CN108752250B - Synthesis method of high-purity fudosteine - Google Patents
Synthesis method of high-purity fudosteine Download PDFInfo
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Abstract
The application relates to a synthesis method of high-purity fudosteine, belonging to the technical field of thioether acyclic compound synthesis. Taking L-cysteine and halopropanol as raw materials, ammonia water or organic base as an acid-binding agent, taking water as a solvent, and carrying out nucleophilic substitution reaction after the raw materials are dissolved to synthesize the fudosteine. The method is applied to the synthesis of fudosteine, and has the advantages of short steps, simplicity in operation, high selectivity, mild conditions, high product quality and the like.
Description
Technical Field
The application relates to a synthesis method of high-purity fudosteine, belonging to the technical field of thioether acyclic compound synthesis.
Background
Fudosteine (chemical name: 3-hydroxypropyl thio-L-alanine) has the following structural formula:
fudosteine is an expectorant with a new action mechanism developed by Mitsubishi pharmaceutical corporation and SS pharmaceutical corporation, has multiple pharmacological effects on chronic respiratory system diseases, can inhibit airway epithelial cell hyperplasia, normalize trehalose/sialic acid ratio in sputum, improve viscosity and elasticity of sputum, restore ciliary transport airway secretion state, promote serous fluid secretion, and has good antitussive and expectorant effects.
Fudosteine is firstly approved to be produced and marketed in Japan in 10 months in 2001, has the advantages of strong drug effect, small side effect, wide adaptation syndrome, large market potential and the like, is expected to be a new generation product of acetylcysteine, carboxymethyl cysteine and other similar drugs, will become a first selective drug for eliminating phlegm caused by chronic respiratory system diseases, and will occupy an important position in the market of phlegm-eliminating drugs in future (Wanyajiang, Liufu Jing, Tianjin pharmacy 2006, 18(5), 73-74). In recent years, clinical studies find that fudosteine can play multiple roles of removing oxygen free radicals, inhibiting inflammatory reaction, inhibiting oxidative stress and the like besides the effect of eliminating phlegm, and has important significance for preventing and treating pulmonary fibrosis (Keyanqi, Li shoang, Yang Shuai, Li, Cheng Qing Lian, J.J.Clinichionaceae, 2017, 22(4), 670-. The pharmaceutical enterprises in China also pay high attention to Fudosteine, and the bulk drug production batch of Fudosteine is obtained by Sichuan New Kaiyuan pharmaceutical Co., Ltd, Zhejiang national Pont pharmaceutical Co., Ltd, Yichang Dongyang Yangtze pharmaceutical Co., Ltd, Tianfang pharmaceutical Co., Ltd, Liyunnanghong run pharmaceutical Co., Ltd and Weihaidi pharmaceutical Co., Ltd.
The existing fudosteine synthesis mainly comprises three methods: (1) reacting L-cysteine with 3-halopropanol, (2) reacting L-cysteine with allyl alcohol, and (3) reacting L-cysteine with oxetane.
The former SS pharmaceutical company first reported that fudosteine was prepared by nucleophilic substitution of L-cysteine with 3-bromo-1-propanol in aqueous sodium hydroxide (Yoshhikuni Itoh, Hiroyuki Mizuno et al, US 5047428, 6.13.1989):
the method has the main problems that inorganic alkali is used as an acid-binding agent to generate equivalent inorganic salt, the fudosteine has good water solubility, the inorganic salt is not easy to remove completely in the alcohol precipitation refining process, the roasting residue of the product is high, an ion exchange resin column chromatography process is needed in the post-treatment of the synthesis method, the equipment requirement is high, and L-cysteine is easy to perform racemization reaction under strong alkaline conditions.
The domestic Henan Tianfang pharmaceutical industry GmbH takes cysteine hydrochloride as a starting material, 1, 3-propanediol and hydrobromic acid are synthesized into an intermediate 3-bromo-1-propanol, then the intermediate and the cysteine hydrochloride are synthesized into Fudosteine in a sodium hydroxide aqueous solution, and after secondary crystallization, the yield is 85 percent, and the product purity is 99.5 percent (newly built every week, CN104418779A, 26 months and 08 days in 2013).
Siwa university uses L-cysteine and 3-chloro-1-propanol as starting materials, sodium hydroxide as an acid-binding agent, and the product is reacted to synthesize fudosteine with the purity of 99% (Mamenlin, CN101851185A, 2009, 10 months and 20 days).
