CN106146386A - A kind of new technology preparing prucalopride intermediate - Google Patents
A kind of new technology preparing prucalopride intermediate Download PDFInfo
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- CN106146386A CN106146386A CN201510190545.8A CN201510190545A CN106146386A CN 106146386 A CN106146386 A CN 106146386A CN 201510190545 A CN201510190545 A CN 201510190545A CN 106146386 A CN106146386 A CN 106146386A
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- 0 CC1*(CCCN(CC2)CCC2=O)C1 Chemical compound CC1*(CCCN(CC2)CCC2=O)C1 0.000 description 2
- VUAHOFKIFXDIFM-UHFFFAOYSA-N COCCCN(CC1)CCC1C(N)=O Chemical compound COCCCN(CC1)CCC1C(N)=O VUAHOFKIFXDIFM-UHFFFAOYSA-N 0.000 description 2
- FTXZBIBMZVXRIM-UHFFFAOYSA-N CCOCCCN(CC1)CCC1=NO Chemical compound CCOCCCN(CC1)CCC1=NO FTXZBIBMZVXRIM-UHFFFAOYSA-N 0.000 description 1
- JWESSHPBZLMQDB-UHFFFAOYSA-N COC(C1CCN(CCCO)CC1)=O Chemical compound COC(C1CCN(CCCO)CC1)=O JWESSHPBZLMQDB-UHFFFAOYSA-N 0.000 description 1
- HIXAJGFVNMKLML-UHFFFAOYSA-N COCCCN(CC1)CCC1N Chemical compound COCCCN(CC1)CCC1N HIXAJGFVNMKLML-UHFFFAOYSA-N 0.000 description 1
- VRJHQPZVIGNGMX-UHFFFAOYSA-N O=C1CCNCC1 Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses the preparation method of 1 (3 methoxycarbonyl propyl) 4 piperidinamines shown in a kind of formula (I), it includes such as the following step: formula (II) compound is reacted in the solution of ammonia and prepares formula (III) compound by (1)；(2) by formula (III) compound and 1,3 dibromo 5,5 dimethyl hydantion react prepared formula (I) compound in the basic conditions.This preparation method is without specific response equipment requirements, easy and simple to handle, is suitable to industrialized production；Yield is high, and the three wastes are few, low cost；Product chemical purity is high, heavy metal free residue problem.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of new technology preparing prucalopride intermediate.
Background technology
Constipation belongs to gastrointestinal motility illness, it it is modal gastroenteropathy syndrome, trend along with social population's aging, the change of dietary structure and psychiatric and the impact of social factor, constipation especially obstipation has become a social problem, and its sickness rate is high, and the cause of disease is complicated, often bring to patient many painful and worried, drastically influence the quality of life of patient.Particularly constipation of old people is a serious health problem.Constipation is relevant with generations such as colon cancer, Cardial or cerebral vascular diseases and alzheimer disease, and Aged in China population increases year by year, and in population, proportion is increasing, and therefore the treatment to constipation is very important.
Drug therapy occupies critical role in constipation, and in clinic, the medicine to constipation has bigger demand, particularly dynamics-promoting medicine.The chemical entitled 4-amino-5-chloro-2 of prucalopride (Prucalopride), 3-dihydro-N-[1-(3-methoxy-propyl)-4-piperidyl]-7-benzofuran carboxamides, it is that in October, 2009 is granted for treating chronic constipation in European Union by the seretonine receptor antagonist of Movetis company of Belgium exploitation.This enterokinesia medicine is a new generation's selectivity, first compound of high-affinity 5-HT4 receptor stimulating agent, and it is by the directly effect impaired intestine activities ability of recovery to intestinal walls.
In prucalopride synthetic route, 1-(3-methoxy-propyl)-4-piperidinamine (compound of formula I) is one of requisite intermediate.
