CN108727351B - Refining method of prucalopride - Google Patents
Refining method of prucalopride Download PDFInfo
- Publication number
- CN108727351B CN108727351B CN201710259121.1A CN201710259121A CN108727351B CN 108727351 B CN108727351 B CN 108727351B CN 201710259121 A CN201710259121 A CN 201710259121A CN 108727351 B CN108727351 B CN 108727351B
- Authority
- CN
- China
- Prior art keywords
- prucalopride
- purified water
- dissolving
- carrying
- out vacuum
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a refining method of prucalopride. Compared with the prior art, the method has the advantages that before the formation of the salt of the prucalopride and the succinic acid, the prucalopride is dissolved by using a mixed solvent of absolute ethyl alcohol and tetrahydrofuran, and is adsorbed and decolored by activated carbon, so that a refined prucalopride product is obtained before the formation of the salt, and the defect that the prucalopride is difficult to recrystallize and refine after the formation of the salt is overcome. The method has the advantages of mild conditions, simple and convenient operation and high purity, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a refining method of prucalopride.
Background
The chemical name of prucalopride (prucalopride) is 4-amino-5-chloro-2, 3-dihydro-N- [1- (3-methoxypropyl) -4-piperidyl]-7-benzofuran carboxamide (CAS:179474-81-8), a benzimidazole drug, the succinate salt (CAS:179474-85-2) of which is commonly used clinically, is a specific 5-HT4The receptor full agonist has higher selectivity and specificity, can increase the release of cholinergic neurotransmitter, stimulate enterokinesia reflex, enhance colon contraction and proximal colon transmission, further effectively relieve the symptoms of constipation patients, and is mainly used for treating various constipation and gastrointestinal motility weakness and pseudo obstruction of operation. The structure is as follows:
chinese patent CN1071332C reports a new benzamide derivative and its pharmaceutically acceptable acid addition salts, pharmaceutical compositions containing the new compound, as well as methods for preparing the compounds and compositions and their use as medicaments, especially in the treatment of diseases with impaired intestinal, especially colonic motility. The synthesis method reported in this patent is as follows:
among them, the synthesis method of B is reported in Chinese patents CN1034502, CN1038936, CN103012337 and chem. pharm. Bull 46(1),42-52 (1998).
A synthetic method of 1- (3-methoxypropyl) -4-aminopiperidine, namely a compound C, is also reported in documents, for example, Chinese patent CN102295594 discloses a method for obtaining C by reacting 4-N substituted piperidine serving as a raw material with 1-methoxy-3-bromopropane and deprotecting, wherein the synthetic route is as follows:
however, the price of formula D is relatively expensive, increasing the synthesis cost of structural formula C.
Chinese patent CN103193699 discloses a method for synthesizing C, which uses piperidone as raw material to react with 1-methoxy-3-bromopropane to obtain G, and uses ammonium formate to reduce to obtain C, the reaction route is as follows:
since C is very polar, the reaction in the last step of the process is incomplete and it is difficult to remove intermediates and by-products. I.e., the difficulty of purification.
Chinese patents CN1143858 and US6479487 disclose another method for synthesizing C, which comprises reacting G with carboxyamine hydrochloride to obtain intermediate H, and reducing with lithium aluminum hydride to obtain C, wherein the synthetic route is as follows:
the method uses lithium aluminum hydride, requires an oxygen-free and water-free environment for experimental operation, and is not easy to filter during post-treatment, so that the method has high industrialization difficulty.
CN103848777B, a new synthesis method of the compound C is found, and the yield is improved.
However, the reported synthesis process has low purity, and even if the prucalopride succinate with the purity of more than 99.8 percent can be obtained, the operation is complex.
Disclosure of Invention
The invention aims to provide a refining method of prucalopride, so as to finally obtain high-purity prucalopride succinate. The method can stably obtain finished products with the concentration of more than 99.8 percent, and has simple and convenient operation and mild conditions.
The method has the specific technical scheme that:
a refining method of prucalopride comprises the following specific steps: dissolving prucalopride in a mixed solvent of ethanol and tetrahydrofuran, and cooling and crystallizing to obtain a refined prucalopride product.
