CN102442972B - Industrial preparation method for pramipexole and its dihydrochloride monohydrate - Google Patents
Industrial preparation method for pramipexole and its dihydrochloride monohydrate Download PDFInfo
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Abstract
The invention discloses an industrial preparation method for pramipexole. The method comprises the following steps: subjecting (-)2-amino-6-propionamido-4,5,6,7-tetrahydrobenzothiazole, NaBH4 and I2 to a reduction reaction in a solvent and treating an obtained reaction solution after the reaction so as to prepare (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole. The invention also discloses a method for synthesizing dihydrochloride monohydrate of pramipexole from the prepared pramipexole. According to the invention, raw materials are simple and easily available, reaction conditions are mild and are easy to control, and security of the reaction is high; the obtained product of pramipexole has molar yield of 93% to 98%, and the prepared dihydrochloride monohydrate of pramipexole has a decomposition point of 290 to 297 DEG C, a purity of more than 99.9% and molar yield of 87% to 93%.
Description
Technical field
The industrialized process for preparing that the present invention relates to a kind of pramipexole and dihydrochloride monohydrate thereof, belongs to technical field of medicine synthesis.
Background technology
Pramipexole is used to the Parkinson disease in early stage and late period as a kind of Dopamine HCL gaonist, for stimulating the Dopamine Receptors of brain.In actual applications, preferably pramipexole dihydrochloride monohydrate obtains compound as treatment Parkinson's disease.The chemical name of pramipexole dihydrochloride monohydrate is (S)-(-)-2-amino-6-(the third amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride monohydrate, wherein (S) represents that body of Pramipexole dihydrochloride is S configuration, and (-) represents that body of Pramipexole dihydrochloride is left-handed.Body of Pramipexole dihydrochloride can be used as medical material, and for preparing the Parkinsonian medicine for the treatment of, body of Pramipexole dihydrochloride must be S configuration, left-handed just have a medical effect.
At present, mainly contain about the synthetic method of pramipexole and dihydrochloride monohydrate thereof:
1, J.Med.Chem.1987,30,494-498 discloses a kind of preparation method of body of Pramipexole dihydrochloride, and the method is with (-) 2-amino-6-propionamido 4,5,6, and 7-tetrahydro benzothiazol is raw material, logical N in THF (tetrahydrofuran (THF))
2under protection, obtain (S)-(-)-2-amino-6-(the third amino)-4,5,6 with the borine solution reaction of THF, 7-tetrahydro benzothiazol, is then converted into dihydrochloride.This preparation method's particular content is, at room temperature logical N
2under protection, toward containing (-) 2-amino-6-propionamido-4, in the THF of 5,6,7-tetrahydro benzothiazol, dropwise add the borine solution of THF, then stirring reaction 1 hour cooling at 50 ℃, then add water and concentrated hydrochloric acid.Evaporate THF and add 25% sodium hydroxide solution in water, then filter and be precipitated ((S)-(-)-2-amino-6-(the third amino)-4,5,6,7-tetrahydro benzothiazol), the precipitation obtaining is washed and it is dissolved in hot ethyl acetate.Remove the moisture (Mg in solution
2sO
4) and concentrated, filtration is precipitated, washs the precipitation obtaining by ethyl acetate, convert it into for dihydrochloride and from methyl alcohol recrystallization obtain (S)-(-)-2-amino-6-(the third amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride.The shortcoming of the method is the borine solution manufacture method complexity of THF, is not suitable for industrial production, and due to the colourless severe toxicity of borine, inflammable, explosive, facile hydrolysis, poor stability, is difficult for preserving transportation, and therefore reaction safety is low.Concrete route is as follows:
2, Chinese patent CN1834092 improves aforesaid method, uses NaBH
4and BF
3generate at the scene borine, but boron trifluoride ether solution is met water decomposition, have the promoting the circulation of qi of stimulation taste, and ether height is inflammable, severe reaction conditions and very high to equipment requirements, also should not carry out suitability for industrialized production.Concrete route is as follows:
3, Chinese patent for CN101676272 sodium borohydride, lithium aluminium hydride reduce as reductive agent, condition comparatively relaxes, but need under reflux state, react, reaction times is very long, tetrahydrofuran (THF) boiling point as solvent is lower, to the organic component corrodibility severity except tetrafluoroethylene, easily cause run, drip, leak, there is the danger of blast in tetrahydrofuran (THF) under reflux state, therefore requires very high to equipment, factory building.And lithium aluminium hydride is expensive and all very sensitive to water and air, there is the danger of combustion explosion.So be difficult for equally carrying out suitability for industrialized production.Concrete route as shown in the formula:
4, Chinese patent CN 101585818A discloses a kind of preparation method of the intermediate for the preparation of body of Pramipexole dihydrochloride, and step is: in solvent, with 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol is at Zn(BH
4)
2under existence, carry out reduction reaction, then from reaction product, collect 2-amino-6-Propylamino-4,5,6,7-tetrahydro benzothiazol.The method need to be carried out under hot environment, low, inflammable and explosive as the tetrahydrofuran (THF) boiling point of solvent.Conversion unit is had to infringement, high to factory building and equipment requirements.And Zn(BH
4)
2preparation difficulty, is difficult for preserving.Be not suitable for equally industrialization.
