CN101676272A - preparation method of pramipexole - Google Patents
preparation method of pramipexole Download PDFInfo
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- CN101676272A CN101676272A CN200810222435A CN200810222435A CN101676272A CN 101676272 A CN101676272 A CN 101676272A CN 200810222435 A CN200810222435 A CN 200810222435A CN 200810222435 A CN200810222435 A CN 200810222435A CN 101676272 A CN101676272 A CN 101676272A
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- pramipexole
- tetrahydrofuran
- sodium borohydride
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Abstract
The invention discloses a preparation process of pramipexole, namely enantiomers or racemates of 2-amino-6-acrylamido-4,5,6,7-tetrahydrobenzothiazole. The pramipexole is prepared from 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole as the raw material by the reduction reaction with a reducing agent. The process has easy operation, and mild reaction condition, is easy to control, and greatly improve the safety of production.
Description
Technical field
The present invention relates to a kind of pramipexole, i.e. 2-amino-6-third amino-4,5,6, the optically active form of 7-tetrahydro benzothiazol or the preparation technology of raceme.
Background technology
Parkinson's disease are a kind of common Neurology Department diseases, are common disease in the elderly.
Pramipexole right and wrong ergot analog derivative, its advantage is: act on the DA-2 acceptor pramipexole high selectivity; Can use the treatment Parkinson's disease separately in early days; can share the treatment Parkinson's disease late period with Dopamine HCL; the external while is used for the treatment of RLS disease (restless leg syndrome) for pramipexole and studies; think effectively; and pramipexole has provide protection to the nerve of Dopamine HCL; the treatment of neuroprotective and RLS disease is its unique advantage, can delay the development of the state of an illness greatly, has guaranteed patient's health.
Non-ergot analog derivative is the focus of present Parkinson's disease research, and wide application prospect is arranged.Pramipexole acts on selectivity because of it, and can be used for Parkinson's disease separately, becomes parkinsonian drug of first choice in the future most probably.
Synthetic patent about pramipexole, J.Med.chem.30 (3) wherein, 494-498 (1987) discloses a kind of preparation method's (seeing route one) of pramipexole, this method is that the borine solution with tetrahydrofuran (THF) is that reductive agent prepares pramipexole, but the colourless severe toxicity of the borine that uses in this method, highly inflammable and explosive, its tetrahydrofuran solution preparation method complexity, production security is poor.
Route one
And patent CN1834092 replaces borine (seeing route two) with the diethyl ether solution of boron trifluoride, but boron trifluoride ether solution is met water decomposition, and irritating smell is arranged, and highly inflammable, severe reaction conditions also is unfavorable for suitability for industrialized production.
Route two
Summary of the invention
The objective of the invention is to avoid the weak point of above-mentioned prior art existence and provide a kind of simple to operate, the reaction conditions gentleness is easy to control the preparation technology of safe pramipexole.
Purpose of the present invention can reach by following measure:
With 2-amino-6-propionamido-4,5,6, the optically active form of 7-tetrahydro benzothiazol or raceme (I formula) are raw material, make by the reductive agent reduction.
Method provided by the invention is simple to operate, and the reaction conditions gentleness is easy to control, has improved the security of producing greatly.
Embodiment
Following embodiment is used to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1
Add tetrahydrofuran (THF) 10L in the 20L there-necked flask successively, sodium borohydride 1.2kg stirred 1 hour.Add (±) 2-amino-6-propionamido-4,5,6 in the time of T=25 ℃, 7-tetrahydro benzothiazol 1kg stirred 4 hours, was heated to back flow reaction 48 hours.Naturally be cooled to 20 ℃～25 ℃.Reaction solution is slowly poured in the 8L frozen water, and temperature control T=10 ℃～20 drip 37% hydrochloric acid 6.4kg.Drip and finish PH=1.Suction filtration, water white transparency liquid, the decompression revolve except that tetrahydrofuran (THF) to constant weight.Revolve completely, transfer PH=14, consume aqueous sodium hydroxide solution 7L with 50% aqueous sodium hydroxide solution.Stirred 1 hour.Suction filtration, 50 ℃ of forced air dryings of solid get off-white color solid (±) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol 870g, yield 93% to constant weight.
