CN114181206A - Preparation method of paliperidone palmitate - Google Patents
Preparation method of paliperidone palmitate Download PDFInfo
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- CN114181206A CN114181206A CN202111581302.9A CN202111581302A CN114181206A CN 114181206 A CN114181206 A CN 114181206A CN 202111581302 A CN202111581302 A CN 202111581302A CN 114181206 A CN114181206 A CN 114181206A
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- paliperidone
- paliperidone palmitate
- palmitate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a preparation method of paliperidone palmitate, which comprises the following preparation steps: s1, condensing paliperidone and palmitic anhydride in tetrahydrofuran by the action of a catalyst to obtain a crude paliperidone palmitate; s2, recrystallizing the crude paliperidone palmitate in acetone to obtain paliperidone palmitate; the preparation method of paliperidone palmitate has the advantages of short reaction time, no (potential) genotoxic impurities introduced into the used reagent, easy purification of the product, high yield, no strong irritation of the raw material, simple reaction operation, contribution to industrial production and obvious industrial production advantages.
Description
Technical Field
The invention relates to the technical field of pharmaceutical engineering, in particular to a preparation method of paliperidone palmitate.
Background
Paliperidone Palmitate (Paliperidone Palmitate) is a long-acting injection of Paliperidone as a second generation antipsychotic drug, is mainly used for treating schizophrenia, and the active ingredient is Paliperidone. Paliperidone is also known as 9-hydroxyrisperidone, chemical name 3- [2- [4- (6-fluorobenzo [ d ] isoxazol-3-yl) -1-piperidinyl ] ethyl ] -7-hydroxy-4-methyl-1, 5-diazabicyclo [4.4.0] dec-3, 5-dien-2-one. Paliperidone palmitate has the following structural formula:
chinese patent CN106220622 reports a preparation method of paliperidone palmitate, in which paliperidone and palmitic acid are condensed to generate paliperidone palmitate under the action of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine. The carbodiimide condensing agent and the urea derivative which is a reaction byproduct thereof are (potential) genotoxic impurities, and the product can be refined for many times to ensure that the impurities reach the qualified limit, so that the product loss is large.
Chinese patent CN110256425 reports a preparation method of paliperidone palmitate, which is characterized in that paliperidone and palmitoyl chloride are condensed to generate paliperidone palmitate under the action of strong organic base triethylamine and 4-dimethylaminopyridine, and the yield is high. However, palmitoyl chloride is an oily liquid, has strong pungent smell, strong corrosiveness and unstable property. Is not beneficial to industrial production.
In order to solve the problems, the application provides a preparation method of paliperidone palmitate.
Disclosure of Invention
Objects of the invention
The invention mainly aims to solve the problems and the defects, and provides the preparation method of the paliperidone palmitate, which is simple in process, safe and controllable in quality.
(II) technical scheme
In order to solve the problems, the invention provides a preparation method of paliperidone palmitate, which comprises the following preparation steps:
s1, condensing paliperidone and palmitic anhydride in tetrahydrofuran by the action of a catalyst to obtain a crude paliperidone palmitate;
s2, recrystallizing the crude paliperidone palmitate in acetone to obtain the paliperidone palmitate.
Preferably, in the S1, tetrahydrofuran with a volume 5-20 times that of paliperidone is added, 0.8-1.3 equivalents of palmitic anhydride and 0.1-0.5 equivalents of catalyst are added, the mixture is heated to react for 1-4 hours, then the temperature is reduced to room temperature, the mixture is filtered, the filter cake is rinsed with tetrahydrofuran, and the filter cake is dried to obtain the crude paliperidone palmitate.
Preferably, in the S2, acetone with the volume 5-15 times that of the crude paliperidone palmitate is added, the mixture is heated and refluxed for 30 minutes, then slowly cooled, kept warm and stirred for 2 hours, filtered, and a filter cake is rinsed with acetone and dried to obtain the paliperidone palmitate.
Preferably, in S1, the tetrahydrofuran is used in an amount of 8 times the volume of the paliperidone.