Summary of the invention
The present invention is directed to above-mentioned deficiency, a kind of industrialized process for preparing of pramipexole is provided, the method raw material is easy to get, mild condition, safe, and left-handed, S configuration structure that products therefrom has, has medical effect.
The present invention also provides the industrialized process for preparing of a kind of pramipexole dihydrochloride monohydrate (two hydrochloric acid one water pramipexoles), and the method is take the above-mentioned pramipexole making as raw material, simple to operate, is easy to realize.
The present invention is achieved by the following measures:
The preparation method of pramipexole of the present invention, is characterized in that comprising the following steps: by (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4and I
2in solvent, carry out reduction reaction, post-reaction treatment reaction solution obtains the 2-amino-6-of (S)-(-) the third amino-4,5,6,7-tetrahydro benzothiazol.
Its reaction equation is as follows:
The present invention prepares pramipexole take sodium borohydride and iodine as reductive agent, can react at low temperatures, and mild condition, temperature is far below solvent boiling point, and reaction process safety, is beneficial to industrialized production.
In above-mentioned preparation method, (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol: NaBH
4: I
2mol ratio be 1: 1: 0.4～1: 5: 2, preferred mol ratio is 1: 2.5: 1～1: 3: 1.25.Can cause product purity not high because sodium borohydride has lacked, therefore in the time of reaction, will keep NaBH
4with I
2mol ratio be greater than 2:1.
In aforesaid method, reactant adds by following method: first by (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol and NaBH
4join in solvent, and then drip I
2tetrahydrofuran solution.Preferable case is that, in the adition process of three kinds of reactants, constantly stirring, is adding NaBH
4with (-) 2-amino-6-propionamido-4, in 5,6,7-tetrahydro benzothiazol process, temperature is envrionment temperature to reduce energy consumption, is adding I
2tetrahydrofuran solution time temperature be-30～10 ℃, preferably-5～0 ℃.Wherein, I
2tetrahydrofuran solution mass concentration be 30～40%, be preferably 30～35%.
In aforesaid method, add (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4and I
2after, be slowly warming up to 20～50 ℃ of reaction 4～12h, be preferably slowly warming up to 35～40 ℃ of reaction 6～10h.
In aforesaid method, solvent for use is tetrahydrofuran (THF), and the volume (L) of tetrahydrofuran (THF) is (-) 2-amino-6-propionamido-4, and the 5-10 of 5,6,7-tetrahydro benzothiazol weight (kg) doubly.