(
1H-NMR(400MHz，DMSO)；δ(ppm)：δ3.47(s，2H)，δ3.04-2.99(dd，1H)，δ2.93-2.84(m，2H)，δ2.80-2.74(m，1H)，δ2.69-2.64(d，1H)，δ2.64-2.56(m，1H)，δ2.27-2.23(m，1H)，δ2.00-1.91(m，1H)，δ1.76(s，1H)，δ1.00-0.96(m，3H))
Embodiment 2
Add tetrahydrofuran (THF) 10L in the 20L there-necked flask successively, sodium borohydride 1.2kg stirred 1 hour.Add (-) 2-amino-6-propionamido-4,5,6 in the time of T=25 ℃, 7-tetrahydro benzothiazol 1kg stirred 4 hours, was heated to back flow reaction 48 hours.Naturally be cooled to 20 ℃～25 ℃.Reaction solution is slowly poured in the 8L frozen water, and temperature control T=10 ℃～20 drip 37% hydrochloric acid 6.4kg.Drip and finish PH=1.Suction filtration, water white transparency liquid, the decompression revolve except that tetrahydrofuran (THF) to constant weight.Revolve completely, transfer PH=14, consume aqueous sodium hydroxide solution 7L with 50% aqueous sodium hydroxide solution.Stirred 1 hour.Suction filtration, 50 ℃ of forced air dryings of solid get off-white color solid (-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol 870g, yield 93% to constant weight.
(
1H-NMR(400MHz，DMSO)；δ(ppm)：δ3.47(s，2H)，δ3.04-2.99(dd，1H)，δ2.93-2.84(m，2H)，δ2.80-2.74(m，1H)，δ2.69-2.64(d，1H)，δ2.64-2.56(m，1H)，δ2.27-2.23(m，1H)，δ2.00-1.91(m，1H)，δ1.76(s，1H)，δ1.00-0.96(m，3H))
Embodiment 3
Add tetrahydrofuran (THF) 10L in the 20L there-necked flask successively, Lithium Aluminium Hydride 1.2kg stirred 2 hours.Add (±) 2-amino-6-propionamido-4,5,6 in the time of T=28 ℃, 7-tetrahydro benzothiazol 1kg stirred 5 hours, was heated to back flow reaction 48 hours.Naturally be cooled to 20 ℃～25 ℃.Reaction solution is slowly poured in the 8L frozen water, and temperature control T=10 ℃～20 drip 37% hydrochloric acid 6.4kg.Drip and finish PH=1.Suction filtration, water white transparency liquid, the decompression revolve except that tetrahydrofuran (THF) to constant weight.Revolve completely, transfer PH=14, consume aqueous sodium hydroxide solution 7L with 50% aqueous sodium hydroxide solution.Stirred 1 hour.Suction filtration, 50 ℃ of forced air dryings of solid get off-white color solid (±) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol 870g, yield 93% to constant weight.
(
1H-NMR(400MHz，DMSO)；δ(ppm)：δ3.47(s，2H)，δ3.04-2.99(dd，1H)，δ2.93-2.84(m，2H)，δ2.80-2.74(m，1H)，δ2.69-2.64(d，1H)，δ2.64-2.56(m，1H)，δ2.27-2.23(m，1H)，δ2.00-1.91(m，1H)，δ1.76(s，1H)，δ1.00-0.96(m，3H))
Claims (6)
1. 2-amino-6-third amino-4,5,6, the preparation method of 7-tetrahydro benzothiazol is characterized in that with 2-amino-6-propionamido-4,5,6, the 7-tetrahydro benzothiazol obtains by reduction reaction in the presence of reductive agent.
2. method according to claim 1 is characterized in that described reductive agent is sodium borohydride or Lithium Aluminium Hydride.
3. method according to claim 1 is characterized in that described reductive agent is a sodium borohydride.
4. method according to claim 1 is characterized in that reduction reaction carries out in the backflow system of the tetrahydrofuran (THF) of sodium borohydride or Lithium Aluminium Hydride.
5. method according to claim 1 is characterized in that the reaction times is 12～48 hours.
