CN102295594A - 4-N-substituted-1-(3-methoxylpropyl)-4-piperylhydrazine compound, preparation method thereof, and application thereof - Google Patents
4-N-substituted-1-(3-methoxylpropyl)-4-piperylhydrazine compound, preparation method thereof, and application thereof Download PDFInfo
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- CN102295594A CN102295594A CN2011101949532A CN201110194953A CN102295594A CN 102295594 A CN102295594 A CN 102295594A CN 2011101949532 A CN2011101949532 A CN 2011101949532A CN 201110194953 A CN201110194953 A CN 201110194953A CN 102295594 A CN102295594 A CN 102295594A
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Abstract
The invention provides a 4-N-substituted-1-(3-methoxylpropyl)-4-piperylhydrazine compound, a preparation method thereof, and an application thereof. The 4-N-substituted-1-(3-methoxylpropyl)-4-piperylhydrazine compound can be conveniently applied in the preparation of a key intermediate of prucalopride succinate. Therefore, prucalopride succinate can be conveniently prepared, such that a requirement of pharmaceutical industry can be satisfied. The provided 4-N-substituted-1-(3-methoxylpropyl)-4-piperylhydrazine compound is a free base of a compound represented by a formula (1), or a salt thereof.
Description
Technical field
The present invention relates to a kind of 4-N-replacement-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-methane amide succinate is developed by Belgian Janssen company, is highly selective, specificity 5-HT
4Receptor stimulant went on the market in Britain in 2010, was used for the treatment of the invalid women's constipation patient of cathartic, and structural formula is as follows:
Along with the extreme deterioration of rapid economy development, ecotope and the quickening of people's rhythm of life, constipation has become society and has gone up ubiquitous problem, and morbidity is ascendant trend year by year.It has a strong impact on patient's quality of life, the patient can with giddy, alliteration, feel sick, receive poor, mood is irritated, dreaminess, sleep less, stomachache, abdominal distension, perineum are weighed down and are expanded, the not congruent malaise symptoms of defecation, can bring out or increase the weight of other disease, as hemorrhoid, intestinal cancer, prostatomegaly and cardiovascular and cerebrovascular diseases, but even threat to life.The succsinic acid prucalopride is such medicine that goes on the market recently, compares with similar medicine, has 5-HT
4Receptor-selective height, avidity are strong; Rapid-action; Untoward reaction is few, better tolerance, patient satisfaction height; The characteristics suitable equally to the elderly.Therefore, the succsinic acid prucalopride has broad clinical application prospect in the constipation therapy field.
At present, only compound patent CN1071332C has reported two synthetic routes of succsinic acid prucalopride, and is specific as follows:
Route one is with 4-amino-5-chloro-2, and 3-Dihydrobenzofuranes-7-formic acid (7) gets the succsinic acid prucalopride with 1-(3-methoxy-propyl)-4-piperidines ammonia (4) condensation, salify.
Route two gets prucalopride with compound 9 and the condensation of 1-chloro-3-methoxy propane.
Route one is than route two, and reaction back residual raw materials compound 7 is easily removed by soda lye wash, and product purity is higher.In addition, the synthetic of compound 7 has bibliographical information, and the synthetic of compound 9 do not see bibliographical information, and higher than compound 7 synthetic difficulty.Compare, route one has good advantage, helps suitability for industrialized production.But the synthetic of compound 4 do not see bibliographical information at present, therefore, seeks 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-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound, with preparation 1-(3-methoxy-propyl)-4-piperylhydrazine (4), is used for the synthetic of succsinic acid prucalopride, to satisfy the needs of relevant branch of industry.