The preferred specific steps are as follows: dissolving prucalopride in a mixed solvent of ethanol and tetrahydrofuran, dropwise adding purified water at 30-40 ℃, gradually cooling and crystallizing after dropwise adding, stirring, carrying out vacuum filtration, leaching a filter cake with the purified water, and carrying out vacuum drying to obtain a white-like solid.
The dissolving temperature is 40-45 ℃.
The mixed solvent is as follows: ethanol: and (3) tetrahydrofuran is 0-5: 1. the mixed solvent may also be ethanol alone or tetrahydrofuran alone. Preferably ethanol: tetrahydrofuran 3:1
The common reed cacapride g: solvent ml ═ 1: 2-10 (mass to volume); preferably 1: 3.
The mixed solvent V: purified water V ═ 1: 0.9 to 1.1 (volume ratio).
The crystallization temperature is 10-16 ℃.
The crystallization time is 4-6 hours.
Compared with the prior art, the method has the advantages that before the formation of the salt of the prucalopride and the succinic acid, the prucalopride is dissolved by using a mixed solvent of absolute ethyl alcohol and tetrahydrofuran, and is adsorbed and decolored by activated carbon, and a refined prucalopride product is obtained before the formation of the salt, so that the defect that the prucalopride is difficult to recrystallize and refine after the formation of the salt is improved. The method has the advantages of mild conditions, simple and convenient operation and high purity, and is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1
Adding 100g of prucalopride, 225mLEtOH and 75mLTHF into a 1L three-mouth bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; at the temperature of 30-40 ℃, dropwise adding 270mL of purified water, after the dropwise adding is finished, gradually cooling to 12-16 ℃, stirring for 4-6 h, carrying out vacuum filtration, leaching a filter cake with purified water (20mL multiplied by 3), and carrying out vacuum drying at the temperature of 30 ℃ for 12h to obtain a white-like solid, wherein the yield is 92.64%, and the m.p.: 91.2-92.2 ℃, HPLC: 99.92 percent.
Example 2
Adding 100g of prucalopride, 150mLEtOH and 150mLTHF into a 1L three-mouth bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropping 300mL of purified water at 30-40 ℃, gradually cooling to 10-16 ℃ after dropping, stirring for 4-6 h, carrying out vacuum filtration under reduced pressure, leaching a filter cake with purified water (20mL multiplied by 3), and vacuum drying at 30 ℃ for 12h to obtain an off-white solid, wherein the yield is 92.49%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.91 percent.
Example 3
Adding 100g of prucalopride, 200mLEtOH and 100mLTHF into a 1L three-mouth bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropwise adding 330mL of purified water at 30-40 ℃, gradually cooling to 10-15 ℃ after dropwise adding, stirring for 4-6 h, carrying out vacuum filtration, leaching a filter cake with purified water (20mL multiplied by 3), and vacuum drying at 30 ℃ for 12h to obtain an off-white solid, wherein the yield is 92.37%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.91 percent.
Example 4
Adding 100g of prucalopride, 300mLEtOH and 200mLTHF into a 1L three-mouth bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropwise adding 500mL of purified water at 30-40 ℃, gradually cooling to 10-15 ℃ after dropwise adding, stirring for 4-6 h, carrying out vacuum filtration under reduced pressure, leaching a filter cake with purified water (20mL multiplied by 3), and vacuum drying at 30 ℃ for 12h to obtain an off-white solid, wherein the yield is 91.41%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.91 percent.
Example 5
Adding 100g of prucalopride, 600mLEtOH and 400mLTHF into a 1L three-mouth bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropwise adding 1000mL of purified water at 30-40 ℃, gradually cooling to 10-15 ℃ after dropwise adding, stirring for 4-6 h, carrying out vacuum filtration under reduced pressure, leaching a filter cake with purified water (20mL multiplied by 3), and vacuum drying at 30 ℃ for 12h to obtain a white-like solid, wherein the yield is 90.15%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.90 percent.