6. method according to claim 1, it is characterized in that reacting segmentation carries out, earlier sodium borohydride or Lithium Aluminium Hydride are joined and reacted in the tetrahydrofuran (THF) system 1～2 hour, add 2-amino-6-propionamido-4 again, 5,6, the 7-tetrahydro benzothiazol, 10 ℃ 3～0 ℃ reactions 1～5 hour, be back to reaction and finish.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810222435A CN101676272A (en) | 2008-09-17 | 2008-09-17 | preparation method of pramipexole |
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| CN200810222435A CN101676272A (en) | 2008-09-17 | 2008-09-17 | preparation method of pramipexole |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103073519A (en) * | 2012-12-21 | 2013-05-01 | 北京万全德众医药生物技术有限公司 | Method for preparing dextro-pramipexole hydrochloride |
| CN103183650A (en) * | 2011-12-31 | 2013-07-03 | 天津药物研究院 | Preparation method of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole |
| CN103183649A (en) * | 2011-12-31 | 2013-07-03 | 天津药物研究院 | Preparation method of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole |
| CN103613562A (en) * | 2013-11-25 | 2014-03-05 | 浙江美诺华药物化学有限公司 | Preparation method of pramipexole |
| CN104031002A (en) * | 2014-06-09 | 2014-09-10 | 福建科瑞药业有限公司 | Process for synthesizing pramipexole |
| CN105753812A (en) * | 2016-03-28 | 2016-07-13 | 赤峰赛林泰药业有限公司 | Synthetic method for intermediate of pramipexoledihydrochloride |
| CN110950819A (en) * | 2018-09-27 | 2020-04-03 | 湖南九典制药股份有限公司 | Preparation method of pramipexole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060069263A1 (en) * | 2004-09-30 | 2006-03-30 | Irina Gribun | Process for the reduction of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzo-thiazole |
| WO2006097014A1 (en) * | 2005-03-15 | 2006-09-21 | Hubei Haoxin Pharmaceutical Co., Ltd | A process for preparing pramipexole |
| US20070191439A1 (en) * | 2004-03-19 | 2007-08-16 | Dipharma S.P.A. | Intermediates for the preparation of pramipexole |
-
2008
- 2008-09-17 CN CN200810222435A patent/CN101676272A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070191439A1 (en) * | 2004-03-19 | 2007-08-16 | Dipharma S.P.A. | Intermediates for the preparation of pramipexole |
| US20060069263A1 (en) * | 2004-09-30 | 2006-03-30 | Irina Gribun | Process for the reduction of (S)-2-amino-6-propionamido-4,5,6,7-tetrahydrobenzo-thiazole |
| WO2006097014A1 (en) * | 2005-03-15 | 2006-09-21 | Hubei Haoxin Pharmaceutical Co., Ltd | A process for preparing pramipexole |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103183650A (en) * | 2011-12-31 | 2013-07-03 | 天津药物研究院 | Preparation method of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole |
| CN103183649A (en) * | 2011-12-31 | 2013-07-03 | 天津药物研究院 | Preparation method of 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole |
| CN103073519A (en) * | 2012-12-21 | 2013-05-01 | 北京万全德众医药生物技术有限公司 | Method for preparing dextro-pramipexole hydrochloride |
| CN103613562A (en) * | 2013-11-25 | 2014-03-05 | 浙江美诺华药物化学有限公司 | Preparation method of pramipexole |
| CN103613562B (en) * | 2013-11-25 | 2015-09-30 | 浙江美诺华药物化学有限公司 | A kind of preparation method of pramipexole |
| CN104031002A (en) * | 2014-06-09 | 2014-09-10 | 福建科瑞药业有限公司 | Process for synthesizing pramipexole |
| CN104031002B (en) * | 2014-06-09 | 2016-06-22 | 福建科瑞药业有限公司 | A kind of synthesis technique of pramipexole |
| CN105753812A (en) * | 2016-03-28 | 2016-07-13 | 赤峰赛林泰药业有限公司 | Synthetic method for intermediate of pramipexoledihydrochloride |
| CN105753812B (en) * | 2016-03-28 | 2017-12-08 | 赤峰赛林泰药业有限公司 | The synthetic method of body of Pramipexole dihydrochloride intermediate |
| CN110950819A (en) * | 2018-09-27 | 2020-04-03 | 湖南九典制药股份有限公司 | Preparation method of pramipexole |
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Application publication date: 20100324 |