CN102295594B - 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications - Google Patents

4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications Download PDF

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CN102295594B
CN102295594B CN201110194953.2A CN201110194953A CN102295594B CN 102295594 B CN102295594 B CN 102295594B CN 201110194953 A CN201110194953 A CN 201110194953A CN 102295594 B CN102295594 B CN 102295594B
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propyl
methoxy
piperylhydrazine
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CN102295594A (en
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李建其
廖云凤
翁志洁
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Abstract

The invention provides a kind of 4-N-and replace-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications, described 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound, the key intermediate of succsinic acid prucalopride can be advantageously used in the preparation of, thus succsinic acid prucalopride can be prepared easily, the needs of medicine industry can be met.4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound, for having free alkali or its salt of the compound shown in formula (1):

Description

4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications
Technical field
The present invention relates to a kind of 4-N-and replace-1-(3-methoxy-propyl)-4-piperidinamines compound and the application in ambroid acid prucalopride thereof.
Background technology
Succsinic acid prucalopride chemistry is by name: N-[1-(3-methoxycarbonyl propyl)-4-piperidyl]-4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxamide succinate salt, being developed by Belgian Janssen company, is highly selective, specificity 5-HT 4receptor stimulant, in 2010 in Britain's listing, be used for the treatment of the female constipation patient that cathartic is invalid, structural formula is as follows:
Along with the quickening of the fast development of economy, the extreme degradation of ecotope and people's rhythm of life, constipation has become the upper ubiquitous problem of society, and morbidity is in ascendant trend year by year.It has a strong impact on the quality of life of patient, patient can with giddy, alliteration, feel sick, receive poor, mood is irritated, dreaminess, sleep less, suffer from abdominal pain, the not congruent malaise symptoms of abdominal distension, perineum falling inflation, defecation, can bring out or increase the weight of Other diseases, as hemorrhoid, intestinal cancer, prostatomegaly and cardiovascular and cerebrovascular diseases, even can threat to life.Succsinic acid prucalopride is such medicine of listing recently, compared with similar drugs, has 5-HT 4receptor-selective is high, avidity is strong; Rapid-action; Untoward reaction is few, better tolerance, and patient satisfaction is high; To the feature that the elderly is suitable for equally.Therefore, succsinic acid prucalopride has wide potential applicability in clinical practice in constipation therapy field.
At present, only compound patent CN1071332C reports two synthetic routes of succsinic acid prucalopride, specific as follows:
Route one obtains succsinic acid prucalopride with chloro-2, the 3-Dihydrobenzofuranes-7-formic acid (7) of 4-amino-5-and ammonia (4) condensation of 1-(3-methoxy-propyl)-4-piperidines, salify.
Route two obtains prucalopride with compound 9 and the condensation of 1-chloro-3-methoxy propane.
Route one is than route two, and after reaction, residual raw materials compound 7 is easily removed by soda lye wash, and product purity is higher.In addition, the synthesis of compound 7 has bibliographical information, and the synthesis of compound 9 has no bibliographical information, and it is higher to synthesize difficulty than compound 7.Compare, route one has good advantage, is conducive to suitability for industrialized production.But the synthesis of current compound 4 has no bibliographical information, therefore, find a kind of synthetic method of compound 4, will have great importance.
