CN110845443B - Method for preparing high-purity tolperisone hydrochloride - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention relates to the technical field of medical technology, in particular to a process method for preparing high-purity tolperisone hydrochloride. The method of the invention strictly controls the addition amount of toluene, anhydrous aluminum trichloride and propionyl chloride in Friedel-crafts acylation reaction, the reaction temperature and the reaction time, and after Mannich reaction is completed, the temperature is reduced to 20-30 ℃, isopropanol and isopropyl ether are added for heat preservation crystallization for more than 2 hours, then the crude product of tolperisone hydrochloride is obtained through solid-liquid separation, thereby reducing the occurrence of Friedel-crafts acylation side reaction, improving the product purity and the product yield, and the method for preparing high-purity tolperisone hydrochloride is environment-friendly, simple and safe to operate.
Description
Technical Field
The invention relates to the technical field of medical technology, in particular to a process method for preparing high-purity tolperisone hydrochloride.
Background
Tolperisone hydrochloride (Tolperisone Hydrochloride), molecular formula C 16 H 24 ClNO; molecular weight: 281.83, structural formula:
tolperisone hydrochloride is a central muscle relaxant, and the indications are suitable for treating ischemic vascular diseases, such as arteriosclerosis, endangiitis and the like; it is also suitable for apoplexy sequela, cerebral palsy, spinal cord peripheral nerve diseases, etc. Has therapeutic effects on headache, dizziness, insomnia, limb numbness, hypomnesis, tinnitus, etc. caused by various cerebrovascular diseases. In recent years, a great deal of research has been conducted on the synthesis of tolperisone hydrochloride at home and abroad, and many synthesis methods have been proposed.
Document [ Chemical and Pharmaceutical Bulletin,1994, 42 (8): 1676-1678 discloses a process for the synthesis of tolperisone by reacting p-toluacetone with piperidine hydrochloride, 1, 2-dioxolane under the catalysis of one or more acids, which process, although in high yields, is inconvenient and costly to work up due to the multiple extractions of the impurities produced.
The process for the preparation of tolperisone disclosed in patent CN101754958A is the same as the previous document, and is characterized in that the crude tolperisone product is filtered from the reaction mixture after cooling, either in free form or in the form of its pharmaceutically compatible hydrochloride, hydrate and addition salts, and the content of 2-methyl-1- (4-methylphenyl) -propenone is reduced by recrystallisation of the crude tolperisone product.
The patent RO 75-83082 uses an aqueous formaldehyde solution for the preparation of tolperisone, but the reaction has some disadvantages such as high toxicity of the aqueous formaldehyde solution mixed into the reaction solution.
Japanese patent JP20390 (1965) likewise uses the Mannich reaction for the preparation of tolperisone, but uses paraformaldehyde as the reactant and the mixed solvents nitromethane, ethanol and toluene, but the use of a larger proportion of nitromethane in the reaction is dangerous and increases costs.
In summary, the existing method for synthesizing tolperisone basically uses Mannich reaction, wherein the raw materials are p-methyl propiophenone and piperidine hydrochloride, and the other raw material is either 1, 2-dioxolane or formaldehyde aqueous solution and paraformaldehyde, but no mention is made of controlling the influence of raw materials on tolperisone products caused by methyl propiophenone impurities. The p-methyl propiophenone is prepared from toluene and propionyl chloride through Friedel-crafts acylation reaction, some ortho-position and meta-position products are easy to generate, impurities are not easy to remove, and reduced pressure distillation and purification are often needed. Because the existence of impurities can have a great influence on the purity of the final product, the finished product is required to be subjected to free impurity removal and then to be reproduced into salt for refinement, so that the operation is complex and the cost is high.
Disclosure of Invention
The invention provides a preparation method of tolperisone hydrochloride, which aims to effectively reduce synthesis procedures, improve atomic utilization rate and quality of tolperisone hydrochloride, and improve yield of the product.