Its common synthetic method is divided into following four kinds:
Route one: this route is common route during current 1-(3-methoxy-propyl)-4-piperidinamine produces, and it is with 4-piperidone hydrochloride monohydrate as raw material.Carbonyl is converted into the key that amino is synthesis, and available oxammonium hydrochloride. makes carbonyl become oxime, then through reducing to obtain amino.This method need to need to use high-pressure catalytic to hydrogenate through two-step reaction, uses heavy metal catalyst palladium carbon, and its cost is high, as used inflammable and explosive Raney Ni then operational danger higher.Use palladium carbon or Raney Ni also to bring the risk (Ref:CN103508939) of heavy-metal residual to crude drug prucalopride, because 1-(3-methoxy-propyl)-4-piperidinamine (compound of formula I) only needs single step reaction just to obtain prucalopride crude drug simultaneously.
Route two: currently also have with Pd/C as catalyst, ammonia is as nitrogen source, and carbonyl reduction, as hydrogen source, is directly amino by hydrogen.This route more difficult control of reaction under high pressure condition, need to use high cost heavy metal catalyst palladium carbon, the same risk (Ref:CN102898356A) bringing heavy-metal residual to crude drug prucalopride.
Route three: this route conditions is gentle, but key starting material market 4-N-Boc-piperidines synthesis technique is complicated, expensive, is not appropriate for for large-scale production 1-(3-methoxy-propyl)-4-piperidinamine (Ref:CN102295594A).
Route four: this route as raw material, generates product by resetting with 4-Methanamide piperidines, hypervalent iodine compounds two (trifluoroacetyl oxygen) iodobenzene (PhI (O2CCF3) 2).Two cost of material are the highest, and the stability that hypervalent iodine compounds still suffers from simultaneously and safety issue the most all restrict it on a large scale for industrialized production (Ref:US6479487).
In sum, above four routes have certain deficiency, and products obtained therefrom production cost is higher so that 1-(3-methoxy-propyl)-4-piperidinamine (compound of formula I) price is higher, the most effectively reduces its production cost and is always study hotspot.Inventor is when repeating this work, and gained portioned product color is relatively deep, and chemical purity is the highest, does not meets quality needs of prucalopride production of raw medicine, it is therefore necessary to develop new synthetic method to reduce cost, while improve product quality further.
Summary of the invention
The technical problem to be solved is to overcome above-mentioned weak point, designs, synthesizes a kind of new method preparing prucalopride intermediate.
Specifically, the present invention provides one to prepare the new technology of prucalopride intermediate 1-(3-methoxy-propyl)-4-piperidinamine
The method is as shown in following reaction equation:
Wherein R is the non-substituted of 1～10 carbon or substituted straight or branched alkyl；
Specifically include following steps:
(1) formula (II) compound is reacted in the solution of ammonia prepared formula (III) compound；
(2) by formula (III) compound and 1,3-bis-bromo-5,5-dimethyl hydantion reacts prepared formula (I) compound in the basic conditions.
Formula (II) compound is 4-methyl formate-1-(3-methoxycarbonyl propyl)-piperidines (II-1) or 4-Ethyl formate-1-(3-methoxycarbonyl propyl)-piperidines (II-2).
Method as above, the organic solution of the ammonia employed in step (1) is one or more mixed solutions in the isobutanol solution of the aqueous solution of ammonia, the methanol solution of ammonia, the ethanol solution of ammonia, the normal propyl alcohol solution of ammonia, the aqueous isopropanol of ammonia, the butanol solution of ammonia, ammonia；The reaction temperature used is 20～100 DEG C；The response time used is 1～12h.
Method as above, the alkali employed in step (2) is sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine；The solvent used is one or more mixed solutions of water, acetonitrile, acetone, butanone, DMF；The temperature used is-10～100 DEG C；1 used, 3-bis-bromo-5,5-dimethyl hydantion and formula (III) compound mole ratio are 0.2～5: 1；The response time used is 1～24h.
Beneficial effects of the present invention
Particularly, the inventors discovered that when employing 1-(3-methoxycarbonyl propyl)-piperidines-4-formic acid esters (Formula II compound) is raw material, it can abundant ammonolysis in the solution of ammonia, obtaining 4-Methanamide-1-(3-methoxycarbonyl propyl)-piperidines (formula III compound) with high yield, reactant liquor i.e. can be used for next step reaction after simple concentration.
