CN103570699A - Method for preparing prucalopride - Google Patents
Method for preparing prucalopride Download PDFInfo
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- CN103570699A CN103570699A CN201310453590.9A CN201310453590A CN103570699A CN 103570699 A CN103570699 A CN 103570699A CN 201310453590 A CN201310453590 A CN 201310453590A CN 103570699 A CN103570699 A CN 103570699A
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- preparation
- chloro
- dihydrobenzofuranes
- prucalopride
- nitro
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- 0 CC1C(*)=C(CCO2)C2=C(*)C1 Chemical compound CC1C(*)=C(CCO2)C2=C(*)C1 0.000 description 3
- RUCBADJJARZKJP-UHFFFAOYSA-N COCCCC(CC1)CCC1N Chemical compound COCCCC(CC1)CCC1N RUCBADJJARZKJP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of prucalopride. Prucalopride succinate is a 5-HT4 receptor stimulant with high selectivity and specificity, and is a novel intestinal motility drug. The drug has the characteristics of high selectivity, rapid onset and less untoward effect, and has wide clinical application prospect in the field of constipation treatment. The invention provides a new method for compounding prucalopride, wherein 4-nitro-5-chlor-2,3-dihydrobenzofuran-7-methanoic acid and 1-(3-methoxypropyl)-4-piperidinamine are employed as initial materials to prepare prucalopride; and the preparation method is simple and convenient to operate, less in side reaction, high in yield, mild in reaction condition and convenient for large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of method of preparing prucalopride.
Background technology
Succsinic acid prucalopride chemistry is by name: N-[1-(3-methoxycarbonyl propyl)-4-amino-5-is chloro-2, and 3-Dihydrobenzofuranes-7-methane amide succinate is in a kind of benzofuran compounds of development in 2009 by Belgian Movetis NV company.It is a kind of have high selectivity and specific 5-HT
4receptor stimulant, is novel intestinal motive force medicine, in the listing of 2010 Nian Britain.Prucalopride can stimulate the wriggling reflection of intestines, strengthens colon and shrinks, and effectively alleviate constipation symptom, utilizes the constipation of prucalopride treatment severe chronic, and short-term can significantly be improved intestinal function in the time.Its structural formula is as follows:
Along with economic development, living environment extremely worsen and the progressively quickening of people's rhythm of life, constipation has become the upper ubiquitous problem of society, and it has had a strong impact on patient's quality of life.The features such as succsinic acid prucalopride is compared with this sick similar drugs for the treatment of, and it has, and selectivity is high, rapid-action, untoward reaction is few.Therefore, succsinic acid prucalopride has wide potential applicability in clinical practice in constipation therapy field.
Chinese patent CN1071332C has reported two synthetic routes of succsinic acid prucalopride.Concrete route is as follows:
Route one is chloro-2 with 4-amino-5-, 3-Dihydrobenzofuranes-7-formic acid (2) and 1-(3-methoxy-propyl)-4-piperidines ammonia condensation, salify obtain succsinic acid prucalopride.
Route two obtains succsinic acid prucalopride with compound 3 and the condensation of the chloro-3-methoxy propane of 1-, salify.
The synthetic existing bibliographical information of compound 2 in route one, but reaction scheme is long, productive rate is not high, and in compound 2, on phenyl ring, amino makes this reaction that side reaction easily occur simultaneously, forms by product, and reaction yield is low.In route two, compou nd synthesis difficulty is high, and bibliographical information is few, is not suitable for suitability for industrialized production.For above problem, we improve above method, have proposed new synthetic route, and the method for the synthetic prucalopride of this route is easy and simple to handle, and side reaction is few, and yield is high, and reaction conditions is gentle, is convenient to large-scale industrial production.Prucalopride structure:
Summary of the invention
The invention provides a kind of method of preparing prucalopride, comprise the following steps:
method one:1) 4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid is dissolved in organic solvent, add condensing agent (CDI, DCC, EDCI-HOBT, HATU), add 1-(3-methoxy-propyl)-4-piperidines ammonia, through condensation, obtain N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide.2) by N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide is dissolved in organic solvent, add reductive agent, through reduction, obtain N-[1-(3-methoxycarbonyl propyl)-4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide.
For method 1, it is characterized in that, the first step reaction reagent is tetrahydrofuran (THF), DMF, methylene dichloride, chloroform, wherein preferred tetrahydrofuran (THF); The condensing agent that the first step is reacted used is CDI, DCC, EDCI-HOBT, HATU, wherein preferred CDI; The temperature of the first step reaction is 50 ℃-90 ℃, wherein preferably 80 ℃; The reagent of second step reaction is C1-C4 alcohols, tetrahydrofuran (THF), wherein preferred alcohol; The reductive agent that second step reaction is used is Pd/C-hydrogen, hydrazine hydrate, Fe-hydrochloric acid, Raney nickel-hydrogen, wherein preferred hydrazine hydrate.