Example 6
Adding 100g of prucalopride, 1120ml ETOH and 160ml THF into a 1L three-necked bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; at the temperature of 30-40 ℃, adding 1280mL of purified water dropwise, after the dropwise addition, gradually cooling to 10-15 ℃, stirring for 4-6 h, carrying out vacuum filtration under reduced pressure, leaching a filter cake with purified water (20mL multiplied by 3), and carrying out vacuum drying at the temperature of 30 ℃ for 12h to obtain an off-white solid, wherein the yield is 90.27%, and the m.p. ═ 91.2-92.2 ℃, HPLC: 99.88 percent.
Example 7
Adding 100g of prucalopride and 300ml of LEtOH into a 1L three-necked bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropwise adding 330mL of purified water at 30-40 ℃, gradually cooling to 10-15 ℃ after dropwise adding, stirring for 4-6 h, carrying out vacuum filtration under reduced pressure, leaching a filter cake with purified water (20mL multiplied by 3), and vacuum drying at 30 ℃ for 12h to obtain an off-white solid, wherein the yield is 92.22%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.86 percent.
Example 8
Adding 100g of prucalopride, 200mLEtOH and 900mLTHF into a 1L three-mouth bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropping 1100mL of purified water at 30-40 ℃, gradually cooling to 10-15 ℃ after dropping, stirring for 4-6 h, carrying out vacuum filtration, leaching a filter cake with purified water (20mL multiplied by 3), and vacuum drying at 30 ℃ for 12h to obtain a white-like solid, wherein the yield is 90.17%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.86 percent.
Example 9
Adding 100g of prucalopride, 200mL of dioxane and 400mL of THF into a 1L three-necked bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropping 600mL of purified water at 30-40 ℃, gradually cooling to 5-10 ℃ after dropping, stirring for 4-6 h, carrying out vacuum filtration under reduced pressure, leaching a filter cake with purified water (20mL multiplied by 3), and carrying out vacuum drying at 30 ℃ for 12h to obtain an off-white solid, wherein the yield is 84.13%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.46 percent.
Example 10
Adding 100g of prucalopride, 300mL of dioxane and 300mL of THF into a 1L three-necked bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropping 600mL of purified water at 30-40 ℃, gradually cooling to 0-5 ℃ after dropping, stirring for 8-10 h, carrying out vacuum filtration under reduced pressure, leaching a filter cake with purified water (20mL multiplied by 3), and carrying out vacuum drying at 30 ℃ for 12h to obtain a white-like solid, wherein the yield is 83.46%, the m.p. ═ 91.2-92.2 ℃, and HPLC: 99.58 percent.
Claims (1)
1. A refining method of prucalopride comprises the following specific steps: adding 100g of prucalopride, 225mLEtOH and 75mLTHF into a 1L three-mouth bottle for dissolving, wherein the dissolving temperature is 40-45 ℃; dropwise adding 270mL of purified water at 30-40 ℃, gradually cooling to 12-16 ℃ after dropwise adding, stirring for 4-6 h, carrying out vacuum filtration, leaching a filter cake for 3 times by using 20mL of purified water, and carrying out vacuum drying at 30 ℃ for 12h to obtain a white-like solid, wherein the yield is 92.64%, the m, p, is 91.2-92.2 ℃, and HPLC: 99.92 percent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710259121.1A CN108727351B (en) | 2017-04-19 | 2017-04-19 | Refining method of prucalopride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710259121.1A CN108727351B (en) | 2017-04-19 | 2017-04-19 | Refining method of prucalopride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108727351A CN108727351A (en) | 2018-11-02 |
| CN108727351B true CN108727351B (en) | 2021-08-31 |
Family
ID=63924063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710259121.1A Active CN108727351B (en) | 2017-04-19 | 2017-04-19 | Refining method of prucalopride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108727351B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1071332C (en) * | 1994-11-24 | 2001-09-19 | 詹森药业有限公司 | Enterokinetic benzamide |