The described 2-amino-6-of (S)-(-) the third amino-4,5,6, the aftertreatment of 7-tetrahydro benzothiazol reaction solution can adopt known method, as first added hydrochloric acid soln, after remaining borine and sodium borohydride are decomposed, then tetrahydrofuran (THF) is reclaimed in evaporation, and then make the 2-amino-6-of (S)-(-) the third amino-4 by strong caustic, 5,6,7-tetrahydro benzothiazol is precipitated out, and isolates solid product, also washing, the dry solid product obtaining.Preferred post-treating method is: first reaction solution is cooled to 10 ℃ following (generally between 0-10 ℃), add again hydrochloric acid to make remaining borine and sodium borohydride decompose complete, then underpressure distillation recovery part solvent, remaining reaction solution adds sodium hydroxide solution alkalization, then reaction solution is cooled to below 10 ℃ (generally between 0-10 ℃), separate out a large amount of solids, separation after solid is separated out completely, washing, the dry 2-amino-6-of (S)-(-) the third amino-4 that to obtain, 5,6,7-tetrahydro benzothiazol.The volume (L) of described hydrochloric acid soln is NaBH
4weight (kg) 10-15 doubly, the concentration of described hydrochloric acid soln is 15-37wt%, adds after hydrochloric acid at 40 ℃ of reaction 30min.The concentration of described sodium hydroxide solution is 20-30wt%, add-on to reaction solution pH be 11-12.Described separation can adopt known method, as vacuum filtration, mechanical centrifugal; Described washing can adopt known method, and as drip washing, immersion, washings can be selected from one or more in water, ethanol, is preferably water; Described being dried can adopt known method and technology, as seasoning, heat drying, forced air drying, vacuum-drying etc.
The preparation method of pramipexole two hydrochloride monohydrates of the present invention, can adopt any method of the prior art by the 2-amino-6-of (S)-(-) the third amino-4, and 5,6,7-tetrahydro benzothiazol reacts with the HCl in concentrated hydrochloric acid.These many documents are had to description more, the description of such as Chinese patent CN1834092 etc.Reaction equation is as follows:
Contriver is in process of the test, what adopt is following method: by solid product obtained above (S)-(-) 2-amino-6-the third amino-4,5,6,7-tetrahydro benzothiazol is dissolved in solvent, adds concentrated hydrochloric acid solution to react and prepares pramipexole dihydrochloride monohydrate.
In aforesaid method, temperature of reaction is 5-15 ℃, and the stirring reaction time is 0.5-20h, and reacted reaction solution is isolated solid product, and washs, is dried the solid product obtaining.Described solvent is selected from one or more in liquid alcohol, liquid ketone, preferably has methyl alcohol, ethanol, propyl alcohol, butanols etc.The volumetric usage (L) of described solvent is the 2-amino-6-of (S)-(-) the third amino-4, and the 6-12 of 5,6,7-tetrahydro benzothiazol weight (kg) is (volume/weight) doubly.
In order to make the 2-amino-6-of (S)-(-) the third amino-4, 5, 6, 7-tetrahydro benzothiazol transforms into (S)-(-)-2-amino-6-(the third amino)-4, 5, 6, 7-tetrahydro benzothiazol dihydrochloride, (S)-(-) 2-amino-6-the third amino-4, 5, 6, the mol ratio of 7-tetrahydro benzothiazol and concentrated hydrochloric acid is at least 1: 2, the increase of concentrated hydrochloric acid consumption can improve the 2-amino-6-of (S)-(-) the third amino-4, 5, 6, the conversion rate of 7-tetrahydro benzothiazol, but, because contain water in concentrated hydrochloric acid, and two hydrochloric acid one water pramipexoles solubleness in water is larger, decline very serious so concentrated hydrochloric acid consumption mol ratio is greater than 2.6 rear yields, so select the 2-amino-6-of (S)-(-) the third amino-4, 5, 6, the mol ratio of the hydrogenchloride in 7-tetrahydro benzothiazol and concentrated hydrochloric acid is 1:2.01-1:2.6.
In aforesaid method, in order further to improve the purity of final product, can add gac to carry out removal of impurities the pramipexole of gained, gac be best at 50 ℃ of left and right impurity-eliminating effects.
In aforesaid method, separation can adopt known method, as vacuum filtration, mechanical centrifugal, press filtration etc.; Described washing can adopt known method, as drip washing, immersion, washs solution used and can be selected from one or more in water, methyl alcohol, ethanol and Virahol, is preferably 95% ethanol; Described being dried can adopt known method and technology, as seasoning, heat drying, forced air drying, vacuum-drying, infrared drying etc.
