL-CYSTEINE AND PROCESS FOR PRODUCING SAME TECHNICAL FIELD This invention relates to single-crystal DL-cysteine and a process for producing the same. More particularly, it relates to DL-cysteine having a crystalline nature characterized by the following X-ray diffraction spectrum and a process for producing the same. Lattice Spacing ( ) Relative Intensity* (I) 11.90 f 5.97 f 3.97 f 2.98 ff *) The relative intensity (I) is expressed on the basis of the following, arbitrarily defined criteria: ff = Very intense; f = Intense. Background Art Dl-cysteine is a sulfur-containing amino acid and has wide applications in the preparation of permanent-wave solutions, the manufacture of drugs, and the like. It is generally known that cysteine is readily oxidized to cystine by atmospheric oxygen or the like. In particular, free DL-cysteine that has been known in the prior art is an amorphous substance having no crystalline form. For this reason, it has the disadvantage of being subject to oxidation during storage and lacking in storage stability. Thus, DL-cysteine is being used for various purposes exclusively in the form of DL-cysteine hydrochloride monohydrate. For example, in the preparation of a cold-wave solution comprising DL-cysteine, DL-cysteine hydrochloride is neutralized with a suitable base and, further, the solution is adjusted to a desired pH value which is generally not less than pH 9. Accordingly, if such a solution could be prepared from free DL-cysteine, only the amount of base used for pH adjustment is needed to economic advantages. In the prior art, a common method for producing DL-cycteine comprised dissolving the hydrochloric acid or p-toluenesulfonic acid salt of DL-cysteine in methanol and neutralizing the solution with a base such as triethylamine or the like. However, the free DL-cysteine produced by this method is not crystalline but amorphous. This fact raises difficult problems because such free DL-cysteine is readily oxidized to cystine during storage and, therefore, lacks in storage stability. Disclosure of the Invention It is an object of the present invention to provide single-crystal DL-cysteine having a crystalline nature and hence good storage stability and a process for producing the same. According to the present invention, there is provided DL-cysteine having the nature of single crystals as is characterized by the above-described X-ray diffraction spectrum. Moreover, there is also provided a process for producing single-crystal DLcysteine in which a hydrochloric acid or aromatic sulfonic acid salt of DL-cysteine is suspended or dissolved in a solvent mixture comprising water and an organic solvent selected from the group consisting of lower alcohols and cellosolves, and then neutralized with a base to form single-crystal DL-cysteine. The single-crystal DL-cysteine produced by the process of the present invention is free DLcysteine having a flaky or short needle-like crystal form and exhibiting good storage stability. Best Mode for Carrying Out the Invention The single-crystal DL-cysteine of the present invention is DL-cysteine having a crystalline nature characterized by the following X-ray diffraction spectrum: o Lattice Spacing (A) Relative Intensity* (I) 11.90 f 5.97 f 3.97 f 2.98 ff *) The relative intensity (I) is expressed on the basis of the following, arbitrarily defined criteria: ff = Very intense; f = Intense. According to the process of the present invention, single-crystal DL-cysteine is produced by suspending or dissolving an aromatic sulfonic acid or hydrochloric acid salt of DL-cysteine in a solvent mixture comprising water and an organic solvent selected from the group consisting of lower alcohols and cellosolves, and then neutralizing it with a base. As the aromatic sulfonic acid salt of DLcysteine used in the process of the present invention, its substituted or unsubstituted benzenesulfonic acid salts are generally useful. Specific examples thereof include benzenesulfonic acid, p-toluenesulfonic acid, p-ethylbenzenesulfonic acid, p-chlorobenzenesulfonic acid, maxylenesulfonic acid, sulfosalicylic acid, m-nitrobenzenesulfonic acid, a-naphtholsulfonic acid and ss-naphtholsulfonic acid salts of DL-cysteine. Where the hydrochloric acid salt of DL-cysteine is used, the salt may be in the form of anhydride or monohydrate. No particular limitation is placed own the type of base used in the process of the present invention. More specifically, a variety of bases are usable provided that, when used to neutralize an aromatic sulfonic acid or hydrochloric acid salt of DL-cysteine, they produce a salt soluble in the water-containing lower alcohol or like solvent used in the process of the present invention. In contrast, bases producing a salt scarcely soluble in the watercontaining lower alcohol or like solvent are undesirable because it is difficult to separate the precipitated free DL-cysteine from the salt. Specific examples of the bases useful in the process of the present invention include organic bases such as ethylamine, diethylamine, triethylamine, monoethanolamine, triethanolamine, pyridine, piperidine, etc,; alkali