CN115057854A - Preparation method of Alvatripopa maleate intermediate - Google Patents
Preparation method of Alvatripopa maleate intermediate Download PDFInfo
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- CN115057854A CN115057854A CN202210410941.7A CN202210410941A CN115057854A CN 115057854 A CN115057854 A CN 115057854A CN 202210410941 A CN202210410941 A CN 202210410941A CN 115057854 A CN115057854 A CN 115057854A
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
The invention relates to a preparation method of an intermediate of maleic acid atorvastatin calcium, which comprises the steps of adding 2, 5, 6-dichloronicotinic acid and pyridine as intermediates in an organic solvent, dropwise adding phosphorus oxychloride at-10-20 ℃ for reaction to obtain an intermediate 3; the intermediate 2 is 4- (4-chlorothien-2-yl) -5- (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-amine, and the intermediate 3 is 5, 6-dichloro-N- [4- (4-chlorothien-2-yl) -5 (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] pyridine-3-carboxamide. The method has the advantages of small pollution, high yield and good quality of the prepared intermediate 3.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of an atorvastatin asperpa maleate intermediate.
Background
Avatrompag maleate (avatrompag maleate), which is a thrombopoietin receptor agonist, was first developed by ansettai pharmaceutical group in japan, several of which were granted, and finally, new drug development was completed by akarrx pharmaceutical company, a subsidiary of the us Dova pharmaceutical company, and a new drug marketing application was proposed to the us Food and Drug Administration (FDA), which was approved to market 5 and 21 months in 2018 under the trade name Doptelet, for adult Chronic Liver Disease (CLD) patients suffering from thrombocytopenia and scheduled to undergo medical or dental surgery. The Alvatriprap tablet (imported) is approved by the national drug administration for repeated drug release and announcement at 16 days 4 and 4 in 2020, and is suitable for treating adult patients with chronic liver disease related thrombocytopenia who are subjected to selective diagnostic operation or operation.
The chemical name of the Alvatripopa maleate is as follows: 1- [ 3-chloro-5- [ [ [4- (4-chloro-2-thienyl) -5- (4-cyclohexyl-1-piperazinyl) -2-thiazolyl ] amino ] carbonyl ] -2-pyridinyl ] -4-piperidinecarboxylic acid maleate.
The original patent CN1639157A describes that the preparation process of the maleic acid avatars asperper is as follows:
in the preparation process, a more key intermediate 3 is involved, and the chemical structural formula is as follows:
5, 6-dichloro-N- "4- (4-chlorothien-2-yl) -5 (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] pyridine-3-carboxamide
The process condition for preparing the intermediate 3 is that pyridine is used as a solvent, phosphorus oxychloride is added at-25 ℃, and the intermediate is subjected to reduced pressure distillation, chloroform extraction and reduced pressure evaporation to dryness to obtain a solid, and then a silica gel chromatographic column is used for refining to obtain a target product. The method has the disadvantages of large pyridine dosage and great environmental pollution; the reaction temperature is too low, and the energy consumption is too high; chloroform which is a highly toxic and easy-to-prepare reagent is used as an extracting agent; multiple times of distillation and silica gel column refining cause the problems of high cost and the like.
Disclosure of Invention
The invention aims to provide a preparation method of an atorvastatin asperpopa maleate intermediate with small pollution, high yield and good quality.
The invention adopts the following technical scheme:
a preparation method of an intermediate of Alvatripopa maleate comprises the steps of adding 2, 5, 6-dichloronicotinic acid and pyridine as intermediates in an organic solvent, dropwise adding phosphorus oxychloride at-5-10 ℃ for reaction to obtain an intermediate 3;
the chemical name of the intermediate 2 is 4- (4-chlorothiophene-2-yl) -5- (4-cyclohexylpiperazine-1-yl) -1, 3-thiazole-2-amine.
The structural formula of the intermediate 2 is as follows:
the chemical name of the intermediate 3 is as follows: 5, 6-dichloro-N- [4- (4-chlorothien-2-yl) -5 (4-cyclohexylpiperazin-1-yl) -1, 3-thiazol-2-yl ] pyridine-3-carboxamide.
The structural formula is as follows:
the reaction equation of the invention is as follows:
wherein the organic solvent comprises dichloromethane, tetrahydrofuran, acetonitrile or methyl tert-butyl ether.