The present invention is with (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol is raw material, makes pramipexole using sodium borohydride and iodine as reductive agent by reduction, then makes its dihydrochloride monohydrate by pramipexole salify, preparation method's of the present invention raw material simply and easily obtains, reaction conditions gentleness, is easy to control, and reaction safety is high.The molar yield of gained pramipexole product is 93-98%, and the decomposition point of gained pramipexole dihydrochloride monohydrate is 290-297 ℃, and purity is more than 99.9%, and ee value is 100%, and molar yield is 87-93%.
Embodiment
To describe in more detail the present invention by embodiment below, following explanation is only in order to explain the present invention, its content is not limited.Reaction raw materials of the present invention all can have been bought on market, wherein (-) 2-amino-6-propionamido-4, and 5,6,7-tetrahydro benzothiazol comes can be by purchase commercially available prod or according to J.Med.Chem.1987, the method preparation that 30,494-498 provides.
embodiment 1
(1) (S)-(-) 2-amino-6-the third amino-4, the preparation of 5,6,7-tetrahydro benzothiazol
By (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol (227.33g, 1mol) joins in tetrahydrofuran (THF) (1362ml), stirs and makes its dissolving, then add fast sodium borohydride (94.68g, 2.5mol) stir, be then cooled to-5 ℃, then at-5～0 ℃, slowly drip I
2(253.8g, 1mol) and tetrahydrofuran (THF) 725ml(I
2mass concentration be 35%) solution, drip and finish, slowly be warming up to 35 ℃, insulation reaction 8h, then be cooled to below 10 ℃, first drip tap water 45ml, avoid reaction too fierce, then drip massfraction and be 37% hydrochloric acid 946.8ml and be then slowly warming up to 40 ℃, keep 30min, then reclaim tetrahydrofuran (THF) by the method for underpressure distillation, after recovery, surplus solution regulates pH=12 with 30% sodium hydroxide solution, separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use Büchner funnel suction filtration, water 600ml washing 2 times, white solid (S)-(-) 2-amino-6-the third amino-4 are dried to obtain in 40 ℃ of air blast, 5, 6, 7-tetrahydro benzothiazol (198.64g, molar yield 94%).
The preparation of (2) two hydrochloric acid one water pramipexoles
By the 2-amino-6-of (S)-(-) the third amino-4 that obtain in (1), 5,6,7-tetrahydro benzothiazol (198.64g, 0.94mol) be dissolved in 1390ml dehydrated alcohol, add needle-use activated carbon 42g, be warming up to 50 ℃, stir 30min, filter, filtrate is cooled to below 10 ℃, and keeps the 10 ℃ of following concentrated hydrochloric acid 198ml that massfraction is 37%, stirring 10h of dripping, suction filtration, 95% ethanol 200ml washing 2 times for filter cake, 40 ℃ of vacuum-dryings obtain product two hydrochloric acid one water pramipexoles (256.48g, molar yield 90.27%).
embodiment 2
(1) (S)-(-) 2-amino-6-the third amino-4, the preparation of 5,6,7-tetrahydro benzothiazol
By (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol (227.33g, 1mol) joins in tetrahydrofuran (THF) (2270ml), stirs and makes its dissolving, then add fast sodium borohydride (37.83g, 1mol) stir, be then cooled to-30 ℃, then at-30～-5 ℃, slowly drip I
2(101.52g, 0.40mol) and tetrahydrofuran (THF) 253.8ml(I
2mass concentration be 40%) solution, drip and finish, slowly be warming up to 40 ℃, insulation reaction 6h, then be cooled to below 10 ℃, first drip water 18ml, avoid reaction too fierce, then drip massfraction and be 37% hydrochloric acid 454ml and be then slowly warming up to 40 ℃, keep 30min, then reclaim tetrahydrofuran (THF) by the method for underpressure distillation, after recovery, surplus solution regulates pH=12 with 30% sodium hydroxide solution, separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use Büchner funnel suction filtration, water 600ml washing 2 times, white solid (S)-(-) 2-amino-6-the third amino-4 are dried to obtain in 40 ℃ of air blast, 5, 6, 7-tetrahydro benzothiazol (197.64g, molar yield 93.52%).