A process for the preparation of tolperisone hydrochloride comprising the steps of:
step (1): toluene and anhydrous aluminum trichloride with the mol ratio of 1:0.6 are reacted in advance at the temperature below 0 ℃;
step (2): slowly and dropwise adding propionyl chloride into the reaction system in the step (1) and maintaining the temperature below 0 ℃, wherein the adding amount of propionyl chloride is 50% of the molar amount of toluene;
step (3): after the dripping is completed, the temperature is raised to 30-40 ℃ for reaction;
step (4): quenching (pouring the reaction liquid into ice water slowly), separating liquid, concentrating to obtain p-methyl propiophenone;
step (5): reflux-reacting p-methyl propiophenone, piperidine hydrochloride and paraformaldehyde in the molar ratio of 1:0.8:1.3 at 90-100 ℃ for 5 hours;
step (6): after the reaction of the step (5) is completed, cooling to 20-30 ℃, adding isopropanol and isopropyl ether, preserving heat and crystallizing for more than 2 hours, and then obtaining a crude product of tolperisone hydrochloride through solid-liquid separation; the addition amount of the isopropyl alcohol and the isopropyl ether is 1 time and 5 times of the volume of the p-methyl propiophenone respectively;
step (7): reflux-dissolving the crude tolperisone hydrochloride product and absolute ethyl alcohol with the mass ratio of 1:1.5 at 85-95 ℃;
step (8): after the reaction of the step (7), carrying out hot filtration, cooling to 25-35 ℃ for crystallization, and then carrying out solid-liquid separation to obtain a topiramate hydrochloride fine product;
the reaction of the invention is as follows:
the synthetic route may have friedel-crafts acylation byproducts and further produce impurities a and B as shown below;
the inventor realizes that the reason why the reduced pressure distillation needs to be carried out on the p-methyl propiophenone is that the by-product of Friedel-crafts acylation reaction is removed, and further considers the reaction itself, and discovers through research that the control is further matched with the accurate control of temperature under the material adding proportion of the technical scheme of the invention, the contents of impurity A and impurity B can be unexpectedly and effectively controlled, and the purity and the yield of the product are improved.
The method of the invention can reduce the occurrence of Friedel-crafts acylation side reaction by strictly controlling the addition amount of materials and the reaction temperature and further controlling the reaction time, thereby improving the purity and the yield of the product, and is environment-friendly, simple and safe to operate and capable of synthesizing the high-purity tolperisone hydrochloride;
preferably, the reaction time of step (3) is 1 to 3 hours, preferably 3 hours;
in order to further control the content of the impurity A and the impurity B, the invention researches that in the step (2), propionyl chloride is dripped into the reaction system in the step (1), the dripping amount of the propionyl chloride needs to be controlled, and the temperature of the system in the dripping process is maintained in the required range;
preferably, the reaction solvent in the step (5) is absolute ethanol;
in the invention, the reaction is innovatively carried out at 20-30 ℃, thus being beneficial to improving the yield of the product;
the inventor further researches and discovers that the content of the impurity A and the impurity B can be further reduced by further controlling the reaction time at 20-30 ℃ and the yield of the product is improved;
preferably, in the step (7), the crude product is crystallized by absolute ethyl alcohol to obtain tolperisone hydrochloride. According to the preparation method, other catalyst residues are avoided, and the quality of tolperisone hydrochloride can be further improved through absolute ethyl alcohol.
The preferred method for synthesizing the high-purity tolperisone hydrochloride adopts the following steps:
(a) Toluene and anhydrous aluminum trichloride are stirred and dispersed below 0 ℃;
(b) Dripping propionyl chloride accounting for 50 percent of the molar weight of toluene into a reaction kettle, wherein the temperature is controlled below 0 ℃ during dripping;
(c) Heating to 30-40 ℃ after the dripping is completed, and preserving heat and stirring for 3 hours;
(d) Quenching, separating liquid, concentrating to obtain high-purity p-methyl propiophenone;
(e) Reflux-reacting p-methyl propiophenone, piperidine hydrochloride and paraformaldehyde at 90-100 ℃ for 5 hours;
(f) After the reaction is finished, cooling to 20-30 ℃, adding isopropanol and isopropyl ether, preserving heat and crystallizing for more than 2 hours, and then carrying out solid-liquid separation to obtain a crude product of tolperisone hydrochloride;
(g) Reflux-dissolving the crude tolperisone hydrochloride and absolute ethyl alcohol at 85-95 ℃;
(h) Through hot filtration, cooling to 25-35 ℃ for crystallization, and then solid-liquid separation, high-purity tolperisone hydrochloride is obtained;
compared with the prior art, the method has the advantages that the addition amount of each starting material, the reaction temperature and the reaction time in the reaction process are strictly controlled, the consumption of raw materials can be reduced, the complex step of reduced pressure distillation is reduced, and the generation of Friedel-crafts acylation reaction byproducts is greatly reduced; the method has the advantages that the operation process and the post-treatment are very simple, other complex post-treatment operations are not needed, the whole reaction process only needs to be controlled by the reaction time, the reaction time is greatly shortened, the obtained product has high yield and good quality, and the method is easy to apply industrially; the method has the advantages of wide medicament sources, little harm to personnel and environment, no residue in products and more contribution to industrial actual production.