Preferably, the organic solvent is tetrahydrofuran or acetonitrile.
Particularly preferably, the organic solvent is acetonitrile.
Wherein the volume dosage range of the organic solvent is 10-15 times of the feeding amount of the intermediate 2.
Wherein the mass ratio of the intermediate 2, 5, 6-dichloronicotinic acid to the pyridine is 20-100: 11-55: 12-60.
Wherein the dropping amount of the phosphorus oxychloride is equal to the mass of the pyridine.
Further, the method specifically comprises the following steps:
(1) mixing the intermediate 2, acetonitrile, 5, 6-dichloronicotinic acid and pyridine, and cooling to-5-0 ℃;
(2) dropwise adding phosphorus oxychloride into the mixed solution in the step (1), and keeping the temperature at-5-10 ℃ in the dropwise adding process;
(3) after the dropwise addition is finished, stirring for 3-4 hours at the temperature of-5-10 ℃;
(4) dropwise adding 20% sodium hydroxide aqueous solution to adjust the pH value to 8-9, and stirring for 2 hours at room temperature after dropwise adding;
(5) filtering, and leaching a filter cake with acetonitrile to obtain a light yellow solid.
Further, in the step (1), the temperature is reduced to-5 DEG C
Further, in the step (2), the temperature is kept between-5 ℃ and 10 ℃ in the dropping process. Preferably 0 to 10 ℃.
Further, in the step (3), stirring is carried out for 3-4 hours at the temperature of-5-10 ℃. Preferably 0 to 10 ℃.
The invention has the beneficial effects that: the invention overcomes the defects of the prior art, and provides a preparation method of the intermediate 3 of the atorvastatin asperpa maleate according to the concept of energy conservation and environmental protection. The method has the advantages of small environmental pollution, high yield and good product quality, and meets the trend requirement of the development of the medicine from extensive production to high precision in the present stage of China.
Drawings
FIG. 1 is an HPLC chart of intermediate 3 obtained in example 1.
FIG. 2 is an HPLC chart of intermediate 3 obtained in example 2.
FIG. 3 is an HPLC chart of intermediate 3 prepared in example 3.
FIG. 4 is an HPLC chart of intermediate 3 obtained in example 4.
FIG. 5 is an HPLC chart of intermediate 3 obtained in example 5.
FIG. 6 is an HPLC chart of intermediate 3 obtained in example 6.
Detailed Description
The technical solution of the present invention is explained in detail below with reference to preferred embodiments. The following examples are only for illustrating and explaining the present invention and do not constitute a limitation to the technical solution of the present invention.
Example 1
20.0g of the intermediate 2, 300ml of acetonitrile, 11.0g of 5, 6-dichloronicotinic acid and 12.0g of pyridine are added into a reaction bottle, the temperature is reduced to-5 ℃, 12.0g of phosphorus oxychloride is slowly dripped, the internal temperature is kept lower than 0 ℃ in the dripping process, after the dripping is finished, the stirring is continued for 4 hours at the temperature of-5 to 0 ℃, 20 percent sodium hydroxide aqueous solution is dripped to adjust the pH value to 8 to 9, and the stirring is carried out for 2 hours at room temperature after the dripping. Filtration and elution of the filter cake with an appropriate amount of acetonitrile gave a pale yellow solid, intermediate 3 in 93.2% yield as shown in figure 1 by HPLC.
Example 2
Adding 25.0g of intermediate 2, 375ml of tetrahydrofuran, 13.8g of 5, 6-dichloronicotinic acid and 15.0g of pyridine into a reaction bottle, cooling to-5 ℃, slowly dropwise adding 15.0g of phosphorus oxychloride, keeping the internal temperature below 0 ℃ in the dropwise adding process, keeping the temperature between-5 ℃ and 0 ℃ after the dropwise adding is finished, continuously stirring for 4 hours, dropwise adding 20% sodium hydroxide aqueous solution to adjust the pH value to 8-9, and stirring for 2 hours at room temperature after the dropwise adding. Filtration and elution of the filter cake with the appropriate amount of acetonitrile gave a pale yellow solid, intermediate 3 in 92.5% yield as shown in figure 2 by HPLC.