Embodiment
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
embodiment 1
By 4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid 12.1g is dissolved in 50mL tetrahydrofuran (THF), adds 8.1gCDI, after it dissolves, adds 1-(3-methoxy-propyl)-4-piperidines ammonia 8.6g, be warming up to 80 ℃ of reactions, TLC detection reaction, is cooled to room temperature after question response finishes, and adds water 200mL, there is solid to wash out, filter to such an extent that N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-is chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield is 95%.
embodiment 2
4-nitro-5-is chloro-2, and 3-Dihydrobenzofuranes-7-formic acid 12.1g is dissolved in 50mL DMF, add 8.1gCDI, after it dissolves, add 1-(3-methoxy-propyl)-4-piperidines ammonia 8.6g, be warming up to 80 ℃ of reactions, TLC detection reaction, after finishing, question response is cooled to room temperature, add water 200mL, have solid to wash out, filter to obtain N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield is 85%.
embodiment 3
By 4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid 12.1g is dissolved in 50mL methylene dichloride, adds 8.1gCDI, after it dissolves, adds 1-(3-methoxy-propyl)-4-piperidines ammonia 8.6g, room temperature reaction, TLC detection reaction, is cooled to room temperature after question response finishes, and adds water 200mL, there is solid to wash out, filter to such an extent that N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-is chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield is 65%.
embodiment 4
By 4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid 12.1g is dissolved in 50mL chloroform, adds 8.1gCDI, after it dissolves, adds 1-(3-methoxy-propyl)-4-piperidines ammonia 8.6g, room temperature reaction, TLC detection reaction, is cooled to room temperature after question response finishes, and adds water 200mL, there is solid to wash out, filter to such an extent that N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-is chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield is 75%.
embodiment 5
By 4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid 12.1g is dissolved in 50mL tetrahydrofuran (THF), adds 12.4g DCC, after it dissolves, adds 1-(3-methoxy-propyl)-4-piperidines ammonia 8.6g, be warming up to 80 ℃ of reactions, TLC detection reaction, is cooled to room temperature after question response finishes, and adds water 200mL, there is solid to wash out, filter to such an extent that N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-is chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield is 60%.
embodiment 6
4-nitro-5-is chloro-2, and 3-Dihydrobenzofuranes-7-formic acid 12.1g is dissolved in 50mL tetrahydrofuran (THF), adds 20.0g EDCI, 8.1g HOBT, after it dissolves, add 1-(3-methoxy-propyl)-4-piperidines ammonia 8.6g, be warming up to 80 ℃ of reactions, TLC detection reaction, after finishing, question response is cooled to room temperature, add water 200mL, have solid to wash out, filter to obtain N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield is 89%.
embodiment 7
By 4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid 12.1g is dissolved in 50mL tetrahydrofuran (THF), adds 22.8g HATU, after it dissolves, adds 1-(3-methoxy-propyl)-4-piperidines ammonia 8.6g, be warming up to 80 ℃ of reactions, TLC detection reaction, is cooled to room temperature after question response finishes, and adds water 200mL, there is solid to wash out, filter to such an extent that N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-is chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield is 84%.
embodiment 8
By N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide 10.0g is dissolved in 100mL ethanol, add the hydrazine hydrate of 2.0mL, the gac of 1.0g, 0.4g iron trichloride, TLC detects, after question response finishes, leach solid, be spin-dried for solvent and obtain N-[1-(3-methoxycarbonyl propyl)-4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield 90%.
embodiment 9
By N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide 10.0g is dissolved in 100mL tetrahydrofuran (THF), add the hydrazine hydrate of 2.0mL, the gac of 1.0g, 0.4g iron trichloride, TLC detects, after question response finishes, leach solid, be spin-dried for solvent and obtain N-[1-(3-methoxycarbonyl propyl)-4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield 75%.
embodiment 10
By N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide 10.0g is dissolved in 100mL ethanol, add Pd/C 0.8g, be filled with hydrogen, under 0.2MPa pressure, react, TLC detects, after question response finishes, leach Pa/C, be spin-dried for solvent and obtain N-[1-(3-methoxycarbonyl propyl)-4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide, yield 80%.