Detailed Description
In order that those skilled in the art will better understand the technical solutions of the present invention, the following description will further describe the present invention with reference to specific embodiments, and the examples are only some examples of the present invention and should not be construed as limiting the scope of the present invention.
Example 1
HPLC was used to test tolperisone hydrochloride with reference to European pharmacopoeia method;
step (1): 99.6g toluene and 86.5g anhydrous aluminum trichloride are added into a 250ml reaction bottle in sequence, and the temperature is reduced to below 0 ℃;
step (2): slowly dripping 50g of propionyl chloride, controlling the internal temperature below 0 ℃, then heating to 30-40 ℃ and reacting for 3 hours;
step (3): slowly pouring the reaction solution into 500g of ice-water mixture after the reaction is finished, controlling the internal temperature to be less than or equal to 15 ℃ for quenching and separating liquid, concentrating and spin-drying a toluene phase to obtain high-purity p-methyl propiophenone;
step (4): 70g of p-methyl propiophenone, 46g of piperidine hydrochloride, 18.4g of paraformaldehyde and 46g of isopropanol are added into a 1000ml three-port reaction bottle, stirred, heated to an internal temperature of 90-100 ℃ and reacted for 5 hours;
step (5): cooling to 20-30 ℃, then adding 70ml of acetone and 350ml of isopropyl ether, precipitating a large amount of solids, and then obtaining a crude product of tolperisone hydrochloride through solid-liquid separation; tolperisone hydrochloride has a chromatographic content of 99.85%, impurity A has a chromatographic content of 0.04%, and impurity B has a chromatographic content of 0.11%.
Step (6): heating 80g of tolperisone hydrochloride crude product and 120g of absolute ethyl alcohol to 85-95 ℃ for refluxing and dissolving, filtering while the crude product is hot, transferring filtrate to another reaction bottle, reheating and dissolving, slowly cooling to 25-35 ℃, and reacting for 2 hours at the temperature in a heat preservation way; then solid-liquid separation is carried out to obtain topiperidone hydrochloride refined products; the total yield was 75%; the HPLC area normalization method results are as follows: tolperisone hydrochloride is 99.93%, impurity A is 0.01%, and impurity B is 0.06%. The individual impurity content is less than 0.15%.
Example 2
Compared with the example 1, the difference is that in the step (2), when 50g of propionyl chloride is slowly dripped, the internal temperature is controlled between 0 and 10 ℃; product purity and impurity control were similar to example 1, but with poorer quality than example 1; as the temperature of dripping propionyl chloride is increased, the byproducts of Friedel-crafts acylation reaction are increased, thereby influencing the product quality.
Example 3
Compared with example 1, the difference is that in the step (6), when the temperature is reduced to 25-35 ℃, the reaction is not carried out for 2 hours, the total yield of the refined product is only 47%, and the purity and impurity control of the product are similar to those of example 1, but the yield is lower; the reaction is not continued for 2 hours at the temperature of 25-35 ℃ again, so that the yield is lower and the product yield is affected.
Example 4
Compared with example 1, the difference is that in the step (4), the temperature is raised to the internal temperature of 90-100 ℃, the reaction is continued for 5 hours without heat preservation, the crude product yield is only 55%, and the purity of the product and the impurity control are similar to those of example 1, but the yield is lower than that of example 1; the reaction is not continued at 90-100 ℃ for 5 hours, so that the yield is lower and the product yield is affected.