metal or alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, etc.; alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, etc.; and ammonia. The process of the present invention is carried out in a solvent mixture comprising water and an organic solvent selected from the group consisting of lower alcohols and cellosolves. Organic solvents having miscibility with water are useful in the process of the present invention. Specific examples thereof include lower alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, tert-butanol, etc.; and cellosolves such as methyl cellosolve, ethyl cellosolve, etc. In the process of the present invention, these organic solvents must contain water. The amount of water contained therein should be not less than 5% by weight. Although its upper limit is not clearly defined, unduly large amounts of water may reduce the recovery of DL-cysteine. Thus, the water is usually used in an amount of 5 to 60% by weight, the preferred range being 10 to 50% by weight. If the amount of water used is less than 5% by weight, the resulting free DL-cysteine will be an amorphous substance having no crystalline form and lacking in storage stability. No particular limitation is placed on the amount of solvent mixture used. However, in view of the actual practice of the reaction and the recovery of DL-cysteine, the solvent mixture is generally used in an amount equaling 0.5 to 10 times, preferably 1 to 6 times, the weight of the aromatic sulfonic acid salt of DL-cysteine or in an amount equaling 1 to 20 times, preferably 2 to 10 times, the weight of the hydrochloric acid salt of DL-cysteine. In carrying out the process of the present invention, an aromatic sulfonic acid or hydrochloric acid salt of DL-cysteine is dissolved or suspended in a solvent mixture as defined above. Then, a base is added thereto, drop by drop or all at once, or blown therethrough at a temperature of -20 to 800C, preferably 0 to 600C, to neutralize the solution or suspension and thereby precipitate free DL-cysteine. After completion of the neutralization, the solution or suspension is cooled as desired and the precipitated free DL-cysteine is separated by filtration. In order to prevent the oxidation of the cycteine to cystine, the neutralization is preferably carried out under an atmosphere of an inert gas such as nitrogen, argon or the like. In this manner, there is obtained free DL-cysteine having a flaky or short needle-like crystal form and exhibiting good storage stability. The present invention is further illustrated by the following examples. Example l 29.3 g of DL-cysteine p-toluenesulfonate was suspended in 70 ml of methanol containing 10 by weight of water. Under an atmosphere of nitrogen, the suspension was neutralized by adding, drop by drop, 10.1 g of triethylamine at 0 - 50C with stirring. After stirring at the same temperature for l hour, the precipitated crystals were separated by filtration, washed with methanol and then dried in vacuo to obtain free DL-cysteine in the form of colorless flakes. Its yield was 11.0 g (90.9% recovery). When measured with a Cu:Ni X-ray tube (20 kV, 10 mA) and at X = 1.5418, the X-ray diffraction spectrum of the crystals showed the following X-ray diffraction pattern. o Lattice spacing (A) Relative Intensity (I) 11.90 0.57 5.97 0.34 4.55 0.01 4.20 0.03 3.97 0.44 3.82 0.03 3.79 0.04 3.71 0.03 3.41 0.01 3.18 0.04 3.08 0.03 2.98 1.00 2.60 0.02 2.52 0.03 2.39 0.03 2.25 0.05 Comparative Example 29.3 g of DL-cysteine p-toluenesulfonate was suspended in 80 ml of methanol. Under an atmosphere of nitrogen, the suspension was neutralized by adding, drop by drop, 10.1 g of triethylamine at 0 - 50C with stirring. After stirring at the same temperature for 1 hour, the resulting precipitate was separated by filtration, washed with methanol and then dried in vacuo to obtain free DL-cysteine in the form of colorless powder. Its yield was 11.6 g (96% recovery). When measured in the same manner as in Example 1, the X-ray diffraction spectrum of the DL-cysteine power showed the following pattern. o Lattice spacing (A) Relative Intensity (I) 11.90 0.37 5.97 0.21 4.93 0.08 4.55 0.28 4.20 1.00 3.97 0.21 3.82 0.29 3.79 0.49 3.75 0.37 3.71 0.26 3.41 0.51 3.18 0.24 3.08 0.11 2.98 0.61 2.68 0.16 2.60 0.08 2.52 0.05 2.39 0.02 2.36 0.09 2.29 0.12 2.25 0.16 Example 2 29.3 g of DL-cysteine p-toluenesulfonate was suspended in 88 ml of isopropanol containing 40% by weight of water. Under an atmosphere of nitrogen, the suspension was neutralized by adding, drop by drop, 10.1 g of triethylamine at 20 - 250C with stirring. After stirring at the same temperature for 1 hour, the precipitated crystals were separated by filtration, washed with isopropanol and then dried in vacuo to obtain free DL-cysteine in the form of colorless flaky crystals. Its yield was 10.9 g (90.1% recovery). The X-ray diffraction pattern of the crystals was substantially the same as that observed in Example 1. Example 3 The procedure of Example 2 was repeated, except that 31.3 g of DL-cysteine p-chlorobenzenesulfonate was used in place of the DL-cysteine ptoluenesulfonate