A method for synthesizing high-purity carbocisteine

Abstract

The present invention relates to the technical field of pharmaceutical preparation, and more specifically, to a method for synthesizing high-purity carbocisteine. The specific synthesis method is as follows: Add L-cysteine hydrochloride monohydrate and chloroacetic acid to a solvent, stir until dissolved, stop stirring and add a base to adjust the pH; raise the temperature and maintain the temperature until the reaction ends; add mercaptoethanol and continue stirring; add acid to adjust the pH, cool down and stir for crystallization, and filter to obtain carbocisteine. The base selected for the reaction in the present invention is a carbonate or bicarbonate, and gas is generated during the reaction, which can effectively protect L-cysteine hydrochloride monohydrate from being oxidized to form cystine, and the obtained carbocisteine has high purity and content. Adding mercaptoacetic acid after the condensation reaction can effectively remove cystine impurities, and the prepared carbocisteine has high purity and good optical activity, and does not require repeated crystallization for purification. The required raw materials are cheap and easily available, no catalyst is used, the operation is simple with few steps, the production cycle is short, and it is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and more specifically, to a method for synthesizing high-purity carbocisteine. Background Art

[0002] The chemical name of carbocisteine: The chemical name is S-carboxymethyl-L-cysteine, molecular formula: C 5 H 9 NO 4 S, molecular weight: 179.19, structural formula:

[0003]

[0004] Carbocisteine is a phlegm-dissolving drug that is safe, highly effective, has a wide range of applications, and has few side effects. It is used for the treatment of difficult expectoration caused by acute and chronic bronchitis, emphysema, pulmonary tuberculosis and other diseases.

[0005] The domestic process for producing carbocisteine mainly uses L-cysteine hydrochloride monohydrate and chloroacetic acid as raw materials to carry out a condensation reaction under weak alkaline conditions to obtain a crude product, and then obtains carbocisteine through refining and recrystallization. Because L-cysteine hydrochloride monohydrate is easily oxidized to form cystine under weak alkaline conditions, resulting in low purity and poor optical rotation of carbocisteine, it is necessary to carry out the reaction under nitrogen protection, and then obtain a qualified product after two refinings.

[0006] Chinese Patent Document Publication No. CN106565565A, patent name "A Method for Carbocisteine" discloses a preparation method of carbocisteine, including three steps of condensation reaction, neutralization crystallization, and recrystallization. The invention greatly reduces the content of impurity amino acids in the finished product and improves the purity and product quality of carbocisteine by adding carbonate and antioxidant to the reaction system and strictly controlling the reaction conditions. The disadvantage of this method is that the preparation process requires refining and recrystallization, the process is complex, and the production cycle is long.

[0007] Chinese Patent Document Publication No. CN105418471A, patent name "A Synthetic Method for Carbocisteine" relates to a method for synthesizing and producing carbocisteine. It changes the existing two-pot reaction process to a one-pot reaction process, simplifies the process, and reduces equipment; changes the low-temperature ammonia protection process to a normal-temperature nitrogen-free protection process, reducing material consumption and energy consumption; changes the two-step crystallization process to a one-step crystallization process, reducing processes and equipment, and improving the yield. The disadvantage of this method is that the alkali used in the preparation process is sodium hydroxide, L-cysteine hydrochloride is easily oxidized to cystine, and the ignition residue is not easily qualified, and the crude product needs to be refined or slurried. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, an object of one aspect of the present invention is to provide a method for synthesizing high-purity carbocisteine, and the specific steps of the synthesis method are as follows:

[0009] S1. Add L-cysteine hydrochloride monohydrate and chloroacetic acid to a solvent, stir until dissolved, stop stirring and add a base to adjust the pH.

[0010] S2. Raise the temperature and maintain the temperature until the reaction ends.

[0011] S3. Add mercaptoethanol and continue stirring.

[0012] S4. Add an acid to adjust the pH, cool down and stir for crystallization, and filter to obtain carbocisteine.

[0013] The preparation reaction equation is as follows:

[0014]

[0015] Preferably, in S1, the molar ratio of L-cysteine hydrochloride monohydrate to chloroacetic acid is 1:1.05 - 1.2.