Example 3
30.0g of intermediate 2, 450ml of acetonitrile, 16.5g of 5, 6-dichloronicotinic acid and 18.0g of pyridine are added into a reaction bottle, the temperature is reduced to-5 ℃, 18.0g of phosphorus oxychloride is slowly dripped, the internal temperature is kept below 10 ℃ in the dripping process, after the dripping is finished, the stirring is continued for 3 hours at the temperature of 0-10 ℃, 20% sodium hydroxide aqueous solution is dripped to adjust the pH value to 8-9, and the stirring is carried out for 2 hours at the room temperature after the dripping. Filtering, eluting the filter cake with a proper amount of acetonitrile to obtain a light yellow solid, wherein the HPLC chart of the intermediate 3 is shown in figure 3, and the yield is 95.5%.
Example 4
100.0g of intermediate 2, 1500ml of tetrahydrofuran, 55.0g of 5, 6-dichloronicotinic acid and 60.0g of pyridine are added into a reaction bottle, the temperature is reduced to-5 ℃, 60.0g of phosphorus oxychloride is slowly dripped, the internal temperature is kept below 10 ℃ in the dripping process, after the dripping is finished, the stirring is continued for 3 hours at 0-10 ℃, 20% sodium hydroxide aqueous solution is dripped to adjust the pH value to 8-9, and the stirring is carried out for 2 hours at room temperature after the dripping. Filtration and elution of the filter cake with the appropriate amount of acetonitrile gave a pale yellow solid, intermediate 4 in 93.4% yield as shown in figure 4 by HPLC.
Example 5
Adding 25.5g of intermediate 2, 382ml of dichloromethane, 14.07g of 5, 6-dichloronicotinic acid and 15.0g of pyridine into a reaction bottle, cooling to-5 ℃, slowly dropwise adding 12.0g of phosphorus oxychloride, keeping the internal temperature below 0 ℃ in the dropwise adding process, keeping the temperature between-5 ℃ and 0 ℃ after the dropwise adding is finished, continuing stirring for 4 hours, dropwise adding 20% sodium hydroxide aqueous solution to adjust the pH value to 8-9, and stirring for 2 hours at room temperature after the dropwise adding. Filtration and elution of the filter cake with the appropriate amount of acetonitrile gave a pale yellow solid, intermediate 3 in 92.1% yield as shown in figure 5 by HPLC.
Example 6
60.0g of intermediate 2, 900ml of methyl tert-butyl ether, 33.0g of 5, 6-dichloronicotinic acid and 36.0g of pyridine are added into a reaction bottle, the temperature is reduced to-5 ℃, 36.0g of phosphorus oxychloride is slowly dripped, the internal temperature is kept below 10 ℃ in the dripping process, after the dripping is finished, the stirring is continued for 3 hours at 0-10 ℃, 20% of sodium hydroxide aqueous solution is dripped to adjust the pH value to 8-9, and the stirring is carried out for 2 hours at room temperature after the dripping. Filtration and elution of the filter cake with the appropriate amount of acetonitrile gave a pale yellow solid, an HPLC profile of intermediate 3 as shown in fig. 6, with a yield of 91.2%.
Claims (8)
1. A preparation method of an intermediate of Alvatripopa maleate is characterized in that the intermediate 2, 5, 6-dichloronicotinic acid and pyridine are added into an organic solvent, and phosphorus oxychloride is added dropwise to react at-5 ℃ to 10 ℃ to obtain an intermediate 3;
the structural formula of the intermediate 2 is as follows:
the structural formula of the intermediate 3 is as follows:
2. the method of claim 1 wherein the organic solvent comprises dichloromethane, tetrahydrofuran, acetonitrile or methyl tert-butyl ether.
3. The method for preparing the atorvastatin intermediate as claimed in claim 1, wherein the volume of the organic solvent is 10 to 15 times of the charge of the intermediate 2.
4. The method for preparing the atorvastatin intermediate as claimed in claim 1, wherein the mass ratio of the intermediate 2, 5, 6-dichloronicotinic acid to pyridine is 20-100: 11-55: 12-60.