It should be noted that simultaneously, when using 4-Methanamide-1-(3-methoxycarbonyl propyl)-piperidines (formula III compound) and 1,3-bis-bromo-5,5-dimethyl hydantion (DBDMH) reacts generation hoffman degradation reaction (Hofmann degraded) in the basic conditions, can acquisition 1-(3-the methoxy-propyl)-4-piperidinamine (compound of formula I) of high yield, product purity is more than 98%, meeting prucalopride production of raw medicine requirement, product can obtain higher purity product (purity is more than 99.5%) through simple rectification simultaneously.
DBDMH is one of critical materials.DBDMH is a kind of disinfectant discharging effective bromine, is the conventional antibacterial of aquaculture, and cost is extremely low, simultaneously compared with the degraded reagent (such as bromine) on ordinary meaning, DBDMH store use the safest.The reactive mode of hoffman degradation reaction is a lot, reagent cost is also not quite similar, finding through repeatedly attempting, DBDMH is that one is effectively degraded reagent, and gained catabolite 1-(3-methoxy-propyl)-4-piperidinamine (compound of formula I) purity is the highest.
Critical materials 1-(3-methoxycarbonyl propyl)-piperidines-4-formic ether compounds (Formula II compound) can be prepared through two-step reaction by 4-piperidine carboxylic acid cheap and easy to get, low cost.
This preparation method is without specific response equipment requirements, easy and simple to handle, is suitable to industrialized production；Yield is high, and the three wastes are few, low cost；Product chemical purity is high, heavy metal free residue problem.This technique is beneficial to promote the industrialization of prucalopride crude drug.
Accompanying drawing explanation
Figure1. formula III compound hydrogen spectrum
Figure2. compound of formula I hydrogen spectrum
Figure3. GC spectrogram before compound of formula I rectification
Figure4. GC spectrogram after compound of formula I rectification
Figure5. the HPLC spectrogram of prucalopride
Detailed description of the invention
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below is to preferably illustrate the present invention, is not for limiting the scope of the present invention.
Embodiment 1
The synthesis of 4-methyl piperidine hydrochloride
4-piperidine carboxylic acid (500g, 3.87mol) and methanol (2.5L) are added reaction bulb, drips thionyl chloride (460.4g, 3.87mol), during dropping, temperature substantially rises, and drips complete, outer temperature rise to 80 DEG C back flow reaction 3h.50 DEG C of concentrating under reduced pressure reactant liquors obtain white solid 687g, yield 98.8%, can be directly used for next step reaction.1H NMR (300MHz, CDCl3) δ 9.63 (m, 2H), 3.70 (s, 3H), 3.36 (m, 2H), 3.05 (m, 2H), 2.59 (m, 1H), 2.16 (m, 4H).
Embodiment 2
The synthesis of 4-piperidine ethyl formate hydrochlorate
Specific embodiments is with embodiment 1, yield 97%.
Embodiment 3
The synthesis of 4-methyl formate-1-(3-methoxycarbonyl propyl)-piperidines (II-1)
By 4-methyl piperidine hydrochloride (681.5g, 3.79mol), methanol (3.4L), potassium carbonate (1.3Kg, 9.48mol) being sequentially added into reaction bulb with 3-bromopropyl methyl ether (638.4g, 4.17mol), outer temperature rise to 75 DEG C refluxes overnight.Reactant liquor sucking filtration, 60 DEG C of concentrating under reduced pressure of filtrate, residue adds 1.5L water, extracts with DCM, and organic layer merging is dried with anhydrous sodium sulfate, and 60 DEG C of concentrating under reduced pressure organic layers obtain faint yellow solid 590g, yield 72.2%, can be directly used for next step reaction.1H NMR (300MHz, CDCl3) δ: 3.68 (s, 3H), 3.39 (t, J=6.3Hz, 2H), 3.31 (s, 3H), 2.86 (m, 2H), 2.24～2.42 (m, 3H), 1.70～2.03 (m, 8H).
Embodiment 4
The synthesis of 4-Ethyl formate-1-(3-methoxycarbonyl propyl)-piperidines (II-2)
Specific embodiments, with embodiment 3, changes solvent methanol into ethanol, it is to avoid ester exchange, and the response time extends to 10 hours, yield 76%.
