CN116143674A - Synthesis method of high-purity carbocisteine - Google Patents
Synthesis method of high-purity carbocisteine Download PDFInfo
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- CN116143674A CN116143674A CN202211639829.7A CN202211639829A CN116143674A CN 116143674 A CN116143674 A CN 116143674A CN 202211639829 A CN202211639829 A CN 202211639829A CN 116143674 A CN116143674 A CN 116143674A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
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Abstract
The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing high-purity carbocisteine. The specific synthesis method comprises the following steps: adding the L-cysteine hydrochloride monohydrate and chloroacetic acid into a solvent, stirring until the L-cysteine hydrochloride monohydrate and chloroacetic acid are dissolved, stopping stirring, and adding alkali to adjust the pH; heating and maintaining the temperature until the reaction is finished; adding mercaptoethanol and continuously stirring; adding acid to regulate pH, cooling, stirring, crystallizing, and filtering to obtain carboxymethyl settane. The alkali selected in the reaction is carbonate or bicarbonate, gas is generated in the reaction process, the L-cysteine hydrochloride monohydrate can be effectively protected from being oxidized to generate cystine, and the purity and the content of the obtained carbocisteine are high. After the condensation reaction is finished, thioglycollic acid is added to effectively remove cystine impurities, and the prepared carbocisteine has high purity and good optical rotation, and does not need repeated crystallization for refining. The method has the advantages of low cost and easy obtainment of the required raw materials, no use of catalyst, simple operation, few steps and short production period, and is suitable for industrialized mass production.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing high-purity carbocisteine.
Background
Carboxymethyl settane chemical name: the chemical name is S-carboxymethyl-L-cysteine, and the molecular formula is: c (C) 5 H 9 NO 4 S, molecular weight: 179.19, structural formula:
carbocisteine is a safe, efficient and wide-application-range phlegm-dispelling medicament with small side effects, and is used for treating cough difficult phlegm caused by diseases such as acute and chronic bronchitis, emphysema, phthisis and the like.
The domestic process for preparing carboxymethyl settane mainly uses L-cysteine hydrochloride monohydrate and chloroacetic acid as raw materials, and makes them undergo the process of condensation reaction under the condition of weak base to obtain crude product, then makes them undergo the process of refining and recrystallization so as to obtain carboxymethyl settane, and because the L-cysteine hydrochloride monohydrate is easily oxidized to produce cystine under the condition of weak base, the purity of carboxymethyl settane is low, and its optical activity is poor, so that it needs to make reaction under the protection of nitrogen gas, and then makes them undergo the process of refining twice so as to obtain the qualified carboxymethyl settane product
The invention discloses a preparation method of carbocisteine, which comprises three steps of condensation reaction, neutralization crystallization and recrystallization, wherein carbonate and antioxidant are added into a reaction system, and meanwhile, the reaction conditions are strictly controlled, so that the content of impurity amino acid in a finished product is greatly reduced, and the purity and the product quality of the carbocisteine are improved. The method has the defects of refining and recrystallization in the preparation process, complex process and long generation period.
The invention relates to a method for synthesizing and producing carbocisteine, which changes the existing two-pot reaction process into a one-pot reaction process, reduces the process and equipment, and has the publication number of CN105418471A and the patent name of carbocisteine synthesis method; the low-temperature ammonia gas protection process is changed into a normal-temperature nitrogen-free protection process, so that the material consumption and the energy consumption are reduced; the two-step crystallization process is changed into a one-step crystallization process, so that the procedures and equipment are reduced, and the yield is improved. The method has the defects that the alkali used in the preparation process is sodium hydroxide, the L-cysteine hydrochloride is easily oxidized into cystine, the burning residue is not easily qualified, and the crude product is required to be refined or pulped.
Disclosure of Invention
The invention aims at solving at least one of the technical problems existing in the prior art, and therefore, one aspect of the invention aims at providing a synthesis method of high-purity carbocisteine, which comprises the following specific steps:
s1, adding an L-cysteine hydrochloride monohydrate and chloroacetic acid into a solvent, stirring until the L-cysteine hydrochloride monohydrate and chloroacetic acid are dissolved, stopping stirring, and adding alkali to adjust the pH;
s2, heating and maintaining the temperature until the reaction is finished;
s3, adding mercaptoethanol and continuously stirring;
s4, adding acid to adjust pH, cooling, stirring, crystallizing, and filtering to obtain the carbocisteine.