Thereafter, SS pharmaceutical Co., Ltd reported another synthesis method of fudosteine, (Ito Yoshikuni, Kuryama Tadatoshi et al, JP08119932, 10.19.1994) prepared fudosteine by radical addition reaction of L-cysteine with allyl alcohol under the catalysis of light or heat, or a radical initiator, the reaction formula is as follows:
the L-cysteine and the allyl alcohol are used as starting materials, and the method solves the problem of high roasting residue in the fudosteine product by utilizing light, heat, microwave or free radical initiator to initiate reaction, and is widely applied in China.
Beijing Dezhongwang medical science and technology Limited reports that Fudosteine is synthesized by thermally-initiated free radical addition reaction with the yield of 80% (koufang Liyan, CN1840524A, 3.31.2005).
The Tianjin pharmaceutical research institute reports that the radical addition reaction is initiated by ultraviolet irradiation to synthesize fudosteine with a yield of 87.8% (Wangyiang, Liufu Jing, Tianjin pharmacy, 2006, 18(5), 73-74.).
The university of Henan university reports that potassium persulfate and sodium bisulfite initiate a free radical addition reaction to synthesize fudosteine with a yield of 91% (Xuluqing, Maoluze, etc., proceedings of the university of Henan, 2011, 39(3), 103-.
Yichang Dongyangguang Yangtze Yangjiang pharmaceutical industry, GmbH, adopts ultraviolet irradiation to initiate free radical addition reaction to synthesize fudosteine, further optimizes reaction conditions, and has a yield of 92% (Yangkai, Xiaoyan, Tangjinlong, etc., CN104326954B, 10 months and 17 days in 2014).
Amikeyue Comkatie pharmaceutical Co., Ltd adopts high potassium sulfate to initiate free radical addition reaction to synthesize fudosteine with yield of more than 95% (Zhou, Liu Wei Tan, Gao Binje, CN105622474A, 2016, 1 month and 12 days).
Fudosteine is synthesized by Zhejiang nation pharmaceutical company Limited by free radical addition reaction, and on the basis of the work of SS pharmaceutical company, ferrous sulfate and hydrogen peroxide are used as free radical initiators, so that the yield is 91.4%, and the content is 99.1% (Jiangdui, Liucong, Lule and the like, CN103113273A, 2 months and 1 day in 2013). Along with the accumulation of production experience in the year and the improvement of column efficiency of a chromatographic column, two trailing impurity peaks appear on a high performance liquid chromatography detection graph of the fudosteine product, and in order to remove the impurity peaks, the post-treatment needs to be carried out for three times of recrystallization to achieve the chromatographic purity of 99.5%. The Zhejiang food and drug inspection institute conjectures that the possible impurity structure is Fudosteine isomer through a structure identification method of hydrophilic interaction chromatography-mass spectrometry (Guxiao, Luoing, Chenyue, pharmacy reports, 2017, 52(8), 1313-1317).
Recently, Weihaidin pharmaceutical Co., Ltd reported a new method for synthesizing fudosteine by reacting L-cysteine with oxetane under alkaline conditions (Wangning, Miao Huaming, Liangsong Jun, He Tian, CN105461603A, 12.29.2015). The method for synthesizing fudosteine has high yield and high purity, and has the similar burning residue problem as the 3-chloro (bromo) -1-propanol method, except that inorganic alkali is still needed and hydrochloric acid is used for regulating the pH value.
As for the S-alkylation of L-cysteine, a strong inorganic base is generally used as an alkaline reagent, and Wlosstowski reports that L-cysteine promoted with tetramethylguanidine, an organic base, is subjected to S-alkylation with a common halogenated hydrocarbon (Wlosstowski M., Czamocka S., Macijewski P., Tetrahedron Lett, 51(2010), 5977-5979).
The present application was made based on this.
Disclosure of Invention
Aiming at the defects in the existing fudosteine preparation, the application provides the high-purity fudosteine synthesis method which is simple in process, mild in reaction conditions, high in product purity and low in ignition residues.
In order to achieve the purpose, the technical scheme adopted by the application is as follows:
a synthesis method of high-purity fudosteine comprises the steps of taking L-cysteine and halopropanol as raw materials, taking ammonia water or organic base as an acid-binding agent, taking water as a solvent, dissolving the raw materials, and then carrying out nucleophilic substitution reaction to synthesize the fudosteine.