Preferably, in S1, the molar ratio of paliperidone to palmitic anhydride is 1:1.1, and the molar ratio of paliperidone to catalyst is 1: 0.3.
Preferably, in the S1, the catalyst is 4-pyrrolidinylpyridine or 4-dimethylaminopyridine.
Preferably, in S1, the reaction temperature of the heating reaction is 40 to 50 ℃.
Preferably, in the S1, the acetone is used in an amount of 10 times by volume.
Preferably, in S1, the temperature for cooling to room temperature is 15 ℃ to 20 ℃.
The technical scheme of the invention has the following beneficial technical effects:
the preparation method of paliperidone palmitate has the advantages of short reaction time, no (potential) genotoxic impurities introduced into the used reagent, easy purification of the product, high yield, no strong irritation of the raw material, simple reaction operation, contribution to industrial production and obvious industrial production advantages.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to specific embodiments. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention. Moreover, in the following description, descriptions of well-known structures and techniques are omitted so as to not unnecessarily obscure the concepts of the present invention.
Example 1
The method comprises the following steps: adding 20.0g of paliperidone into a reaction bottle, adding 160ml of tetrahydrofuran, adding 25.7g of palmitic anhydride and 1.7g of 4-dimethylaminopyridine into the reaction bottle under stirring, heating the reaction bottle until the temperature of the reaction liquid is between 40 and 50 ℃, and stirring the reaction bottle for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction product is filtered, a filter cake is rinsed by 20ml of tetrahydrofuran, and 28.0g of crude paliperidone palmitate is obtained after drying, and the yield is 90%.
Step two: adding 25.0g of paliperidone palmitate crude product into a reaction bottle, adding 250ml of acetone, heating to reflux and stirring for 30min, slowly cooling to 15-20 ℃ for crystallization for 2h, filtering, leaching a filter cake with 30ml of acetone, and drying to obtain 21.3g of paliperidone palmitate finished product with the yield of 85%.
Example 2
The method comprises the following steps: adding 20.0g of paliperidone into a reaction bottle, adding 160ml of tetrahydrofuran, adding 25.7g of palmitic anhydride and 2.1g of 4-pyrrolidinylpyridine under stirring, heating to the temperature of the reaction solution of 40-50 ℃, and stirring for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction product is filtered, a filter cake is rinsed by 20ml of tetrahydrofuran, and 28.9g of crude paliperidone palmitate is obtained after drying, wherein the yield is 93%.
Step two: adding 25.0g of paliperidone palmitate crude product into a reaction bottle, adding 250ml of acetone, heating to reflux and stirring for 30min, slowly cooling to 15-20 ℃ for crystallization for 2h, filtering, leaching a filter cake with 30ml of acetone, and drying to obtain 21.8g of paliperidone palmitate finished product with the yield of 87%.
Example 3
The method comprises the following steps: adding 70.0g of paliperidone into a reaction bottle, adding 560ml of tetrahydrofuran, adding 90.1g of palmitic anhydride and 7.3g of 4-pyrrolidinylpyridine under stirring, heating to the temperature of the reaction solution of 40-50 ℃, and stirring for 3 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction product is filtered, a filter cake is rinsed by 70ml of tetrahydrofuran, and 100.4g of crude paliperidone palmitate is obtained after drying, wherein the yield is 92%.
Step two: adding 100.0g of paliperidone palmitate crude product into a reaction bottle, adding 1000ml of acetone, heating to reflux and stirring for 30min, slowly cooling to 15-20 ℃ for crystallization for 2h, filtering, leaching a filter cake with 120ml of acetone, and drying to obtain 86.1g of paliperidone palmitate finished product with the yield of 86%.
Example 4
The method comprises the following steps: adding 20.0g of paliperidone into a reaction bottle, adding 140ml of tetrahydrofuran, adding 25.7g of palmitic anhydride and 2.1g of 4-pyrrolidinylpyridine under stirring, heating to the temperature of the reaction solution of 40-50 ℃, and stirring for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction product is filtered, a filter cake is rinsed by 20ml of tetrahydrofuran, and 28.3g of crude paliperidone palmitate is obtained after drying, and the yield is 91%.