Claims (9)
1. a method of preparing prucalopride, is characterized in that:
1) 4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid is dissolved in organic solvent, adds condensing agent, adds 1-(3-methoxy-propyl)-4-piperidines ammonia, through condensation, obtain N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide;
2) by N-[1-(3-methoxycarbonyl propyl)-4-nitro-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide is dissolved in organic solvent, add reductive agent, through reduction, obtain N-[1-(3-methoxycarbonyl propyl)-4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-methane amide
2. preparation method according to claim 1, is characterized in that, the first step organic solvent is tetrahydrofuran (THF), DMF, methylene dichloride or chloroform; Condensing agent is CDI, DCC, EDCI-HOBT or HATU.
3. preparation method according to claim 2, is characterized in that, the first step organic solvent is tetrahydrofuran (THF); Condensing agent is CDI.
4. preparation method according to claim 1, is characterized in that, the temperature of the first step reaction is 50 ℃-90 ℃.
5. preparation method according to claim 4, is characterized in that, the temperature of the first step reaction is 80 ℃.
6. preparation method according to claim 1, is characterized in that, second step organic solvent is C1-C4 alcohols or tetrahydrofuran (THF).
7. preparation method according to claim 6, is characterized in that, second step organic solvent is ethanol.
8. preparation method according to claim 1, is characterized in that, the reductive agent that second step reaction is used is Pd/C-hydrogen, hydrazine hydrate, Fe-hydrochloric acid or Raney nickel-hydrogen.
9. preparation method according to claim 8, is characterized in that, the reductive agent that second step reaction is used is hydrazine hydrate.
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| CN201310453590.9A CN103570699A (en) | 2013-09-29 | 2013-09-29 | Method for preparing prucalopride |
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| CN201310453590.9A CN103570699A (en) | 2013-09-29 | 2013-09-29 | Method for preparing prucalopride |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294620A (en) * | 2014-06-16 | 2016-02-03 | 上海法默生物科技有限公司 | Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid |
| CN108976216A (en) * | 2018-09-07 | 2018-12-11 | 江苏工程职业技术学院 | A kind of preparation method of prucalopride |
| CN109232544A (en) * | 2018-09-07 | 2019-01-18 | 江苏工程职业技术学院 | A kind of preparation method of prucalopride |
| EP3413891A4 (en) * | 2016-02-11 | 2019-10-02 | Symed Labs Limited | Processes for the preparation of highly pure prucalopride succinate and its intermediates |
| CN113791149A (en) * | 2021-09-07 | 2021-12-14 | 石家庄四药有限公司 | Detection method of 1-chloro-3-methoxypropane related substances |
| CN115197182A (en) * | 2022-07-01 | 2022-10-18 | 安徽秀朗新材料科技有限公司 | Synthesis process of halogenated dibenzofuran derivative |
| CN116082319A (en) * | 2020-06-04 | 2023-05-09 | 南京恒通医药开发有限公司 | Continuous synthesis method of prucalopride succinate |
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| CN103012337A (en) * | 2012-12-20 | 2013-04-03 | 芷威（上海）化学科技有限公司 | Synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate |
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| CN1582274A (en) * | 2001-11-29 | 2005-02-16 | 沃纳-兰伯特公司 | Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294620A (en) * | 2014-06-16 | 2016-02-03 | 上海法默生物科技有限公司 | Synthetic method for 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid |
| EP3413891A4 (en) * | 2016-02-11 | 2019-10-02 | Symed Labs Limited | Processes for the preparation of highly pure prucalopride succinate and its intermediates |
| CN108976216A (en) * | 2018-09-07 | 2018-12-11 | 江苏工程职业技术学院 | A kind of preparation method of prucalopride |
| CN109232544A (en) * | 2018-09-07 | 2019-01-18 | 江苏工程职业技术学院 | A kind of preparation method of prucalopride |
| CN108976216B (en) * | 2018-09-07 | 2021-02-12 | 江苏工程职业技术学院 | Preparation method of prucalopride |
| CN109232544B (en) * | 2018-09-07 | 2021-09-14 | 江苏工程职业技术学院 | Preparation method of prucalopride |
| CN116082319A (en) * | 2020-06-04 | 2023-05-09 | 南京恒通医药开发有限公司 | Continuous synthesis method of prucalopride succinate |
| CN113791149A (en) * | 2021-09-07 | 2021-12-14 | 石家庄四药有限公司 | Detection method of 1-chloro-3-methoxypropane related substances |
| CN115197182A (en) * | 2022-07-01 | 2022-10-18 | 安徽秀朗新材料科技有限公司 | Synthesis process of halogenated dibenzofuran derivative |
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Application publication date: 20140212 |