Further, as preferable:
and (3) carrying out purification treatment on the fudosteine synthesized by the nucleophilic reaction: the fudosteine obtained by nucleophilic substitution is a crude product, after the crude product is dissolved by adding water, 95% ethanol is added, the temperature is raised to 30-80 ℃, the mixture is stirred and filtered, the 95% ethanol is added into the filtrate, the temperature is lowered to-5-20 ℃ for crystallization, and the pure product is obtained after the filtration and the drying.
The synthesis method of the high-purity fudosteine comprises the following steps:
A. adding food-grade L-cysteine into water, stirring at room temperature for 15min, adding ammonia water or organic base, continuously stirring for 0.5h after the addition is finished, dropwise adding 3-halogeno-1-propanol into a reaction system at the temperature of 20 +/-5 ℃, heating to the temperature of 30-80 ℃ after the dropwise addition is finished, stirring for reacting for at least 2 h, cooling to the temperature of 20 +/-5 ℃, and adjusting the pH to 4-6 by using glacial acetic acid; filtering, cooling the filtrate to (-5) DEG C-20 ℃, starting crystallization, filtering and drying to obtain the crude fudosteine.
B. And D, dissolving the crude product obtained in the step A in water, adding 95% ethanol (the mass percent of the 95% ethanol relative to the water is 20% -70%, preferably 35%), heating to 30-80 ℃, stirring for 1 hour, filtering, adding 95% ethanol into the filtrate, cooling to-5-20 ℃, crystallizing, filtering, and drying to obtain the pure fudosteine.
The reaction formula of the above reaction can be described as follows:
more preferably, it is a mixture of more preferably,
in the step A, the L-cysteine is commercial food grade L-cysteine (the content of the L-cysteine is more than 95 percent), and the 3-halogeno-1-propanol halogen is selected from chlorine and bromine, preferably 3-chloro-1-propanol.
In step A, L-cysteine: the mass ratio of water is 1:1 to 1:10, and preferably 1:3 to 1: 5.
In the step a, the organic base is any one of aqueous methylamine solution, triethylamine, ethylenediamine, diisobutylamine, tert-butylamine, diethylamine, cyclohexylamine, tri-n-butylamine, tetramethylguanidine, imidazole or pyridine, preferably aqueous methylamine solution.
In step a, organic base: the molar ratio of L-cysteine is 1:1 to 10:1, preferably 1:2 to 1: 4.
In step A, L-cysteine: the molar ratio of halopropanol is 1:1 to 1:10, preferably 1: 1.2.
In step A, the reaction temperature is preferably 20 to 80 ℃, preferably 30 to 45 ℃, and more preferably 30 to 40 ℃.
The method takes food-grade L-cysteine and 3-halogeno-1-propanol as initial raw materials, ammonia water or organic alkali as an acid-binding agent, water as a solvent, and performs nucleophilic substitution to synthesize fudosteine in the presence of the acid-binding agent; and recrystallizing with ethanol-water to obtain the final product. Compared with the conventional synthesis method, the method avoids using inorganic strong base such as sodium hydroxide, omits the step of removing inorganic salt by using ion exchange resin, has the advantages of short steps, simple operation, mild conditions and the like, is suitable for industrial production, particularly uses ammonia water or organic base to replace inorganic base as an acid-binding agent, reduces burning residues of products, inhibits racemization reaction of L-cysteine under the condition of the inorganic strong base, has high selectivity and improves the product quality, the total yield of the fudosteine prepared by the method is about 70 percent, the purity is more than 99.5 percent (HPLC detection), and the burning residues are less than 0.05 percent and reach the medicinal standard.
Detailed Description
Example 1
Adding 10g of L-cysteine into 70mL of water, adding 16.7g (2.0eq) of triethylamine, stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.9g of crude product with the mass yield of 109%.
Adding 27.3g of purified water into 10.9g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 18.2g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; and (3) dropwise adding 118g of absolute ethyl alcohol into the filtrate, cooling to 0 ℃, keeping the temperature for 30min, performing suction filtration and drying (at the temperature of 65 ℃ for 8h) to obtain 10g of fudosteine, wherein the mass yield is 100%, and the HPLC analysis content is 99.59%.
Example 2
Adding 10g of L-cysteine into 70mL of water, adding 9.92g (2.0eq) of ethylenediamine, stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.8g of crude product with the mass yield of 108%.
Adding 27.0g of purified water into 10.8g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 18.0g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; 117g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at 65 ℃) to obtain 9.8g of fudosteine, the mass yield is 98%, and the HPLC analysis content is 99.44%.