Step two: adding 25.0g of paliperidone palmitate crude product into a reaction bottle, adding 225ml of acetone, heating to reflux and stirring for 30min, slowly cooling to 15-20 ℃ for crystallization for 2h, filtering, leaching a filter cake with 30ml of acetone, and drying to obtain 21.3g of paliperidone palmitate finished product with the yield of 85%.
Example 5
The method comprises the following steps: adding 20.0g of paliperidone into a reaction bottle, adding 180ml of tetrahydrofuran, adding 25.7g of palmitic anhydride and 2.1g of 4-pyrrolidinylpyridine under stirring, heating to the temperature of the reaction solution of 40-50 ℃, and stirring for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction product is filtered, a filter cake is rinsed by 20ml of tetrahydrofuran, and 28.3g of crude paliperidone palmitate is obtained after drying, and the yield is 91%.
Step two: adding 25.0g of paliperidone palmitate crude product into a reaction bottle, adding 275ml of acetone, heating to reflux and stirring for 30min, slowly cooling to 15-20 ℃ for crystallization for 2h, filtering, leaching a filter cake with 30ml of acetone, and drying to obtain 21.5g of paliperidone palmitate finished product with the yield of 86%.
Example 6
The method comprises the following steps: 20.0g of paliperidone and 160ml of tetrahydrofuran are added into a reaction bottle, 23.39g of palmitic anhydride (1.0 equivalent of paliperidone) and 2.1g of 4-pyrrolidinylpyridine are added under stirring, and the temperature is raised to 40-50 ℃ and the mixture is stirred for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction product is filtered, a filter cake is rinsed by 20ml of tetrahydrofuran, and 28.3g of crude paliperidone palmitate is obtained after drying, and the yield is 91%.
Step two: adding 25.0g of paliperidone palmitate crude product into a reaction bottle, adding 250ml of acetone, heating to reflux and stirring for 30min, slowly cooling to 15-20 ℃ for crystallization for 2h, filtering, leaching a filter cake with 30ml of acetone, and drying to obtain 21.8g of paliperidone palmitate finished product with the yield of 87%.
Example 7
The method comprises the following steps: adding 20.0g of paliperidone into a reaction bottle, adding 160ml of tetrahydrofuran, adding 28.08g of palmitic anhydride (1.2 times of the equivalent of paliperidone) and 2.1g of 4-pyrrolidinylpyridine under stirring, heating to the temperature of the reaction solution of 40-50 ℃, and stirring for 2 hours. After the reaction is finished, the temperature is reduced to room temperature, the reaction product is filtered, a filter cake is rinsed by 20ml of tetrahydrofuran, and 28.6g of crude paliperidone palmitate is obtained after drying, and the yield is 92%.
Step two: adding 25.0g of paliperidone palmitate crude product into a reaction bottle, adding 250ml of acetone, heating to reflux and stirring for 30min, slowly cooling to 15-20 ℃ for crystallization for 2h, filtering, leaching a filter cake with 30ml of acetone, and drying to obtain 21.8g of paliperidone palmitate finished product with the yield of 87%.
As is clear from the above three examples, the yield of example 3 is the maximum, wherein the tetrahydrofuran is used in an amount of 8 times the volume of the paliperidone, the molar ratio of the paliperidone to the palmitic anhydride is 1:1.1, the molar ratio of the paliperidone to the catalyst is 1:0.3, and the acetone is used in an amount of 10 times the volume of the crude paliperidone palmitate, and the example is suitable for popularization and application and can produce the greatest economic benefit.
The preparation method of paliperidone palmitate has the advantages of short reaction time, no (potential) genotoxic impurities introduced into the used reagent, easy purification of the product, high yield, no strong irritation of the raw material, simple reaction operation, contribution to industrial production and obvious industrial production advantages.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and the preferred embodiments of the present invention are described in the above embodiments and the description, and are not intended to limit the present invention.