The structure of compound 4 is as follows:
Summary of the invention
The object of the invention is to provide a kind of 4-N-to replace-1-(3-methoxy-propyl)-4-piperidinamines compound, to prepare 1-(3-methoxy-propyl)-4-piperylhydrazine (4), for the synthesis of succsinic acid prucalopride, to meet the needs of related industries department.
Described 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound, for having free alkali or its salt of the compound shown in formula (1):
Wherein,
R represents N blocking group carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc) or C 1-6straight chained alkyl acyl group, preferred carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), ethanoyl or propionyl;
Described salt is inorganic acid salt, comprising: hydrochloride, hydrogen bromide salt or vitriol etc., also can be organic acid salt, as: acetate, trifluoroacetate, mesylate or tosilate etc., preferably salt hydrochlorate or hydrobromate;
Preferably, described 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound is:
4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-1),
4-N-carbobenzoxy-(Cbz)-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-2),
4-N-ethanoyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-3)
Described 4-N-replaces the preparation method of-1-(3-methoxy-propyl)-4-piperidinamines compound, comprises the steps:
By compound 2 and compound 3 in a solvent, condensation under alkaline matter effect, can obtain described 4-N-and replace-1-(3-methoxy-propyl)-4-piperidinamines compound, route is as follows:
Wherein, as defined hereinabove, X represents the easily leavings group such as Cl, Br, I, methylsulfonyl, p-toluenesulfonyl to R, preferred Cl, Br, I;
The alkali used is selected from mineral alkali or organic bases, preferably sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine or diethylamine etc.;
Reaction solvent can be acetonitrile, acetone, butanone, DMF or methylene dichloride etc.;
Compound 2 is 0.8-5 with the molar ratio of compound 3, preferred 1-2;
The molar ratio of alkali and compound 2 is 1 ~ 5, preferred 1-2;
Setting-up point is room temperature extremely backflow, and the reaction times is 1-12h;
Compound 2,3 can directly be purchased.
Compound 1 can be used for preparing succsinic acid prucalopride key intermediate 4,4 condensation of amino-5 chloro-2,3-Dihydrobenzofuranes-7-formic acid (5) with 4-again, and can obtain succsinic acid prucalopride after salify, route is as follows:
According to the difference of R structure, compound 1 deprotection condition also has difference, and the deprotection condition as tertbutyloxycarbonyl (Boc) is generally acidolysis, and common acid is hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid etc.;
The deprotection condition of carbobenzoxy-(Cbz) (Cbz) is generally hydrogenolysis or acidolysis cracking (HBt or TMSI); Ethanoyl, propionyl remove with alkaline hydrolysis or acidolysis usually.
Compound 4 and compound 5 condensation, salify are prepared succsinic acid prucalopride and are operated according to document CN1071332C.
Adopt 4-N-of the present invention to replace-1-(3-methoxy-propyl)-4-piperidinamines compound, compound 4 can be prepared easily, thus succsinic acid prucalopride can be prepared easily, the needs of medicine industry can be met.
Embodiment
Embodiment 1
The preparation of 4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-1)
4-Boc-amino piperidine (30.04g is added in 1000ml reaction flask, 0.15mol), the bromo-3-methoxy propane of 1-(22.95g, 0.15mol), salt of wormwood (20.73g, 0.15mol) with acetonitrile (500ml), back flow reaction 5h, concentrating under reduced pressure, add water (200ml) to stir, filter, with water (100ml) washing leaching cake, off-white color solid 4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (39.11g, yield 95.85%) is obtained, fusing point 72.5-73.5 DEG C after drying.
MS(m/z)：273.22([M+H] +)
1H-NMR(400MHz，DCCl 3)δ：1.41(9H，s)，1.59(2H，m)，1.60-1.86(4H，m)，2.43-2.53(6H，m)，3.36(3H，s)，3.42(2H，t)，3.63(1H，m)。