The preparation of (2) two hydrochloric acid one water pramipexoles
By the 2-amino-6-of (S)-(-) the third amino-4 that obtain in (1), 5,6,7-tetrahydro benzothiazol (197.64g) is dissolved in 1380ml dehydrated alcohol, add gac 40g, be warming up to 50 ℃, stir 30min, filter, filtrate is cooled to below 10 ℃, and keep 10 ℃ to drip below the concentrated hydrochloric acid 200ml that massfractions are 37%, stir 10h, suction filtration, 95% ethanol 200ml washing 2 times for filter cake, 40 ℃ of vacuum-dryings obtain product two hydrochloric acid one water pramipexoles (250.28g, molar yield 88.54%).
embodiment 3
(1) (S)-(-) 2-amino-6-the third amino-4, the preparation of 5,6,7-tetrahydro benzothiazol
By (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol (227.33g, 1mol) joins in tetrahydrofuran (THF) (1362ml), stirs and makes its dissolving, then add fast sodium borohydride (94.68g, 2.5mol) stir, be then cooled to-30 ℃, then at-30～-20 ℃, slowly drip I
2(253.8g, 1mol) and tetrahydrofuran (THF) 725ml(I
2mass concentration be 35%) solution, drip and finish, slowly be warming up to 35 ℃, insulation reaction 8h, then be cooled to below 10 ℃, first drip water 45ml, avoid reaction too fierce, then drip massfraction and be 37% hydrochloric acid 946.8ml and be then slowly warming up to 40 ℃, keep 30min, then reclaim tetrahydrofuran (THF) by the method for underpressure distillation, after recovery, surplus solution regulates pH=12 with 30% sodium hydroxide solution, separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use Büchner funnel suction filtration, water 600ml washing 2 times, white solid (S)-(-) 2-amino-6-the third amino-4 are dried to obtain in 40 ℃ of air blast, 5, 6, 7-tetrahydro benzothiazol (206.41g, molar yield 97.67%).
The preparation of (2) two hydrochloric acid one water pramipexoles
By the 2-amino-6-of (S)-(-) the third amino-4 that obtain in (1), 5,6,7-tetrahydro benzothiazol (206.41g, 0.9767mol) be dissolved in 1340ml dehydrated alcohol, add gac 35g, be warming up to 50 ℃, stir 30min, filter, filtrate is cooled to below 5 ℃, and keeps the 5 ℃ of following concentrated hydrochloric acid 165ml that massfraction is 37%, stirring 10h of dripping, suction filtration, 95% ethanol 200ml washing 2 times for filter cake, 40 ℃ of vacuum-dryings obtain product two hydrochloric acid one water pramipexoles (295.22g, molar yield 92.51%).
embodiment 4
(1) (S)-(-) 2-amino-6-the third amino-4, the preparation of 5,6,7-tetrahydro benzothiazol
By (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol 1mol joins in tetrahydrofuran (THF) (1800ml), stirring makes its dissolving, then add fast sodium borohydride 5mol to stir, be then cooled to-10 ℃, then at-10～10 ℃, slowly drip the I that mass concentration is 30%
2tetrahydrofuran solution (I
2content 2mol), drip and finish, slowly be warming up to 50 ℃, insulation reaction 4h, then be cooled to below 10 ℃, first drip water 45ml, avoid reaction too fierce, then drip massfraction and be 37% hydrochloric acid 1906.8ml and be then slowly warming up to 40 ℃, keep 30min, then reclaim tetrahydrofuran (THF) by the method for underpressure distillation, after recovery, surplus solution regulates pH=11 with 20% sodium hydroxide solution, separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use Büchner funnel suction filtration, water 600ml washing 2 times, white solid (S)-(-) 2-amino-6-the third amino-4 are dried to obtain in 40 ℃ of air blast, 5, 6, 7-tetrahydro benzothiazol (molar yield 93.25%).