Described 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound is free alkali or its salt with the compound shown in the formula (1):
Wherein,
R represents N blocking group carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc) or C
1-6The straight 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)
The preparation method of described 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound comprises the steps:
In solvent, condensation under the alkaline matter effect can obtain described 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound with compound 2 and compound 3, and route is as follows:
Wherein, R such as preamble define, and X represents easily leavings group such as Cl, Br, I, methylsulfonyl, p-toluenesulfonyl, preferred Cl, Br, I;
Employed alkali is selected from mineral alkali or organic bases, preferably yellow soda ash, 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 that room temperature extremely refluxes, 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 again with 4-amino-5 chloro-2, the condensation of 3-Dihydrobenzofuranes-7-formic acid (5) can make the succsinic acid prucalopride behind the salify, route is as follows:
According to the difference of R structure, compound 1 deprotection condition also has difference, is generally acidolysis as the deprotection condition of tertbutyloxycarbonyl (Boc), 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 prepares the succsinic acid prucalopride with compound 5 condensations, salify to be operated according to document CN1071332C.
Adopt 4-N-replacement-1-of the present invention (3-methoxy-propyl)-4-piperidinamines compound, can prepare compound 4 easily, thereby can prepare the succsinic acid prucalopride easily, can satisfy the needs of medicine industry.
Embodiment
Embodiment 1
The preparation of 4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-1)
In the 1000ml reaction flask, add 4-Boc-amino piperidine (30.04g, 0.15mol), 1-bromo-3-methoxy propane (22.95g, 0.15mol), salt of wormwood (20.73g, 0.15mol) and acetonitrile (500ml), back flow reaction 5h, concentrating under reduced pressure adds entry (200ml) and stirs, and filters, water (100ml) washing leaching cake, get off-white color solid 4-N-tertbutyloxycarbonyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (39.11g, yield 95.85%), fusing point 72.5-73.5 ℃ after the 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) is added in the reaction flask, room temperature reaction 3h, ethanol (200ml) solution that adds NaOH (20g) behind the concentrating under reduced pressure, concentrate the back with adding methylene dichloride (200ml), filter, filtrate concentrate 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)
The 4-Cbz-amino piperidine (23.43g, 0.1mol), 1-bromo-3-methoxy propane (15.30g, 0.1mol), salt of wormwood (8.30g, 0.1mol) and acetone (250ml) be added in the 500ml reaction flask back flow reaction 5h.Add entry behind the concentrating under reduced pressure and stir, filter, dry white solid 4-N-carbobenzoxy-(Cbz)-1-(3-the methoxycarbonyl propyl)-4-piperylhydrazine (24.97g, 81.49%) that gets.
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) is added in the reaction flask, back flow reaction 7h, ethanol (200ml) solution that adds NaOH (20g) behind the concentrating under reduced pressure, concentrate the back with adding methylene dichloride (100ml), filter, filtrate concentrate 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), 1-bromo-3-methoxy propane (2.30g, 0.015mol), yellow soda ash (1.25g, 0.015mol) and acetonitrile (40ml) be added in the 100ml reaction flask back flow reaction 6h.Add entry behind the concentrating under reduced pressure and stir, filter, dry white solid 4-N-ethanoyl-1-(3-the methoxycarbonyl propyl)-4-piperylhydrazine (2.53g, 78.82%) that gets.
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) is added in the reaction flask back flow reaction 3h.Add methylene dichloride (30ml) behind the concentrating under reduced pressure, filter, filtrate concentrate 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) and THF (125ml) be added in the 250ml reaction flask, the ice bath cooling adds CDI (9.95g down, 0.061mol), after removing ice bath room temperature reaction 1.25h, (3.44g 0.002mol) is added to reaction system stirring at room 24h with 4.Add CDI (0.69g, 0.00426mol) stir and to add 4 behind the 1.25h again (0.74g, 0.00430mol), back flow reaction 3h behind the stirring at room 3h, cooled and filtered, filtrate concentrates, and adds entry (50ml), filters, dry off-white color solid prucalopride 11.11g.With ethanol (55ml) dissolving prucalopride (11.11g), add succsinic acid (3.56g, ethanol water (10/3.5 0.03mol), V/V) solution (30ml), stirring is spent the night, and filters, dry white solid succsinic acid prucalopride 24.90g (yield 83.55%), fusing point: 195.6-196.5 ℃ of getting.