Comparative example 1
The difference compared with example 1 is that the ratio of toluene, anhydrous aluminum trichloride and propionyl chloride is 1:0.6:1. The purity of the crude product is 99.55%, and the contents of the impurity A and the impurity B are respectively 0.11 and 0.32; the purity of the crystallized product is 99.68 percent, and the contents of the impurity A and the impurity B are respectively 0.09 and 0.22;
because the proportion of toluene, anhydrous aluminum trichloride and propionyl chloride is not controlled, the chromatographic contents of impurities A and B of the product are higher, and the purity of the product is affected;
comparative example 2
The difference compared with example 1 is only that the reaction temperature in step (2) is 10 to 20 ℃. The purity of the crude product is 99.12%, and the contents of the impurity A and the impurity B are respectively 0.18% and 0.56%; the purity of the crystallized product is 99.23, and the contents of the impurity A and the impurity B are respectively 0.16 and 0.50 percent;
because the reaction temperature is not controlled, the chromatographic content of impurities A and B of the product is higher, and the purity of the product is affected;
comparative example 3
The difference compared with example 1 is that the ratio of the p-methyl propiophenone, piperidine hydrochloride and paraformaldehyde in the step (4) is 1:0.8:1.2, the crude product purity is 99.58%, and the content of the impurity A and the impurity B is 0.11 and 0.30 respectively; the purity of the crystallized product is 99.66 percent, and the contents of the impurity A and the impurity B are respectively 0.09 and 0.20;
because the proportion of the p-methyl propiophenone, the piperidine hydrochloride and the paraformaldehyde is not controlled, the chromatographic content of impurities A and B of the product is higher, and the purity of the product is influenced;
comparative example 4
The difference from example 1 is that in step (4), the reaction temperature is 80 to 90 ℃; the purity of the crude product is 99.42%, and the contents of the impurity A and the impurity B are respectively 0.11% and 0.36; the purity of the recrystallized product is 99.51 percent, and the contents of the impurity A and the impurity B are 0.08 percent and 0.32 percent respectively;
because the reaction temperature is not controlled, the chromatographic content of impurities A and B of the product is higher, and the purity of the product is affected;
it is to be understood that the above embodiments are merely illustrative of the application of the principles of the present invention, but not in limitation thereof. Various modifications and improvements may be made by those skilled in the art without departing from the spirit and substance of the invention, and are also considered to be within the scope of the invention.
Claims (2)
1. A process for the preparation of tolperisone hydrochloride, comprising the steps of: step (1): the molar ratio was set to 1: toluene and anhydrous aluminum trichloride of 0.6 are reacted in advance at a temperature below 0 ℃; step (2): slowly dropwise adding propionyl chloride into the reaction system of the step (1); step (3): after the dripping is completed, heating up for reaction; step (4): quenching, separating liquid and concentrating to obtain p-methyl propiophenone; step (5): the molar ratio was set to 1:0.8:1.3, carrying out reflux reaction on the p-methyl propiophenone, piperidine hydrochloride and paraformaldehyde at 90-100 ℃ for 5 hours; step (6): after the reaction of the step (5), cooling, adding acetone and isopropyl ether, preserving heat and crystallizing for more than 2 hours, and then obtaining a crude product of tolperisone hydrochloride through solid-liquid separation; step (7): the mass ratio is 1:1.5, refluxing and dissolving the crude tolperisone hydrochloride and absolute ethyl alcohol at 85-95 ℃; step (8): after the reaction of the step (7), carrying out hot filtration, cooling to 25-35 ℃ for crystallization, and then carrying out solid-liquid separation to obtain a topiramate hydrochloride fine product; the method is characterized in that in the step (1) and the step (2), the molar ratio of toluene, anhydrous aluminum trichloride and propionyl chloride is 1:0.6: and 0.5, controlling the temperature of the dripping temperature in the step (2) below 0 ℃, heating to 30-40 ℃ after the dripping is finished, and preserving heat and stirring for 3 hours.
2. The process for preparing tolperisone hydrochloride according to claim 1, wherein after the completion of the reaction in step (5), the temperature is lowered to 20 to 30 ℃ and the addition amounts of acetone and isopropyl ether are 1 time and 5 times the volume of p-methyl propiophenone, respectively.