| CN102295594B (en) * | 2011-07-12 | 2016-01-20 | 上海医药工业研究院 | 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications |
| CN106146386A (en) * | 2015-04-21 | 2016-11-23 | 江苏威凯尔医药科技有限公司 | A kind of new technology preparing prucalopride intermediate |
-
2017
- 2017-04-19 CN CN201710259121.1A patent/CN108727351B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1071332C (en) * | 1994-11-24 | 2001-09-19 | 詹森药业有限公司 | Enterokinetic benzamide |
| CN102295594B (en) * | 2011-07-12 | 2016-01-20 | 上海医药工业研究院 | 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications |
| CN106146386A (en) * | 2015-04-21 | 2016-11-23 | 江苏威凯尔医药科技有限公司 | A kind of new technology preparing prucalopride intermediate |
Non-Patent Citations (2)
| Title |
|---|
| PROCESS FOR PREPARING A BENZOFURANCARBOXAMIDE COMPOUND;Anonymously;《IP.com Journal》;20160602;第16卷(第6B期);第1-4页 * |
| 琥珀酸普芦卡必利的合成;欧阳婷，等;《广东化工》;20160131;第43卷(第2期);第44页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108727351A (en) | 2018-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6591944B2 (en) | Nalmefene hydrochloride dihydrate | |
| CN108503621B (en) | Preparation method of vonoprazan fumarate | |
| TWI624447B (en) | Process for producing pyrrole derivative and crystalline form thereof | |
| JP6166721B2 (en) | 4-tert-Butyl-N- [4-chloro-2- (1-oxy-pyridine-4-carbonyl) -phenyl] -benzenesulfonamide sodium salt polymorph | |
| AU1641592A (en) | Crystalline tiagabine hydrochloride monohydrate, its preparation and use | |
| KR20180003542A (en) | Polymorphs of afatinib and its salts and process for the preparation of quinazolinyl derivatives | |
| CA2890961A1 (en) | Novel polymorphs of azilsartan medoxomil | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| EA017631B1 (en) | Crystalline base of trans-1-((1r,3s)-3-phenyl-6-chloroindan-1-yl)-3,3-dimethylpiperazine | |
| WO2010092591A2 (en) | Novel crystalline polymorphs of 5-[[(2r,3s)-2-[(1r)-1-[3,5- bis(trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2- dihydro-3h-1,2,4-triazol-3-one and process for preparation thereof | |
| AU2001272872B2 (en) | Novel form of (R)-N-(5-methyl-8-(4-methylpiperazin-1-YL)-1,2,3,4-tetrahydro -2-naphthyl)-4-morpholinobenzamide | |
| WO2019167085A1 (en) | Process for the preparation of (s)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate | |
| CN108727351B (en) | Refining method of prucalopride | |
| CA2489723C (en) | Novel aryl-{4-halo-4-[heteroaryl-methylamino)-methyl]-piperidin-1-yl}-methanone derivatives, methods for production and use thereof as medicaments | |
| JP2018528233A (en) | Process for producing indoline compounds and novel indoline salts | |
| JP2024510651A (en) | Polymorphic forms of compounds and their preparation and use | |
| JP6748329B1 (en) | Crystal form of sofupyronium bromide and method for producing the same | |
| CN111202744A (en) | Ledipasvir and sofosbuvir compound tablet and preparation method and application thereof | |
| CN108586450B (en) | Recrystallization purification method of choline M receptor anticaking agent | |
| EP1828208A2 (en) | Crystalline form of cefdinir cesium salt | |
| CN103288813A (en) | Preparation method of aprepitant | |
| MXPA04010846A (en) | Process for preparing 1, 2, 3, 9- tetrahydro -9-methyl -3-[(2 -methyl -1h- imidazol -1-yl) methyl]- 4h-carbazol -4 -one. | |
| JP2015007000A (en) | Method for producing crystal of montelukast free acid | |
| CN113754643A (en) | Refining method of benzopyran derivative, crystal form thereof and preparation method of crystal form | |
| JP5419570B2 (en) | Method for purifying 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221208 Address after: 276006 No. 209 Hongqi Road, Shandong, Linyi Patentee after: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Address before: 276005 No. 209 Hongqi Road, Shandong, Linyi Patentee before: LUNAN PHARMACEUTICAL Group Corp. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A refining method of procarbili Effective date of registration: 20230117 Granted publication date: 20210831 Pledgee: Industrial and Commercial Bank of China Limited Linyi Shizhong Sub-branch Pledgor: LUNNAN BETTER PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980031096 |