CN103508939A - Method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine - Google Patents
Method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine Download PDFInfo
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- CN103508939A CN103508939A CN201310267361.8A CN201310267361A CN103508939A CN 103508939 A CN103508939 A CN 103508939A CN 201310267361 A CN201310267361 A CN 201310267361A CN 103508939 A CN103508939 A CN 103508939A
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- China
- Prior art keywords
- methoxy
- organic solvent
- propyl
- methoxypropyl
- piperidinamine
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
Abstract
The invention belongs to the field of pharmaceutical chemistry, and relates to a method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine. The method comprises following step: 1) 1-(3-methoxylpropyl)-4-piperidone is dissolved in an organic solvent, appropriate amounts of hydroxylamine hydrochloride and vinegar are added for heating reflux dehydration so as to obtain 1-(3-methoxypropyl)-4-piperidine oxime; and 2) 1-(3-methoxypropyl)-4-piperidine oxime is dissolved in an organic solvent, an appropriate amount of a catalyst is added, and H2 is added so as to obtain 1-(3-methoxypropyl)-4-piperidinamine after complete reaction. Operation of the method is simple and convenient, reaction conditions are mild, yield is high, and the method is suitable for large scale industrialized production.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, relate to a kind of prucalopride important intermediate 1-(3-methoxy-propyl of preparing) method (structure is shown in I) of-4-piperylhydrazine.
I
Background technology
Prucalopride is the selectivity 5-HT----------------------------------------------by the development of Belgian Movetis NV company
4receptor stimulant, in October, 2009, Europe Drug Administration ratified its monosuccinic acid salt listing, clinically be used for the treatment of the female constipation that hypocatharsis can not be alleviated, prucalopride is the novel prokinetic agent of first Dihydrobenzofuranes carboxylic acid derivative class, can high efficiency selected sexual stimulus 5-HT
4aand 5-HT
4bacceptor, increases gastrointestinal peristalsis, improves constipation symptom.In numerous prucalopride synthetic routes, in general 1-(3-the methoxy-propyl)-4-piperylhydrazine intermediate that is absolutely necessary, this intermediate synthetic causes very large concern, in US Patent No. 6479487, disclose and take 1-(3-methoxy-propyl)-4-piperidone obtains 1-(3-methoxy-propyl through oximate reduction as raw material) method of-4-piperylhydrazine, the method adopts lithium aluminum hydride to make reductive agent, and aftertreatment is loaded down with trivial details, and reaction yield is low.Reaction scheme is as follows:
In CN 102295594, disclosing and take 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines is raw material, by N-alkylation and Deprotection, obtains target product.Reaction scheme is as follows:
This method cost of material is expensive, does not substantially have the market competitiveness, for above problem, we develop a synthetic 1-(3-methoxy-propyl in prucalopride synthetic work) method of-4-piperylhydrazine, the method is easy and simple to handle, reaction conditions is gentle, and yield is high, is suitable for large-scale commercial production.
Summary of the invention
The invention provides a kind of prucalopride intermediate 1-(3-methoxy-propyl of preparing) its step of method of-4-piperylhydrazine is: by 1-(3-methoxy-propyl)-4-piperidone is dissolved in organic solvent, add again appropriate hydrochloric acid azanol, reflux dehydration, obtains 1-(3-methoxy-propyl after reacting completely)-4-piperidines oxime.2) 1-(3-methoxy-propyl)-4-piperidines oxime is dissolved in organic solvent, adds proper catalyst, then passes into H2, and the aftertreatment that reacts completely obtains 1-(3-methoxy-propyl)-4-piperylhydrazine.
The organic solvent of the first step is toluene, dimethylbenzene and chlorobenzene, wherein preferred toluene.
Second step organic solvent is C1-C4 alcohols and tetrahydrofuran (THF), wherein particular methanol.
The catalyzer using in second step is Raney's nickel and palladium charcoal, wherein preferred Raney's nickel.