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| CN114409620A (en) * | 2022-02-18 | 2022-04-29 | 海南普利制药股份有限公司 | Preparation method of amiodarone hydrochloride intermediate |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002088100A2 (en) * | 2001-05-02 | 2002-11-07 | Turicum Drug Development Ag | Deuterated 3-piperidinopropiophenone and medicaments containing said compounds |
| CN101754958A (en) * | 2007-04-26 | 2010-06-23 | 萨诺化学药物股份公司 | Prepare highly purified 2,4 '-method of dimethyl-3-piperidines-Propiophenone (tolperisone), the active substance formulations that comprises its pharmaceutical composition and comprise tolperisone |
| CN103193620A (en) * | 2013-04-07 | 2013-07-10 | 天长市禾益化学药品有限公司 | Method for preparing 2-(4-Chloromethylphenyl) propionic acid as loxoprofen key intermediate |
| CN103232415A (en) * | 2013-05-07 | 2013-08-07 | 湖南亚大制药有限公司 | Eperisone hydrochloride production method |
| KR20140067368A (en) * | 2012-11-26 | 2014-06-05 | 주식회사 엔지켐생명과학 | Process for preparing eperisone hydrochloride |
| CN104761524A (en) * | 2014-01-07 | 2015-07-08 | 清华大学 | Compounds and application thereof in preparation of anti-parasitosis drugs |
| CN106588817A (en) * | 2016-12-13 | 2017-04-26 | 湖南亚大制药有限公司 | Method for synthesizing eperisone hydrochloride |
| CN107868065A (en) * | 2017-10-19 | 2018-04-03 | 湖北美林药业有限公司 | A kind of Flubuperone Hydrochloride compound and preparation method thereof |
| CN109134261A (en) * | 2017-06-15 | 2019-01-04 | 北京蓝丹医药科技有限公司 | A kind of loxoprofen derivative |
| WO2019195775A1 (en) * | 2018-04-06 | 2019-10-10 | Flex Pharma, Inc. | Tolperisone analogs and methods of use |
-
2019
- 2019-12-11 CN CN201911272197.3A patent/CN110845443B/en active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002088100A2 (en) * | 2001-05-02 | 2002-11-07 | Turicum Drug Development Ag | Deuterated 3-piperidinopropiophenone and medicaments containing said compounds |
| CN1527823A (en) * | 2001-05-02 | 2004-09-08 | ͼ���ķҩ�x{FDE2}չ�ɷݹ�˾ | Deuterated 3-piperidinopropiophenone and medicaments containing said compounds |
| CN101754958A (en) * | 2007-04-26 | 2010-06-23 | 萨诺化学药物股份公司 | Prepare highly purified 2,4 '-method of dimethyl-3-piperidines-Propiophenone (tolperisone), the active substance formulations that comprises its pharmaceutical composition and comprise tolperisone |
| KR20140067368A (en) * | 2012-11-26 | 2014-06-05 | 주식회사 엔지켐생명과학 | Process for preparing eperisone hydrochloride |
| CN103193620A (en) * | 2013-04-07 | 2013-07-10 | 天长市禾益化学药品有限公司 | Method for preparing 2-(4-Chloromethylphenyl) propionic acid as loxoprofen key intermediate |
| CN103232415A (en) * | 2013-05-07 | 2013-08-07 | 湖南亚大制药有限公司 | Eperisone hydrochloride production method |
| CN104761524A (en) * | 2014-01-07 | 2015-07-08 | 清华大学 | Compounds and application thereof in preparation of anti-parasitosis drugs |
| CN106588817A (en) * | 2016-12-13 | 2017-04-26 | 湖南亚大制药有限公司 | Method for synthesizing eperisone hydrochloride |
| CN109134261A (en) * | 2017-06-15 | 2019-01-04 | 北京蓝丹医药科技有限公司 | A kind of loxoprofen derivative |
| CN107868065A (en) * | 2017-10-19 | 2018-04-03 | 湖北美林药业有限公司 | A kind of Flubuperone Hydrochloride compound and preparation method thereof |
| WO2019195775A1 (en) * | 2018-04-06 | 2019-10-10 | Flex Pharma, Inc. | Tolperisone analogs and methods of use |
Non-Patent Citations (1)
| Title |
|---|
| 李爱军等.碘催化芳基重排法合成2-(4-溴甲基苯基)丙酸.《精细化工》.2006,第613-614、619页. * |
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