Claims (9)
1. The preparation method of paliperidone palmitate is characterized by comprising the following preparation steps:
s1, condensing paliperidone and palmitic anhydride in tetrahydrofuran by the action of a catalyst to obtain a crude paliperidone palmitate;
s2, recrystallizing the crude paliperidone palmitate in acetone to obtain the paliperidone palmitate.
2. The method for preparing paliperidone palmitate as claimed in claim 1, wherein in S1, tetrahydrofuran with volume 5-20 times that of paliperidone is added, 0.8-1.3 equivalents of palmitic anhydride and 0.1-0.5 equivalents of catalyst are added, heating reaction is carried out, after reaction for 1-4 hours, cooling to room temperature, filtering is carried out, filter cake is rinsed with tetrahydrofuran, and drying is carried out to obtain crude paliperidone palmitate.
3. The preparation method of paliperidone palmitate as claimed in claim 1, wherein in S2, acetone with 5-15 times volume of the crude paliperidone palmitate is added, heated and refluxed for 30 minutes, then slowly cooled, kept warm and stirred for 2 hours, filtered, the filter cake is rinsed with acetone, and dried to obtain paliperidone palmitate.
4. The method for preparing paliperidone palmitate as claimed in claim 2, wherein the tetrahydrofuran is used in an amount 8 times the volume of paliperidone in S1.
5. The method for preparing paliperidone palmitate as claimed in claim 2, wherein the molar ratio of paliperidone to palmitic anhydride is 1:1.1 and the molar ratio of paliperidone to catalyst is 1:0.3 in S1.
6. The method of claim 1, wherein in S1, the catalyst is 4-pyrrolidinylpyridine or 4-dimethylaminopyridine.
7. The method for preparing paliperidone palmitate as claimed in claim 2, wherein the reaction temperature of the heating reaction in S1 is 40-50 ℃.
8. The method for preparing paliperidone palmitate as claimed in claim 2, wherein the acetone is used in an amount 10 times the volume of the crude paliperidone palmitate in S1.
9. The method for preparing paliperidone palmitate as claimed in claim 2, wherein the temperature of the S1 decreased to room temperature is 15-20 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111581302.9A CN114181206A (en) | 2021-12-22 | 2021-12-22 | Preparation method of paliperidone palmitate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111581302.9A CN114181206A (en) | 2021-12-22 | 2021-12-22 | Preparation method of paliperidone palmitate |
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| CN202111581302.9A Pending CN114181206A (en) | 2021-12-22 | 2021-12-22 | Preparation method of paliperidone palmitate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090209757A1 (en) * | 2008-01-10 | 2009-08-20 | Santiago Ini | Processes for the preparation and purification of paliperidone palmitate |
| WO2013046225A2 (en) * | 2011-08-10 | 2013-04-04 | Glenmark Generics Limited | Process for the preparation of paliperidone palmitate |
| CN106220622A (en) * | 2016-06-30 | 2016-12-14 | 广州仁恒医药科技有限公司 | A kind of preparation method of Palmic acid 9-hydroxy-risperidone |
| CN110256425A (en) * | 2019-07-08 | 2019-09-20 | 华裕(无锡)制药有限公司 | A kind of synthesis technology of palmitinic acid 9-hydroxy-risperidone |
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2021
- 2021-12-22 CN CN202111581302.9A patent/CN114181206A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090209757A1 (en) * | 2008-01-10 | 2009-08-20 | Santiago Ini | Processes for the preparation and purification of paliperidone palmitate |
| WO2013046225A2 (en) * | 2011-08-10 | 2013-04-04 | Glenmark Generics Limited | Process for the preparation of paliperidone palmitate |
| CN106220622A (en) * | 2016-06-30 | 2016-12-14 | 广州仁恒医药科技有限公司 | A kind of preparation method of Palmic acid 9-hydroxy-risperidone |
| CN110256425A (en) * | 2019-07-08 | 2019-09-20 | 华裕(无锡)制药有限公司 | A kind of synthesis technology of palmitinic acid 9-hydroxy-risperidone |
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Application publication date: 20220315 |