Embodiment 5
The synthesis of 4-Methanamide-1-(3-methoxycarbonyl propyl)-piperidines (III)
4-methyl formate-1-(3-methoxycarbonyl propyl)-piperidines (II-1) (590g, 2.74mol), ammonia spirit (2.07L, 27.4mol) are added reaction bulb；Outer temperature rise is to reaction overnight after 60 DEG C.55 DEG C of concentrating under reduced pressure reactant liquors, remove ammonia, are concentrated to give thick semi-solid 576.3g, are directly used in next step reaction.Take sample oil pump to continue to draw and dry send nuclear-magnetism.1H NMR (300MHz, CDCl3) δ: 5.55 (br s, 2H), 3.40 (t, J=6.3Hz, 2H), 3.34 (s, 3H), 2.95 (m, 2H), 2.38～2.43 (m, 2H), 2.11～2.20 (m, 1H), 1.69～2.01 (m, 8H).
Embodiment 6
The synthesis of 4-Methanamide-1-(3-methoxycarbonyl propyl)-piperidines (III)
Specific embodiments is with embodiment 5, with 4-Ethyl formate-1-(3-methoxycarbonyl propyl)-piperidines (II-2) as raw material, with the methanol solution of ammonia as solvent, and yield 95%.
Embodiment 7
The synthesis of 1-(3-methoxycarbonyl propyl)-4-piperidinamine (I)
By 4-Methanamide-1-(3-methoxycarbonyl propyl)-piperidines (III) (229g, 1.14mol), water (2.06L) and acetonitrile (571.9g) add reaction bulb, add KOH (287.3g, 5.13mol after), in controlling, temperature adds DBDMH (180.2g less than 5 DEG C, 0.63mol), 15-25 DEG C of reaction 13h it is warming up to.Stopped reaction, in 55 DEG C of concentrating under reduced pressure reactant liquors, reclaims acetonitrile.Residue DCM extracts, and organic layer anhydrous sodium sulfate is dried, and in 50 DEG C of concentrating under reduced pressure organic faciess, obtains weak yellow liquid 178.2g, yield 95% (in terms of II-1), GC purity 98.6%.Product is placed in alembic, oil pump rectification under vacuum (barbed type rectifying column), outer temperature gradient increased temperature (5 DEG C/time), when interior temperature rise to 72～73 DEG C, collect fraction, obtaining colourless transparent liquid 148g, rectification yield is 83%, GC purity 99.8% [GC method: chromatographic column AT OV-1 post (30m*0.325mm*0.5 μm)；Injector temperature 250 DEG C；Column temperature keeps 2min in 100 DEG C；20 DEG C/min rises to 275 DEG C；275 DEG C keep 3min；Detector temperature: 260 DEG C].1H NMR (300MHz, CDCl3) δ: 3.35 (m, 2H), 3.29 (s, 3H), 2.80 (m, 2H), 2.57～2.64 (m, 1H), 2.33～2.38 (m, 2H), 1.90 (t, J=11.4Hz, 2H), 1.68～1.79 (m, 4H), 1.28～1.40 (m, 4H)；ESI-MS (m/z): 173.2 [M+H]+。
Embodiment 8
The synthesis of succinic acid prucalopride API
THF it is sequentially added in reaction bulb, 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-formic acid (1.0g), a small amount of CDI, stir 25min, keep less than 20 DEG C, dropping 1-(3-methoxy-propyl)-4-piperidinamine (I) (0.8g, GC ＞ 98%), is heated to 45-50 DEG C, reaction 4h, TLC detection is to reaction completely；Lower the temperature, remove solvent under reduced pressure；Residue adds water (30g), separates out a large amount of solid, 25 DEG C of stirring 1h；Sucking filtration, 20g water wash, collect filter cake, be dried, obtain prucalopride 1.5g, yield 85% (m.p.=91-92 DEG C).In reaction bulb, add prucalopride (1.0g) and 75% ethanol (5mL), be heated under 40 DEG C, stirring adding succinic acid (0.35g), stir 3h.Filter, filter cake 75% ethyl alcohol recrystallization, dried obtain white granular crystal 1.17g, yield 93% (m.p.=197-198 DEG C, HPLC:99.8%).