The preparation reaction equation is as follows:
preferably, the molar ratio of the L-cysteine hydrochloride monohydrate to the chloroacetic acid in the S1 is 1:1.05-1.2.
Preferably, the solvent in S1 is purified water.
Preferably, the alkali in S1 is carbonate or bicarbonate, and the pH is adjusted to 7.0-8.0.
Preferably, the carbonate or bicarbonate in S1 is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
Preferably, the temperature is raised and maintained at 58-62 ℃ in the step S2.
Preferably, the reaction is carried out for 1h while maintaining the temperature in the step S2.
Preferably, the mass of the mercaptoethanol added in the S3 is 2-4% of the mass of the L-cysteine hydrochloride monohydrate, and stirring is continued for 1h.
Preferably, the acid added in the S4 is hydrochloric acid, and the pH is adjusted to 2.5-3.0.
Preferably, the temperature in the S1 is reduced to 10-20 ℃ and stirred for crystallization for 2 hours.
The invention has the following beneficial effects:
the alkali selected in the reaction is carbonate or bicarbonate, gas is generated in the reaction process, the L-cysteine hydrochloride monohydrate can be effectively protected from being oxidized to generate cystine, and the purity and the content of the obtained carbocisteine are high.
After the condensation reaction is finished, mercaptoethanol is added, the high reduction performance of mercaptoethanol to disulfide bonds is utilized, cystine impurities are effectively removed, and the prepared carbocisteine has high purity and good optical activity and does not need repeated crystallization for refining.
The method has the advantages of low cost and easy acquisition of the required raw materials, no use of catalyst, less three wastes, no environmental pollution, simple operation, few steps, short production period, no high-temperature and high-pressure reaction in the whole reaction, easy operation and safe personnel, and is suitable for industrial mass production.
Additional aspects and advantages of the invention will become apparent in the following description or may be learned by practice of the invention.
Detailed Description
In order that the above-recited objects, features and advantages of the invention will be more clearly understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof. It should be noted that, in the case of no conflict, the embodiments of the present application and the features in the embodiments may be combined with each other.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced otherwise than as described, and therefore the scope of the present invention is not limited to the specific embodiments disclosed below.
Example 1
S1, sequentially adding 50g of L-cysteine hydrochloride monohydrate, 29g of chloroacetic acid and 250g of purified water into a 500ml four-mouth bottle, stirring until all the materials are dissolved, stopping stirring, slowly adding 80g of potassium carbonate at room temperature, and stirring to adjust the pH to 7-8;
s2, heating to 62 ℃ and keeping the temperature for reaction for 1h until the reaction is finished;
s3, adding 1g of mercaptoethanol and continuously stirring for 1h;
s4, regulating the pH to 2.5-3.0 by using hydrochloric acid, cooling to 10 ℃, stirring and crystallizing for 2 hours, and filtering to obtain 45.78g of carbocisteine with the purity of 99.943% and the yield of 89.75%.
Example two
S1, sequentially adding 50g of L-cysteine hydrochloride monohydrate, 30g of chloroacetic acid and 250g of purified water into a 500ml four-mouth bottle, stirring until all the materials are dissolved, stopping stirring, slowly adding 86g of potassium bicarbonate at room temperature, and stirring to adjust the pH to 7-8;
s2, heating to 58 ℃ and keeping the temperature for reaction for 1h until the reaction is finished;
s3, adding 1.5g of mercaptoethanol and continuously stirring for 1h;
s4, regulating the pH to 2.5-3.0 by using hydrochloric acid, cooling to 15 ℃, stirring and crystallizing for 2 hours, and filtering to obtain 46.21g of carbocisteine with the purity of 99.935% and the yield of 89.76%.