Reaction scheme is as follows:
embodiment
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
embodiment 1:
By 1-(3-methoxy-propyl)-4-piperidone 10.0g, oxammonium hydrochloride 4.06g, toluene 150mL joins in 250mL there-necked flask, is heated to reflux dewatering 24 hours, treat that raw material reaction is complete, be down to room temperature, reaction is filtered, filter cake is washed with toluene, is dried to obtain white solid, yield 90%.
embodiment 2:
By 1-(3-methoxy-propyl)-4-piperidone 10.0g, oxammonium hydrochloride 4.06g, dimethylbenzene 120mL joins in 250mL there-necked flask, is heated to reflux dewatering 24 hours, treat that raw material reaction is complete, be down to room temperature, reaction is filtered, filter cake is washed with toluene, is dried to obtain white solid, yield 94%.
embodiment 3:
By 1-(3-methoxy-propyl)-4-piperidines oxime 10.0g, 10%Pd/C 10g, methyl alcohol 100mL joins in 250mL there-necked flask, under normal temperature and pressure, passes into H
2, reaction 10h, obtains water white transparency oily thing 8.7g, yield 95% through aftertreatment.
embodiment 4:
By 1-(3-methoxy-propyl)-4-piperidines oxime 10.0g, Raney's nickel 10g, methyl alcohol 100mL joins in 250mL there-necked flask, under normal temperature and pressure, passes into H
2, reaction 10h, obtains water white transparency oily thing 7.8g, yield 84.5% through aftertreatment.
Claims (7)
1. prepare prucalopride intermediate 1-(3-methoxy-propyl for one kind) method of-4-piperylhydrazine, comprise the following steps, 1) by 1-(3-methoxy-propyl)-4-piperidone is dissolved in organic solvent, add again oxammonium hydrochloride, reflux dehydration, obtains 1-(3-methoxy-propyl after reacting completely)-4-piperidines oxime; 2) 1-(3-methoxy-propyl)-4-piperidines oxime is dissolved in organic solvent, adds catalyzer, then passes into H
2, the aftertreatment that reacts completely obtains 1-(3-methoxy-propyl) and-4-piperylhydrazine
。
2. according to the method for claim 1, it is characterized in that, the organic solvent of the first step is toluene, dimethylbenzene and chlorobenzene.
3. according to the method for claim 1, it is characterized in that, the organic solvent of the first step is toluene.
4. according to the method for claim 1, it is characterized in that, second step organic solvent is C1-C4 alcohols and tetrahydrofuran (THF).
5. according to the method for claim 1, it is characterized in that, second step organic solvent is methyl alcohol.
6. according to the method for claim 1, it is characterized in that, the catalyzer using in second step is Raney's nickel and/or palladium charcoal.
7. according to the method for claim 1, it is characterized in that, the catalyzer using in second step is Raney's nickel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310267361.8A CN103508939A (en) | 2013-06-30 | 2013-06-30 | Method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310267361.8A CN103508939A (en) | 2013-06-30 | 2013-06-30 | Method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103508939A true CN103508939A (en) | 2014-01-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310267361.8A Pending CN103508939A (en) | 2013-06-30 | 2013-06-30 | Method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848777A (en) * | 2014-03-18 | 2014-06-11 | 悦康药业集团有限公司 | Method for synthesizing N-(3-methoxy propyl)-4-amino-piperidine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6479487B1 (en) * | 1998-02-26 | 2002-11-12 | Aventis Pharmaceuticals Inc. | 6, 9-disubstituted 2-[trans-(4-aminocyclohexyl)amino] purines |
| CN102295594A (en) * | 2011-07-12 | 2011-12-28 | 上海医药工业研究院 | 4-N-substituted-1-(3-methoxylpropyl)-4-piperylhydrazine compound, preparation method thereof, and application thereof |
-
2013
- 2013-06-30 CN CN201310267361.8A patent/CN103508939A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6479487B1 (en) * | 1998-02-26 | 2002-11-12 | Aventis Pharmaceuticals Inc. | 6, 9-disubstituted 2-[trans-(4-aminocyclohexyl)amino] purines |
| CN102295594A (en) * | 2011-07-12 | 2011-12-28 | 上海医药工业研究院 | 4-N-substituted-1-(3-methoxylpropyl)-4-piperylhydrazine compound, preparation method thereof, and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 马宇衡: "《有机合成反应速查手册》", 30 April 2009 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103848777A (en) * | 2014-03-18 | 2014-06-11 | 悦康药业集团有限公司 | Method for synthesizing N-(3-methoxy propyl)-4-amino-piperidine |
| CN103848777B (en) * | 2014-03-18 | 2016-04-13 | 悦康药业集团有限公司 | A kind of synthetic method of N-(3-methoxy-propyl)-4-amino piperidine |
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Application publication date: 20140115 |
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