Claims (10)
1. the method preparing formula (I) compound:
The method is as shown in following reaction equation:
Wherein R is the non-substituted of 1～10 carbon or substituted straight or branched alkyl；
Specifically include following steps:
(1) formula (II) compound is reacted in the solution of ammonia prepared formula (III) compound；
(2) by formula (III) compound and 1,3-bis-bromo-5,5-dimethyl hydantion reacts prepared formula (I) chemical combination in the basic conditions
Thing.
2. the method for claim 1, it is characterised in that formula (II) compound is 4-methyl formate-1-(3-methoxycarbonyl propyl)
-piperidines (II-1) or 4-Ethyl formate-1-(3-methoxycarbonyl propyl)-piperidines (II-2).
3. the method for claim 1, it is characterised in that the solution of the ammonia employed in step (1) be the aqueous solution of ammonia,
The methanol solution of ammonia, the ethanol solution of ammonia, the normal propyl alcohol solution of ammonia, the aqueous isopropanol of ammonia, the butanol solution of ammonia,
One or more mixed solutions in the isobutanol solution of ammonia.
4. the method for claim 1, it is characterised in that the reaction temperature employed in step (1) is 20～100 DEG C.
5. the method for claim 1, it is characterised in that the response time employed in step (1) is 1～12h.
6. the method for claim 1, it is characterised in that the alkali employed in step (2) is sodium hydroxide, hydroxide
Potassium, ammonium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.
7. the method for claim 1, it is characterised in that the solvent employed in step (2) be water, acetonitrile, acetone,
Butanone, one or more mixed solutions of DMF.
8. the method for claim 1, it is characterised in that the temperature employed in step (2) is-10～100 DEG C.
9. the method for claim 1, it is characterised in that 1 employed in step (2), 3-bis-bromo-5,5-dimethyl
Glycolylurea and formula (III) compound mole ratio are 0.3～5: 1.
10. the method for claim 1, it is characterised in that the response time is 1～24h in step (2).
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| 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 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035649A1 (en) * | 2001-10-22 | 2003-05-01 | Pfizer Japan Inc. | Imidazopyridine compounds as 5-ht4 receptor modulators |
| EP1325921A2 (en) * | 2002-01-07 | 2003-07-09 | Pfizer Inc. | Oxo or oxy-pyridine compounds as 5-HT4 receptor modulators |
| CN101514184A (en) * | 2009-04-07 | 2009-08-26 | 南京工业大学 | Synthetic method for 5-bromine-2-methylpyridine |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
| CN103193699A (en) * | 2013-04-18 | 2013-07-10 | 安徽赛诺医药化工有限公司 | Novel method for preparing prucalopride intermediate |
| 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 |
-
2015
- 2015-04-21 CN CN201510190545.8A patent/CN106146386A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003035649A1 (en) * | 2001-10-22 | 2003-05-01 | Pfizer Japan Inc. | Imidazopyridine compounds as 5-ht4 receptor modulators |
| EP1325921A2 (en) * | 2002-01-07 | 2003-07-09 | Pfizer Inc. | Oxo or oxy-pyridine compounds as 5-HT4 receptor modulators |
| CN101514184A (en) * | 2009-04-07 | 2009-08-26 | 南京工业大学 | Synthetic method for 5-bromine-2-methylpyridine |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
| CN103193699A (en) * | 2013-04-18 | 2013-07-10 | 安徽赛诺医药化工有限公司 | Novel method for preparing prucalopride intermediate |
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| 刑其毅，等: "《基础有机化学-下册》", 30 June 2005 * |
| 原友志，等: "琥珀酸普卡必利的合成", 《中国医药工业杂志》 * |
| 谭红梅,等: "4-氨基-4-甲基哌啶二对甲苯磺酸盐的合成", 《广东药学院学报》 * |
Cited By (2)
| 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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Application publication date: 20161123 |