Example III
S1, sequentially adding 50g of L-cysteine hydrochloride monohydrate, 30.5g of chloroacetic acid and 250g of purified water into a 500ml four-mouth bottle, stirring until all the materials are dissolved, stopping stirring, slowly adding 86g of sodium bicarbonate at room temperature, and stirring to adjust the pH to 7-8;
s2, heating to 60 ℃ and keeping the temperature for reaction for 1h until the reaction is finished;
s3, adding 2g of mercaptoethanol and continuously stirring for 1h;
s4, regulating the pH to 2.5-3.0 by using hydrochloric acid, cooling to 20 ℃, stirring and crystallizing for 2 hours, and filtering to obtain 45.93g of carbocisteine with the purity of 99.944% and the yield of 90.04%.
Comparative example
S1, sequentially adding 50g of L-cysteine hydrochloride monohydrate, 29g of chloroacetic acid and 250g of purified water into a 500ml four-mouth bottle, stirring until all the materials are dissolved, stopping stirring, slowly adding 80g of potassium carbonate at room temperature, and stirring to adjust the pH to 7-8;
s2, heating to 62 ℃ and keeping the temperature for reaction for 1h until the reaction is finished;
s3, regulating the pH to 2.5-3.0 by using hydrochloric acid, cooling to 10 ℃, stirring and crystallizing for 2 hours, and filtering to obtain 44.98g of carbocisteine with the purity of 98.531% and the yield of 88.18%.
The product of the embodiment of the invention is used for impurity detection, and the result is shown in the following table 1:
TABLE 1 impurity detection results for one to three products of the examples of the present invention
The detection method of related substances such as impurities comprises the following steps:
test solution: the embodiment of the invention prepares the product. 100mg of the product is taken, precisely weighed, placed in a 50ml measuring flask, added with 6ml of 0.1mol/L sodium hydroxide solution for dissolution, diluted to scale with water and shaken well.
Control solution: precisely measuring 1ml, placing in a 100ml measuring flask, diluting with water to scale, and shaking to obtain the final product.
According to high performance liquid chromatography (China pharmacopoeia 2015 edition, ministry of the fourth edition 0512), octadecylsilane chemically bonded silica is used as filler (Hypersil BDS,250mm×4.6mm,5 μm or chromatographic column with equivalent efficacy); taking phosphate buffer solution (taking 6.8g of monopotassium phosphate and 3.0g of sodium heptanesulfonate, adding water for dissolution and dilution to 1000ml, and adjusting the pH value of the solution to 2.5 by using phosphoric acid) as a mobile phase, wherein the detection wavelength is 215nm; the flow rate is 1.0ml per minute; the column temperature was 25 ℃.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for synthesizing high-purity carbocisteine is characterized by comprising the following steps: the synthesis method comprises the following specific steps:
s1, adding an L-cysteine hydrochloride monohydrate and chloroacetic acid into a solvent, stirring until the L-cysteine hydrochloride monohydrate and chloroacetic acid are dissolved, stopping stirring, and adding alkali to adjust the pH;
s2, heating and maintaining the temperature until the reaction is finished;
s3, adding mercaptoethanol and continuously stirring;
s4, adding acid to adjust pH, cooling, stirring, crystallizing, and filtering to obtain the carbocisteine.
2. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: the molar ratio of the L-cysteine hydrochloride monohydrate to the chloroacetic acid in the S1 is 1:1.05-1.2.
3. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: the solvent in S1 is purified water.
4. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: and adding alkali in the S1 into carbonate or bicarbonate, and regulating the pH value to 7.0-8.0.
5. The method for synthesizing high-purity carbocisteine according to claim 4, wherein the method comprises the following steps: the carbonate or bicarbonate in the S1 is one or a combination of more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
6. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: and in the step S2, the temperature is raised and kept at 58-62 ℃.
7. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: and (2) maintaining the temperature for reaction for 1h in the step (S2).
8. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: and adding 2-4% of mercaptoethanol which is L-cysteine hydrochloride monohydrate in the S3, and continuously stirring for 1h.
9. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: and adding hydrochloric acid into the S4, and adjusting the pH value to 2.5-3.0.
10. The method for synthesizing high-purity carbocisteine according to claim 1, wherein the method comprises the following steps: and (2) cooling to 10-20 ℃ in the step (S1), stirring and crystallizing for 2 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211639829.7A CN116143674A (en) | 2022-12-20 | 2022-12-20 | Synthesis method of high-purity carbocisteine |
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| CN202211639829.7A CN116143674A (en) | 2022-12-20 | 2022-12-20 | Synthesis method of high-purity carbocisteine |
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