Embodiment 2
The preparation of 1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (4)
4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (39.11g, 0.144mol), concentrated hydrochloric acid (250ml) and ethanol (500ml) are added in reaction flask, room temperature reaction 3h, ethanol (200ml) solution of NaOH (20g) is added after concentrating under reduced pressure, with adding methylene dichloride (200ml) after concentrated, filter, filtrate concentrates give light yellow oil 4 (21.75g, yield 87.9%).
MS(m/z)：173.18([M+H]+)
Embodiment 3
The preparation of 4-N-carbobenzoxy-(Cbz)-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-2)
4-Cbz-amino piperidine (23.43g, 0.1mol), the bromo-3-methoxy propane of 1-(15.30g, 0.1mol), salt of wormwood (8.30g, 0.1mol) and acetone (250ml) is added in 500ml reaction flask, back flow reaction 5h.Add water after concentrating under reduced pressure to stir, filter, dry white solid 4-N-carbobenzoxy-(Cbz)-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (24.97g, 81.49%).
MS(m/z)：307.21([M+H]+)
1H-NMR(400MHz，DCCl3)δ：1.59(2H，m)，1.62-1.85(4H，m)，2.43-2.53(6H，m)，3.36(3H，s)，3.42(2H，t)，3.63(1H，m)，5.16(2H，s)，7.30-7.51(5H，m)。
Embodiment 4
The preparation of 1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (4)
4-N-carbobenzoxy-(Cbz)-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (24.97g, 0.081mol), 40%HBr (120ml) and ethanol (300ml) are added in reaction flask, back flow reaction 7h, ethanol (200ml) solution of NaOH (20g) is added after concentrating under reduced pressure, with adding methylene dichloride (100ml) after concentrated, filter, filtrate concentrates give light yellow oil 1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (8.82g, yield 63.44%).
MS(m/z)：173.18([M+H]+)
Embodiment 5
The preparation of 4-N-ethanoyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-3)
4-acetylamino piperidines (2.13g; 0.015mol), the bromo-3-methoxy propane of 1-(2.30g; 0.015mol), sodium carbonate (1.25g, 0.015mol) and acetonitrile (40ml) be added in 100ml reaction flask, back flow reaction 6h.Add water after concentrating under reduced pressure to stir, filter, dry white solid 4-N-ethanoyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (2.53g, 78.82%).
MS(m/z)：215.25([M+H]+)
1H-NMR(400MHz，DCCl3)δ：1.59(2H，m)，1.60-1.86(7H，m)，2.41-2.55(6H，m)，3.36(3H，s)，3.42(2H，t)，3.63(1H，m)。
Embodiment 6
The preparation of 1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (4)
4-N-ethanoyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (2.53g, 0.018mol), 15%KOH (15g) and ethanol (15ml) are added in reaction flask, back flow reaction 3h.Add methylene dichloride (30ml) after concentrating under reduced pressure, filter, filtrate concentrates give light yellow oil 1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1.73g, yield 67.05%).
MS(m/z)：173.18([M+H]+)
Embodiment 7
The preparation of succsinic acid prucalopride
4-amino-5 chloro-2,3-Dihydrobenzofuranes-7-formic acid (13.11g, 0.061mol) be added in 250ml reaction flask with THF (125ml), CDI (9.95g is added under ice bath cooling, 0.061mol), after removing ice bath room temperature reaction 1.25h, 4 (3.44g, 0.002mol) are added to reaction system stirring at room temperature 24h.Add CDI (0.69g, 4 (0.74g are added again after 0.00426mol) stirring 1.25h, 0.00430mol), back flow reaction 3h after stirring at room temperature 3h, cooled and filtered, filtrate concentrates, and adds water (50ml), filter, dry off-white color solid prucalopride 11.11g.Prucalopride (11.11g) is dissolved with ethanol (55ml), add succsinic acid (3.56g, ethanol water (10/3.5 0.03mol), V/V) solution (30ml), stirring is spent the night, filter, dry white solid succsinic acid prucalopride 24.90g (yield 83.55%), fusing point: 195.6-196.5 DEG C.
MS(m/z)：368.18([M+H-118]+)
1H-NMR(400MHz，DMSO-d6)δ：7.47(s，1H，Ar-H)，7.26(d，1H，NH)，5.78(s，2H，NH2)，4.73(t，2H，CH2)，3.75(m，1H，CH)，3.34(t，2H，CH2)，3.22(s，3H，CH3)，3.04(t，2H，CH2)，2.70(m，2H，CH2)，2.31(t，2H，CH2)，2.07(t，2H，CH2)，1.83(m，2H，CH2)，1.64(m，2H，CH2)，1.40～1.49(m，2H，CH2)。