Example 3
Adding 10g of L-cysteine into 70mL of water, adding 21.33g (2.0eq) of diisobutylamine, stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after the dropwise adding is finished, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.5g of crude product, wherein the mass yield is 105%.
Adding 26.25g of purified water into 10.5g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 17.5g of absolute ethyl alcohol, heating to 40 ℃, keeping the temperature for 30min, and filtering by using filter paper; 113.75g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at the temperature of 65 ℃) to obtain 9.5g of fudosteine, the mass yield is 95%, and the HPLC analysis content is 99.46%.
Example 4
Adding 10g of L-cysteine into 70mL of water, adding 12.1g (2.0eq) of tert-butylamine, stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.8g of crude product with the mass yield of 108%.
Adding 27.0g of purified water into 10.8g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 18.0g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; 117g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at 65 ℃) to obtain 9.8g of fudosteine, the mass yield is 98%, and the HPLC analysis content is 99.42%.
Example 5
Adding 10g of L-cysteine into 70mL of water, adding 12.05g (2.0eq) of diethylamine, stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.8g of crude product with the mass yield of 108%.
Adding 27.0g of purified water into 10.8g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 18.0g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; 117g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at 65 ℃) to obtain 9.8g of fudosteine, the mass yield is 98%, and the HPLC analysis content is 99.52%.
Example 6
Adding 10g of L-cysteine into 70mL of water, adding 16.34g (2.0eq) of cyclohexylamine, stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.8g of crude product with the mass yield of 108%.
Adding 27.0g of purified water into 10.8g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 18.0g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; 117g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at 65 ℃) to obtain 9.8g of fudosteine, the mass yield is 98%, and the HPLC analysis content is 99.61%.
Example 7
Adding 10g of L-cysteine into 62.3mL of water, adding 12.8g (2.0eq) of methylamine water solution (40% w), stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, regulating the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring at 35 ℃ for 10min, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.8g of crude product with the mass yield of 108%.
Adding 27.0g of purified water into 10.8g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 18.0g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; 117g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at the temperature of 65 ℃) to obtain 10.1g of fudosteine, the mass yield is 101%, and the HPLC analysis content is 99.73%.
Example 8
Adding 10g of L-cysteine into 70mL of water, adding 16.7g (2.0eq) of triethylamine, stirring, dropwise adding 13.78g (1.2eq) of 3-bromo-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 10.6g of crude product with the mass yield of 106%.
Adding 26.5g of purified water into 10.6g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 17.7g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; and (3) dropwise adding 115g of absolute ethyl alcohol into the filtrate, cooling to 0 ℃, keeping the temperature for 30min, performing suction filtration and drying (at the temperature of 65 ℃ for 8h) to obtain 9.6g of fudosteine, wherein the mass yield is 96%, and the HPLC analysis content is 99.34%.
Example 9
Adding 10g of L-cysteine into 28.5mL of water, adding 19.2g (3.0eq) of methylamine water solution (40% w), stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 167g (6 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 11.1g of crude product, wherein the mass yield is 111%.
Adding 27.7g of purified water into 11.1g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 18.5g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; and (3) dropwise adding 136.9g of absolute ethyl alcohol into the filtrate, cooling to 0 ℃, preserving heat for 30min, performing suction filtration and drying (at the temperature of 65 ℃ for 8h) to obtain 10.5g of fudosteine, wherein the mass yield is 105%, and the HPLC analysis content is 99.56%.
Example 10
Adding 10g of L-cysteine into 22.3mL of water, adding 12.8g (2.0eq) of methylamine water solution (40% w), stirring, dropwise adding 9.4g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (13g), stirring for 10min at 35 ℃, and filtering; adding 120g (4 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 107g of crude product with the mass yield of 107%.
Adding 26.8g of purified water into 107g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 17.8g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; and (3) dropwise adding 132.0g of absolute ethyl alcohol into the filtrate, cooling to 0 ℃, preserving heat for 30min, performing suction filtration and drying (8 h at 65 ℃) to obtain 9.7g of fudosteine, wherein the mass yield is 97%, and the HPLC analysis content is 99.58%.
Example 11
Adding 50g of L-cysteine into 111.5mL of water, adding 64g (2.0eq) of methylamine aqueous solution (40% w), stirring, dropwise adding 47g (1.2eq) of 3-chloro-1-propanol at room temperature after the solution is clarified, heating to 40 ℃, and stirring for reacting for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (64g), stirring for 10min at 35 ℃, and filtering; 835g (4 times) of absolute ethyl alcohol is added into the filtrate for crystallization, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the crude product 57.06g is obtained after suction filtration and drying (8 h at 65 ℃), and the mass yield is 114.13%.