5. The method of claim 1, wherein the amount of phosphorus oxychloride added is equal to the mass of pyridine.
6. The method for preparing the atorvastatin intermediate as claimed in claim 1, comprising the following steps:
(1) mixing the intermediate 2, an organic solvent, 5, 6-dichloronicotinic acid and pyridine, and cooling to-5-0 ℃;
(2) dropwise adding phosphorus oxychloride into the mixed solution in the step (1), and keeping the temperature at-5-10 ℃ in the dropwise adding process;
(3) after the dropwise addition is finished, stirring for 3-4 hours at the temperature of-5-10 ℃;
(4) dropwise adding 20% sodium hydroxide aqueous solution to adjust the pH value to 8-9, and stirring for 2 hours at room temperature after dropwise adding;
(5) filtering, and leaching a filter cake with an organic solvent to obtain a light yellow solid.
7. The method for preparing the atorvastatin intermediate as claimed in claim 6, wherein in the step (2), the temperature is maintained at 0 to 10 ℃ during the dropwise addition.
8. The method for preparing the atorvastatin intermediate as claimed in claim 6, wherein in the step (3), the mixture is stirred for 3 to 4 hours at a temperature of 0 to 10 ℃.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391555A (en) * | 1999-09-17 | 2003-01-15 | 千禧药品公司 | Benzamides and related inhibitors of factor Xa |
| WO2004029049A1 (en) * | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | Novel salt of 2-acylaminothiazole derivative |
| US20040077690A1 (en) * | 2000-09-29 | 2004-04-22 | Bing-Yan Zhu | Quaternary amidino based inhibitors of factor xa |
| CN1639157A (en) * | 2002-01-18 | 2005-07-13 | 山之内制药株式会社 | 2-acylaminothiazole derivative or salt thereof |
| US20110065717A1 (en) * | 2007-08-07 | 2011-03-17 | Cadila Healthcare Limited | Sulfoximine derivatives as factor xa inhibitors |
| CN102336702A (en) * | 2005-11-08 | 2012-02-01 | 米伦纽姆医药公司 | Pharmaceutical salts and polymorphs of a factor XA inhibitor n-(5-chloro-pyridin-2-yl)-2-(4-cyano-benzoyl-amino)-5-methoxy-benzamide hydrochloride |
| CN107778223A (en) * | 2016-08-31 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of preparation method of maleic acid betrixaban |
| CN107868039A (en) * | 2017-11-27 | 2018-04-03 | 中国药科大学 | A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method |
| CN109438331A (en) * | 2018-09-20 | 2019-03-08 | 山东科源制药股份有限公司 | A method of preparing Ropivacaine intermediate |
-
2022
- 2022-04-19 CN CN202210410941.7A patent/CN115057854A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391555A (en) * | 1999-09-17 | 2003-01-15 | 千禧药品公司 | Benzamides and related inhibitors of factor Xa |
| US20040077690A1 (en) * | 2000-09-29 | 2004-04-22 | Bing-Yan Zhu | Quaternary amidino based inhibitors of factor xa |
| CN1639157A (en) * | 2002-01-18 | 2005-07-13 | 山之内制药株式会社 | 2-acylaminothiazole derivative or salt thereof |
| WO2004029049A1 (en) * | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | Novel salt of 2-acylaminothiazole derivative |
| CN102336702A (en) * | 2005-11-08 | 2012-02-01 | 米伦纽姆医药公司 | Pharmaceutical salts and polymorphs of a factor XA inhibitor n-(5-chloro-pyridin-2-yl)-2-(4-cyano-benzoyl-amino)-5-methoxy-benzamide hydrochloride |
| US20110065717A1 (en) * | 2007-08-07 | 2011-03-17 | Cadila Healthcare Limited | Sulfoximine derivatives as factor xa inhibitors |
| CN107778223A (en) * | 2016-08-31 | 2018-03-09 | 鲁南制药集团股份有限公司 | A kind of preparation method of maleic acid betrixaban |
| CN107868039A (en) * | 2017-11-27 | 2018-04-03 | 中国药科大学 | A kind of shellfish Qu Shaban intermediate Ns（5- chloro-2-pyridyls）- 2-（4- cyanobenzoyls）Amino ］ -5- methoxy benzamides preparation method |
| CN109438331A (en) * | 2018-09-20 | 2019-03-08 | 山东科源制药股份有限公司 | A method of preparing Ropivacaine intermediate |
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