The preparation of (2) two hydrochloric acid one water pramipexoles
By the 2-amino-6-of (S)-(-) the third amino-4 that obtain in (1), 5,6,7-tetrahydro benzothiazol is dissolved in the anhydrous butanols of 1400ml, add gac 35g, be warming up to 50 ℃, stir 30min, filter, filtrate is cooled to below 5 ℃, and keep 5 ℃ following be 37% concentrated hydrochloric acid by adding massfraction with the mol ratio of the pramipexole minim that is 2.6:1, stir 0.5h, suction filtration, 95% ethanol 200ml washing 2 times for filter cake, 40 ℃ of vacuum-dryings obtain product two hydrochloric acid one water pramipexoles (295.22g, molar yield 92.67%).
embodiment 5
(1) (S)-(-) 2-amino-6-the third amino-4, the preparation of 5,6,7-tetrahydro benzothiazol
By (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol 1mol joins in tetrahydrofuran (THF) (1400ml), stirring makes its dissolving, then add fast sodium borohydride 3mol to stir, be then cooled to-5 ℃, then at-5～0 ℃, slowly drip the I that mass concentration is 40%
2tetrahydrofuran solution (I
2content 1.25mol), drip and finish, slowly be warming up to 20 ℃, insulation reaction 12h, then be cooled to below 10 ℃, first drip water 45ml, avoid reaction too fierce, then drip massfraction and be 15% hydrochloric acid 1700ml and be then slowly warming up to 40 ℃, keep 30min, then reclaim tetrahydrofuran (THF) by the method for underpressure distillation, after recovery, surplus solution regulates pH=12 with 20% sodium hydroxide solution, separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use Büchner funnel suction filtration, water 600ml washing 2 times, white solid (S)-(-) 2-amino-6-the third amino-4 are dried to obtain in 40 ℃ of air blast, 5, 6, 7-tetrahydro benzothiazol (molar yield 96.16%).
The preparation of (2) two hydrochloric acid one water pramipexoles
By the 2-amino-6-of (S)-(-) the third amino-4 that obtain in (1), 5,6,7-tetrahydro benzothiazol is dissolved in the anhydrous butanols of 2200ml, add gac 35g, be warming up to 50 ℃, stir 30min, filter, filtrate is cooled to below 15 ℃, and keep 15 ℃ following be 37% concentrated hydrochloric acid by adding massfraction with the mol ratio of the pramipexole minim that is 2.1:1, stir 20h, suction filtration, 95% ethanol 200ml washing 2 times for filter cake, 40 ℃ of vacuum-dryings obtain product two hydrochloric acid one water pramipexoles (molar yield 89.97%).
Claims (1)
1. the preparation method of a pramipexole, it is characterized in that comprising the following steps: by 1mol (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol joins in 1362ml tetrahydrofuran (THF), stirs it is dissolved, and then adds fast 2.5mol sodium borohydride to stir, then be cooled to-30 ℃, then at-30～-20 ℃, slowly drip 1mol I
2solution with 725ml tetrahydrofuran (THF), drip and finish, slowly be warming up to 35 ℃, insulation reaction 8h, then be cooled to below 10 ℃, first drip water 45ml, avoid reaction too fierce, then drip massfraction and be 37% hydrochloric acid 946.8ml and be then slowly warming up to 40 ℃, keep 30min, then reclaim tetrahydrofuran (THF) by the method for underpressure distillation, after recovery, surplus solution regulates pH=12 with 30% sodium hydroxide solution, separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use Büchner funnel suction filtration, water 600ml washing 2 times, white solid (S)-(-) 2-amino-6-the third amino-4 are dried to obtain in 40 ℃ of air blast, 5, 6, 7-tetrahydro benzothiazol.
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| 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 |
| CN104177309A (en) * | 2013-05-23 | 2014-12-03 | 北京凯瑞科德药物技术研究有限公司 | Preparation process for 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 |
| CN104230846B (en) * | 2014-09-05 | 2016-06-08 | 杭州华东医药集团新药研究院有限公司 | A kind of method preparing pramipexole 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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