and 88 ml of isopropanol containing 30% by weight of water was used as the solvent. Thus, there was obtained 11.4 g of free DL-cysteine in the form of colorless flaky crystals. Again, the X-ray diffraction pattern of the crystals was substantially the same as that observed in Example 1. Example 4 52.7 g of DL-cysteine hydrochloride monohydrate was dissolved in 240 ml of methanol containing 10% by weight of water. Under an atmosphere of nitrogen, the solution was neutralized by adding, drop by drop, 30.3 g of triethylamine at 20 - 250C with stirring over a period of about 20 minutes. After stirring at the same temperature for 1 hour, the precipitated crystals were separated by filtration, washed with methanol and then dried in vacuo to obtain 35.1 g of free DL-cysteine in the form of colorless, short needle-like crystals. Upon analysis by highspeed liquid chromatography, the product was found to have a purity of 100% and contain no cystine. When measured with a Cu:Ni X-ray tube (25 kV, 14 mA) and at A = 1.5418, the X-ray diffraction spectrum of the DL-cysteine crystals showed the following X-ray diffraction pattern. o Lattice spacing (A) Relative Intensity (I) 11.90 0.63 5.97 0.33 4.55 0.03 4.20 0.07 3.97 0.39 3.82 0.06 3.79 0.12 3.75 0.04 3.71 0.05 3.41 0.03 3.18 0.05 3.08 0.05 2.98 1.00 2.68 0.01 2.60 0.01 2.52 0.03 Example 5 The procedure of Example 4 was repeated, except that the water-containing methanol was replaced by 240 ml of isopropanol containing 40% by weight of water and the triethylamine was replaced by 23.7 g of pyridine. Thus, there was obtained 32.5 g of free DL-cysteine in the form of colorless flaky crystals. Its purity was 100%, and the X-ray diffraction pattern of the crystals was substantially the same as that observed in Example 4. Example 6 The procedure of Example 4 was repeated, except that the triethylamine was replaced by 18.5 g of 28% aqueous ammonia. Thus, there was obtained 33.8 g of free DL-cysteine in the form of short needle-like crystals. Its purity was 100%, and the X-ray diffraction pattern of these crystals was substantially the same as that observed in Example 4. Example 7 52.7 g of DL-cysteine hydrochloride monohydrate was suspended in 200 ml of methanol containing 20% by weight of water. Under an atmosphere of nitrogen, the solution was neutralized by adding 12.6 g of lithium hydroxide, little by little, at 20 - 250C with stirring. After stirring at the same temperature for 1 hour, the precipitated crystals were separated by filtration, washed with methanol and then dried in vacuo to obtain free DL-cysteine in the form of colorless flaky crystals. Its yield was 32.7 g (90% recovery) and its purity was 100%. The X-ray diffraction pattern of the crystals was substantially the same as that observed in Example 4. Reference Example The free DL-cysteine obtained in Example 1 and that obtained in Comparative Example were tested for storage stability by placing them in crystallizing dishes made of glass and allowing them to stand under ordinary room conditions. The results thus obtained are shown in Table 1. Table 1 EMI14.1 <tb> <SEP> Sample <SEP> Formation <SEP> of <SEP> Cystine <tb> <SEP> Formation <SEP> of <SEP> Cystine <tb> <SEP> After <SEP> After <SEP> 30 <SEP> Days <SEP> (wt.%)* <SEP> <tb> Example <SEP> 1 <SEP> 0 <tb> Comparative <SEP> Example <SEP> 5 <tb> *) Analyzed by high-speed liquid chromatography.

Claims: CLAIMS 1. Single-crystal DL-cysteine characterized by an X-ray diffraction spectrum in which intense diffracted rays appear at the following lattice spacings: o Lattice Spacing (A) Relative Intensity (I) 11,90 f 5.97 f 3.97 f 2.98 ff where, in the column of the relative intensity (I), f means that the spectral intensity is high and ff means that the spectral intensity is very high. 2. A process for producing single-crystal DL-cysteine which comprises neutralizing an aromatic sulfonic acid or hydrochloric acid salt of DL-cysteine with a base in a solvent mixture comprising water and an organic solvent selected from the group consisting of lower alcohols and cellosolves. 3. A process as claimed in claim 2 wherein the organic solvent is selected from the group consisting of alcohols having 1 to 4 carbon atoms, methyl cellosolve and ethyl cellosolve. 4. A process as claimed in claim 2 wherein the content of water in the solvent mixture ranges from 5 to 60% by weight. 5. A process as claimed in claim 2 wherein the base is at least one compound selected from the group consisting of ethylamine, diethylamine, triethylamine, monoethanolamine, triethanolamine, pyridine and piperidine. 6. A process as claimed in claim 2 wherein the base is at least one compound selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate , calcium carbonate, barium carbonate and ammonia. 7. A process as claimed in claim 2 wherein the neutralization is carried out at a temperature of -20 to 800C.

Inventors: HIGUCHI, CHOJIRO, KATOH, TOSHIO, MITA, RYUICHI, OHOKA, MASAHARU, YAMAGUCHI, AKIHIRO
Applicants: MITSUI TOATSU CHEMICALS, INCORPORATED
Application year: 1983
Main classification: C07C149
IPC codes: C07C313, C30B29, C07C323, C07C67