[0016] Preferably, in S1, the solvent is purified water.

[0017] Preferably, in S1, the base added is a carbonate or bicarbonate, and the pH is adjusted to 7.0 - 8.0.

[0018] Preferably, in S1, the carbonate or bicarbonate is one or a combination of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0019] Preferably, in S2, the temperature is raised and maintained at 58°C - 62°C.

[0020] Preferably, in S2, the reaction is maintained at the temperature for 1 h.

[0021] Preferably, in S3, the mass of mercaptoethanol added is 2% - 4% of the mass of L-cysteine hydrochloride monohydrate, and stirring is continued for 1 h.

[0022] Preferably, in S4, the acid added is hydrochloric acid, and the pH is adjusted to 2.5 - 3.0.

[0023] Preferably, in S1, the temperature is cooled to 10°C - 20°C and stirred for crystallization for 2 h.

[0024] The beneficial effects of the present invention are as follows:

[0025] The base selected for the reaction of the present invention is carbonate or bicarbonate. Gas is generated during the reaction, which can effectively protect L-cysteine hydrochloride monohydrate from being oxidized to form cystine, and the obtained carbocisteine has high purity and content.

[0026] After the condensation reaction of the present invention is completed, mercaptoethanol is added. By utilizing the strong reducing property of mercaptoethanol for disulfide bonds, cystine impurities can be effectively removed. The prepared carbocisteine has high purity and good optical activity, and does not require repeated crystallization for purification.

[0027] The raw materials required for the present invention are cheap and easily available, no catalyst is used, there is little three wastes and it will not cause the burden of polluting the environment. The operation is simple with few steps, the production cycle is short, the overall reaction does not involve high temperature and high pressure reactions, it is easy to operate and personnel safety is ensured, which is suitable for large-scale industrial production.

[0028] The additional aspects and advantages of the present invention will become apparent in the following description or be learned through the practice of the present invention. Detailed implementation manners

[0029] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that, without conflict, the embodiments of the present application and the features in the embodiments can be combined with each other.

[0030] Many specific details are set forth in the following description in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from this description. Therefore, the protection scope of the present invention is not limited by the specific embodiments disclosed below.

[0031] Example 1

[0032] S1. Add 50 g of L-cysteine hydrochloride monohydrate, 29 g of chloroacetic acid and 250 g of purified water to a 500 ml four-necked flask in sequence, stir until completely dissolved, stop stirring, and slowly add 80 g of potassium carbonate at room temperature and stir to adjust the pH to 7-8;

[0033] S2. Heat up to 62 °C and maintain the temperature for reaction for 1 h until the reaction ends;

[0034] S3. Add 1 g of mercaptoethanol and continue stirring for 1 h;

[0035] S4. Adjust the pH to 2.5-3.0 with hydrochloric acid, cool down to 10 °C and stir for crystallization for 2 h, filter to obtain 45.78 g of carbocisteine, with a purity of 99.943% and a yield of 89.75%.

[0036] Example 2

[0037] S1. Add 50 g of L-cysteine hydrochloride monohydrate, 30 g of chloroacetic acid and 250 g of purified water into a 500 ml four-necked flask in sequence. Stir until all are dissolved, then stop stirring. Slowly add 86 g of potassium bicarbonate at room temperature and stir to adjust the pH to 7 - 8;

[0038] S2. Heat up to 58 °C and maintain the temperature for reaction for 1 h until the reaction ends;

[0039] S3. Add 1.5 g of mercaptoethanol and continuously stir for 1 h;

[0040] S4. Adjust the pH to 2.5 - 3.0 with hydrochloric acid, cool down to 15 °C and stir for crystallization for 2 h. Filter to obtain 46.21 g of carbocisteine, with a purity of 99.935% and a yield of 89.76%.