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 (8)
1.4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound is characterized in that, is free alkali or its salt with the compound shown in the formula (1):
Wherein,
R represents N blocking group carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc) or C
1-6The straight chained alkyl acyl group.
2. 4-N-replacement-1-according to claim 1 (3-methoxy-propyl)-4-piperidinamines compound is characterized in that, R represents N blocking group carbobenzoxy-(Cbz) (Cbz), tertbutyloxycarbonyl (Boc), ethanoyl or propionyl.
3. 4-N-replacement-1-according to claim 1 and 2 (3-methoxy-propyl)-4-piperidinamines compound is characterized in that described salt is hydrochloride, hydrogen bromide salt, vitriol, acetate, trifluoroacetate, mesylate or tosilate.
4. 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) or
4-N-ethanoyl-1-(3-methoxycarbonyl propyl)-4-piperylhydrazine (1-3).
5. according to the preparation method of each described 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound of claim 1～4, it is characterized in that, comprise the steps: compound 2 and compound 3 in solvent, condensation under the alkaline matter effect, can obtain described 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines compound, reaction expression is as follows:
Wherein, R such as preamble define, and X represents Cl, Br, I, methylsulfonyl or p-toluenesulfonyl.
6. method according to claim 5 is characterized in that described alkali is selected from yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine or diethylamine; Reaction solvent is acetonitrile, acetone, butanone, DMF or methylene dichloride.
7. method according to claim 5 is characterized in that, compound 2 is 0.8-5 with the molar ratio of compound 3; The molar ratio of alkali and compound 2 is 1～5, and setting-up point is that room temperature extremely refluxes, and the reaction times is 1-12h.
8. according to each described 4-N-replacement-1-(3-methoxy-propyl)-4-piperidinamines application of compound of claim 1～4, it is characterized in that be used to prepare the key intermediate 4 of succsinic acid prucalopride, the structure of key intermediate 4 is as follows:
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103508939A (en) * | 2013-06-30 | 2014-01-15 | 北京万全德众医药生物技术有限公司 | Method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine |
| CN103664912A (en) * | 2013-12-31 | 2014-03-26 | 南京正大天晴制药有限公司 | Synthesis process of prucalopride |
| CN103755689A (en) * | 2013-12-25 | 2014-04-30 | 连云港恒运医药科技有限公司 | Preparation method for prucalopride degradation impurities |
| 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 |
| CN105130880A (en) * | 2015-09-18 | 2015-12-09 | 上海皓伯化工科技有限公司 | Method for preparing 1-(3-methoxypropyl)-4-piperidinamine |
| 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 |
| EP3413891A4 (en) * | 2016-02-11 | 2019-10-02 | Symed Labs Limited | Processes for the preparation of highly pure prucalopride succinate and its intermediates |
| WO2020238753A1 (en) * | 2019-05-24 | 2020-12-03 | 江阴技源药业有限公司 | Preparation method for 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103508939A (en) * | 2013-06-30 | 2014-01-15 | 北京万全德众医药生物技术有限公司 | Method used for preparing prucalopride intermediate 1-(3-methoxypropyl)-4-piperidinamine |
| 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 |
| CN103755689A (en) * | 2013-12-25 | 2014-04-30 | 连云港恒运医药科技有限公司 | Preparation method for prucalopride degradation impurities |
| CN103664912A (en) * | 2013-12-31 | 2014-03-26 | 南京正大天晴制药有限公司 | Synthesis process of prucalopride |
| 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 |
| CN105130880A (en) * | 2015-09-18 | 2015-12-09 | 上海皓伯化工科技有限公司 | Method for preparing 1-(3-methoxypropyl)-4-piperidinamine |
| 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 |
| 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 |
| CN108976216B (en) * | 2018-09-07 | 2021-02-12 | 江苏工程职业技术学院 | Preparation method of prucalopride |
| WO2020238753A1 (en) * | 2019-05-24 | 2020-12-03 | 江阴技源药业有限公司 | Preparation method for 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 |
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