Claims (1)

  1. The application of 1.4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine, is characterized in that, for the preparation of the key intermediate 4 of succsinic acid prucalopride, the structure of key intermediate 4 is as follows:
    Preparation method, comprises the steps:
    4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine 39.11g, concentrated hydrochloric acid 250ml and ethanol 500ml are added in reaction flask, room temperature reaction 3h, the ethanol 200ml solution containing NaOH20g is added after concentrating under reduced pressure, methylene dichloride 200ml is added after concentrated, filter, filtrate concentrates, and obtains key intermediate 4.
CN201110194953.2A 2011-07-12 2011-07-12 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications Expired - Fee Related CN102295594B (en)

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CN103755689B (en) * 2013-12-25 2016-06-29 连云港恒运医药科技有限公司 The preparation method of prucalopride degradation impurity
CN103664912B (en) * 2013-12-31 2015-11-25 南京正大天晴制药有限公司 A kind of synthesis technique of prucalopride
CN104193730A (en) * 2014-07-19 2014-12-10 江苏礼华生物技术有限公司 Succinic acid prucalopride crystal type I and preparation thereof
CN105130880B (en) * 2015-09-18 2017-07-11 上海皓伯化工科技有限公司 The method that one kind prepares the amine of 1 (3 methoxycarbonyl propyl) piperidines 4
WO2017137910A1 (en) * 2016-02-11 2017-08-17 Symed Labs Limited Processes for the preparation of highly pure prucalopride succinate and its intermediates
CN108976216B (en) * 2018-09-07 2021-02-12 江苏工程职业技术学院 Preparation method of prucalopride
CN111978185B (en) * 2019-05-24 2022-03-22 技源集团股份有限公司 Preparation method of salicylamine acetate
CN114539133A (en) * 2020-11-24 2022-05-27 鲁南制药集团股份有限公司 Method for preparing prucalopride intermediate 1- (3-methoxypropyl) -4-piperidinamine

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1045781A (en) * 1989-03-22 1990-10-03 詹森药业有限公司 N-(3-hydroxy-4-piperidinyl base) (Dihydrobenzofuranes, dihydro-2H-chromene or dihydrobenzo two  English) carboxamides derivatives
CN1054598A (en) * 1990-03-06 1991-09-18 詹森药业有限公司 The preparation method of carboxamides derivatives
CN1164233A (en) * 1994-11-24 1997-11-05 詹森药业有限公司 Enterokinetic benzamide
US6479487B1 (en) * 1998-02-26 2002-11-12 Aventis Pharmaceuticals Inc. 6, 9-disubstituted 2-[trans-(4-aminocyclohexyl)amino] purines
WO2003080610A1 (en) * 2002-03-22 2003-10-02 Glaxo Group Limited Imidazopyridine derivatives as kinase inhibitors
US20060122171A1 (en) * 2002-11-15 2006-06-08 Wei Xu Kinase modulators
CN101437820A (en) * 2006-03-07 2009-05-20 阿雷生物药品公司 Heterobicyclic pyrazole compounds and methods of use
CN101553482A (en) * 2006-09-15 2009-10-07 艾科睿制药公司 Kinase inhibitor compounds

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1045781A (en) * 1989-03-22 1990-10-03 詹森药业有限公司 N-(3-hydroxy-4-piperidinyl base) (Dihydrobenzofuranes, dihydro-2H-chromene or dihydrobenzo two  English) carboxamides derivatives
CN1054598A (en) * 1990-03-06 1991-09-18 詹森药业有限公司 The preparation method of carboxamides derivatives
CN1164233A (en) * 1994-11-24 1997-11-05 詹森药业有限公司 Enterokinetic benzamide
US6479487B1 (en) * 1998-02-26 2002-11-12 Aventis Pharmaceuticals Inc. 6, 9-disubstituted 2-[trans-(4-aminocyclohexyl)amino] purines
WO2003080610A1 (en) * 2002-03-22 2003-10-02 Glaxo Group Limited Imidazopyridine derivatives as kinase inhibitors
US20060122171A1 (en) * 2002-11-15 2006-06-08 Wei Xu Kinase modulators
CN101437820A (en) * 2006-03-07 2009-05-20 阿雷生物药品公司 Heterobicyclic pyrazole compounds and methods of use
CN101553482A (en) * 2006-09-15 2009-10-07 艾科睿制药公司 Kinase inhibitor compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108727351A (en) * 2017-04-19 2018-11-02 鲁南制药集团股份有限公司 A kind of process for purification of general reed Ka Bili
CN108727351B (en) * 2017-04-19 2021-08-31 鲁南制药集团股份有限公司 Refining method of prucalopride

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