Adding 141g of purified water into 57.06g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 94g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; 850g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at 65 ℃) to obtain 47.95g of fudosteine, the mass yield is 96%, and the HPLC analysis content is 99.77%.
Example 12
100g of L-cysteine is added into 223.2mL of water, 128g (2.0eq) of methylamine water solution (40% w) is added and stirred, 94g (1.2eq) of 3-chloro-1-propanol is added dropwise at room temperature after the solution is clarified, and the temperature is raised to 40 ℃ after the dropwise addition is finished and the stirring reaction is carried out for 3.5 hours. After the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 30% absolute ethyl alcohol (128g), stirring for 10min at 35 ℃, and filtering; adding 1200g (4 times) of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, preserving heat for 30min, filtering and drying (8 h at 65 ℃) to obtain 116.05g of crude product with the mass yield of 116.05%.
Adding 290g of purified water into 116.05g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 193.4g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by using filter paper; 1260g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, and the filtrate is filtered and dried (8 h at 65 ℃) to obtain 104.06g of fudosteine with the mass yield of 104.06%, the HPLC analysis content of 99.52%, the burning residue of 0.04% and the chloride ion concentration of less than 0.02%.
The above description is provided for the purpose of describing the preferred embodiments of the present invention in more detail, and it should not be construed that the embodiments of the present invention are limited to the description above, and it will be apparent to those skilled in the art that the present invention can be implemented in many different forms without departing from the spirit and scope of the present invention.
Claims (1)
1. A method for synthesizing fudosteine is characterized by comprising the following steps: adding 100g L-cysteine into 223.2mL of water, adding 128g of 40% w of methylamine aqueous solution, stirring, dropwise adding 94g of 3-chloro-1-propanol at room temperature after the solution is clear, heating to 40 ℃ after dropwise adding, and stirring for reacting for 3.5 hours; after the reaction is finished, adjusting the pH value to 5-6 by using glacial acetic acid, adding 128g of 30% absolute ethyl alcohol, stirring for 10min at 35 ℃, and filtering; adding 1200g of absolute ethyl alcohol into the filtrate for crystallization, cooling to 0 ℃, keeping the temperature for 30min, performing suction filtration, and drying at 65 ℃ for 8h to obtain 116.05g of crude product with the mass yield of 116.05%;
adding 290g of purified water into 116.05g of fudosteine crude product, stirring at 35 ℃ until no obvious particles exist, adding 193.4g of absolute ethyl alcohol, heating to 40 ℃, preserving heat for 30min, and filtering by filter paper; 1260g of absolute ethyl alcohol is dripped into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept for 30min, the filtration is carried out, and the drying is carried out for 8h at 65 ℃, so that 104.06g of fudosteine is obtained, the mass yield is 104.06%, the HPLC analysis content is 99.52%, the burning residue is 0.04%, and the chloride ion concentration is lower than 0.02%.
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| CN101113178A (en) * | 2002-08-12 | 2008-01-30 | 昆士兰医学研究所理事会 | Novel immunogenic lipopeptides comprising t-helper and cytotoxic t lymphocyte (CTL) epitopes |
| CN103102294A (en) * | 2012-03-28 | 2013-05-15 | 新沂市汉菱生物工程有限公司 | Production method carboxymethyl cysteine |
| CN104418779A (en) * | 2013-08-26 | 2015-03-18 | 河南天方药业股份有限公司 | Preparation method of high-purity fudosteine |
| CN104744324A (en) * | 2013-12-26 | 2015-07-01 | 张云 | Fudosteine preparation method |
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| CN101113178A (en) * | 2002-08-12 | 2008-01-30 | 昆士兰医学研究所理事会 | Novel immunogenic lipopeptides comprising t-helper and cytotoxic t lymphocyte (CTL) epitopes |
| CN103102294A (en) * | 2012-03-28 | 2013-05-15 | 新沂市汉菱生物工程有限公司 | Production method carboxymethyl cysteine |
| CN104418779A (en) * | 2013-08-26 | 2015-03-18 | 河南天方药业股份有限公司 | Preparation method of high-purity fudosteine |
| CN104744324A (en) * | 2013-12-26 | 2015-07-01 | 张云 | Fudosteine preparation method |
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