[0041] Example 3

[0042] S1. Add 50 g of L-cysteine hydrochloride monohydrate, 30.5 g of chloroacetic acid and 250 g of purified water into a 500 ml four-necked flask in sequence. Stir until all are dissolved, then stop stirring. Slowly add 86 g of sodium bicarbonate at room temperature and stir to adjust the pH to 7 - 8;

[0043] S2. Heat up to 60 °C and maintain the temperature for reaction for 1 h until the reaction ends;

[0044] S3. Add 2 g of mercaptoethanol and continuously stir for 1 h;

[0045] S4. Adjust the pH to 2.5 - 3.0 with hydrochloric acid, cool down to 20 °C and stir for crystallization for 2 h. Filter to obtain 45.93 g of carbocisteine, with a purity of 99.944% and a yield of 90.04%.

[0046] Comparative Example

[0047] S1. Add 50 g of L-cysteine hydrochloride monohydrate, 29 g of chloroacetic acid and 250 g of purified water into a 500 ml four-necked flask in sequence. Stir until all are dissolved, then stop stirring. Slowly add 80 g of potassium carbonate at room temperature and stir to adjust the pH to 7 - 8;

[0048] S2. Heat up to 62 °C and maintain the temperature for reaction for 1 h until the reaction ends;

[0049] S3. Adjust the pH to 2.5 - 3.0 with hydrochloric acid, cool down to 10 °C and stir for crystallization for 2 h. Filter to obtain 44.98 g of carbocisteine, with a purity of 98.531% and a yield of 88.18%.

[0050] Use the product of the example of the present invention for impurity detection, and the results are shown in Table 1 below:

[0051]

[0052] Table 1. Impurity detection results of the products in the first to third embodiments of the present invention

[0053] The detection method for related substances such as impurities is as follows:

[0054] Test solution: The product prepared in the embodiment of the present invention. Take 100 mg of this product, weigh accurately, place it in a 50 ml volumetric flask, add 6 ml of 0.1 mol / L sodium hydroxide solution to dissolve and dilute to the mark with water, and shake well.

[0055] Reference solution: Accurately measure 1 ml and place it in a 100 ml volumetric flask, dilute to the mark with water, and shake well to obtain...

[0056] Test according to the high performance liquid chromatography method (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2015 Edition), using octadecylsilane chemically bonded silica gel as the filler (Hypersil BDS, 250 mm × 4.6 mm, 5 μm or a chromatographic column with equivalent efficiency); use phosphate buffer solution (take 6.8 g of potassium dihydrogen phosphate and 3.0 g of sodium heptanesulfonate, dissolve in water and dilute to 1000 ml, adjust the pH value of the solution to 2.5 with phosphoric acid) as the mobile phase, the detection wavelength is 215 nm; the flow rate is 1.0 ml per minute; the column temperature is 25 °C.

[0057] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, various modifications and changes can be made to the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A synthesis method of carbocisteine, characterized in that: The specific steps of the synthesis method are as follows: S1. Add L-cysteine hydrochloride monohydrate and chloroacetic acid into a solvent, stir until dissolved, stop stirring and add alkali to adjust the pH; S2. Raise the temperature and maintain the temperature until the reaction ends; S3. Add mercaptoethanol and continue stirring; S4. Add acid to adjust the pH, cool down and stir for crystallization, and filter to obtain carbocisteine; In the S1, the molar ratio of L-cysteine hydrochloride monohydrate to chloroacetic acid is 1:1.05 - 1.2; In the S1, the alkali added is carbonate or bicarbonate, and the pH is adjusted to 7.0 - 8.0; In the S2, the temperature is raised and maintained at 58°C - 62°C; In the S4, the acid added is hydrochloric acid, and the pH is adjusted to 2.5 - 3.

0.

2. The synthesis method of carbocisteine according to claim 1, characterized in that: The solvent in the S1 is purified water.

3. The synthesis method of carbocisteine according to claim 1, characterized in that: The carbonate or bicarbonate in the S1 is one or a combination of more than one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

4. The synthesis method of carbocisteine according to claim 1, characterized in that: The temperature is maintained for 1 h in the S2.

5. The synthesis method of carbocisteine according to claim 1, characterized in that: The mass of mercaptoethanol added in the S3 is 2% - 4% of the mass of L-cysteine hydrochloride monohydrate, and stirring continues for 1 h.

6. The synthesis method of carbocisteine according to claim 1, characterized in that: Cool down to 10°C - 20°C in the S1 and stir for crystallization for 2 h.

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