CN102442972A - 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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- CN102442972A CN102442972A CN2011103151349A CN201110315134A CN102442972A CN 102442972 A CN102442972 A CN 102442972A CN 2011103151349 A CN2011103151349 A CN 2011103151349A CN 201110315134 A CN201110315134 A CN 201110315134A CN 102442972 A CN102442972 A CN 102442972A
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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 present invention relates to the industrialized process for preparing of a kind of pramipexole and dihydrochloride monohydrate thereof, belong to technical field of medicine synthesis.
Background technology
Pramipexole is used in early days and the Parkinson disease in late period as a kind of Dopamine HCL gaonist, is used for stimulating the Dopamine Receptors of brain.In practical application, preferred pramipexole dihydrochloride monohydrate gets compound as the treatment Parkinson's disease.The chemical name of pramipexole dihydrochloride monohydrate is (S)-(-)-2-amino-6-(third amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride monohydrate, and wherein (S) expression SND-919 is the S configuration, (-) expression SND-919 is left-handed.SND-919 can be used as medical material, is used for the Parkinsonian medicine of preparation treatment, and SND-919 must be the S configuration, left-handed just have a medical effect.
At present, the compound method about pramipexole and dihydrochloride monohydrate thereof mainly contains:
1, J.Med.Chem.1987,30,494-498 discloses a kind of preparation method of SND-919, and this method is with (-) 2-amino-6-propionamido 4,5,6, and the 7-tetrahydro benzothiazol is a raw material, logical N in THF (THF)
2Protection obtains (S)-(-)-2-amino-6-(third amino)-4,5,6 with the borine solution reaction of THF down, and the 7-tetrahydro benzothiazol is converted into dihydrochloride then.This preparing method's particular content does, at room temperature and logical N
2Protection toward containing (-) 2-amino-6-propionamido-4,5,6, dropwise adds the borine solution of THF down among the THF of 7-tetrahydro benzothiazol, in 50 ℃ of following stirring reactions 1 hour and cooling, add entry and concentrated hydrochloric acid more then.Evaporate THF and add 25% sodium hydroxide solution toward aqueous phase, filter then and obtain deposition ((S)-(-)-2-amino-6-(third amino)-4,5,6,7-tetrahydro benzothiazol), the deposition that obtains is washed and it is dissolved in the ETHYLE ACETATE of heat.Remove the moisture (Mg in the solution
2SO
4) and concentrate, filter precipitated, with the deposition that the ETHYLE ACETATE washing obtains, convert it into for dihydrochloride and from methyl alcohol recrystallization obtain (S)-(-)-2-amino-6-(third amino)-4,5,6,7-tetrahydro benzothiazol dihydrochloride.The shortcoming of this method is that the borine solution method of manufacture of THF is complicated, is not suitable for industrial production, and because the colourless severe toxicity of borine is inflammable, explosive, facile hydrolysis, poor stability be difficult for preserving transportation, so reaction safety is low.Concrete route is following:
2, Chinese patent CN1834092 improves aforesaid method, uses NaBH
4And BF
3Generate borine at the scene, but boron trifluoride ether solution is met water decomposition, the promoting the circulation of qi of stimulation flavor is arranged, and the ether height is inflammable, severe reaction conditions and very high to equipment requirements also should not be carried out suitability for industrialized production.Concrete route is following:
3, Chinese patent CN101676272 reduces as reductive agent with Peng Qinghuana, lithium aluminium hydride; Condition comparatively relaxes, but need under reflux state, react, and the reaction times is very long; THF boiling point as solvent is lower, severe to the organic component corrodibility except that tetrafluoroethylene; Cause run, drip, leak easily, there is the danger of blast in THF under reflux state, therefore requires very high to equipment, factory building.And lithium aluminium hydride costs an arm and a leg and all very sensitive to water and air, has the danger of combustion explosion.So be difficult for carrying out suitability for industrialized production equally.Concrete route as shown in the formula:
4, Chinese patent CN 101585818A discloses a kind of preparation method who is used to prepare intermediate body of pramipexole dihydrochloride, and step is: in solvent, with 2-amino-6-propionamido-4,5,6, the 7-tetrahydro benzothiazol is at Zn (BH
4)
2Exist down, carry out reduction reaction, from reaction product, collect 2-amino-6-Propylamino-4,5,6,7-tetrahydro benzothiazol then.This method need be carried out under hot environment, and is low, inflammable and explosive as the THF boiling point of solvent.Conversion unit there is infringement, high to factory building and equipment requirements.And Zn (BH
4)
2The preparation difficulty is difficult for preserving.Be not suitable for industriallization equally.
Summary of the invention
The present invention is directed to above-mentioned deficiency, a kind of industrialized process for preparing of pramipexole is provided, this 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 pramipexole), and this method is raw material with the above-mentioned pramipexole that makes, and is simple to operate, is easy to realize.
The present invention realizes through following measure:
The preparation method of pramipexole of the present invention is characterized in that may further comprise the steps: with (-) 2-amino-6-propionamido-4,5,6, and 7-tetrahydro benzothiazol, NaBH
4And I
2In solvent, carry out reduction reaction, the post-reaction treatment reaction solution gets the 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol.
Its reaction equation is following:
The present invention is that reductive agent prepares pramipexole with Peng Qinghuana and iodine, can react at low temperatures, and mild condition, temperature are far below solvent boiling point, and reaction process safety is beneficial to industrialized production.
Among the 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 Peng Qinghuana has lacked, therefore when reaction, will keep NaBH
4With I
2Mol ratio greater than 2:1.
In the aforesaid method, reactant adds by following method: earlier with (-) 2-amino-6-propionamido-4,5,6, and 7-tetrahydro benzothiazol and NaBH
4Join in the solvent, and then drip I
2Tetrahydrofuran solution.Preferable case is in the adition process of three kinds of reactants, constantly to stir, at adding NaBH
4With (-) 2-amino-6-propionamido-4,5,6, temperature is that envrionment temperature is to cut down the consumption of energy, at adding I in the 7-tetrahydro benzothiazol process
2Tetrahydrofuran solution the time temperature be-30～10 ℃, preferred-5～0 ℃.Wherein, I
2The tetrahydrofuran solution mass concentration be 30～40%, be preferably 30～35%.
In the aforesaid method, add (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4And I
2After, slowly be warming up to 20～50 ℃ of reaction 4～12h, preferably slowly be warming up to 35～40 ℃ of reaction 6～10h.
In the aforesaid method, solvent for use is a THF, and the volume of THF (L) is (-) 2-amino-6-propionamido-4,5,6, and the 5-10 of 7-tetrahydro benzothiazol weight (kg) doubly.
The said 2-amino-6-of (S)-(-) third amino-4,5,6; The aftertreatment of 7-tetrahydro benzothiazol reaction solution can be adopted known method, as adding earlier hydrochloric acid soln, after making remaining borine decomposition finishing with Peng Qinghuana; THF is reclaimed in evaporation then, and then makes the 2-amino-6-of (S)-(-) third amino-4,5 with strong caustic; 6, the 7-tetrahydro benzothiazol is precipitated out, the solid product that isolate solid product, also wash, drying obtains.Preferred post-treating method is: earlier reaction solution is cooled to (generally between 0-10 ℃) below 10 ℃, adds hydrochloric acid again and make remaining borine and Peng Qinghuana decomposition finish the solvent of underpressure distillation recovery part then; Remaining reaction solution adds the sodium hydroxide solution alkalization, and reaction solution is cooled to below 10 ℃ (generally between 0-10 ℃) then, separates out a large amount of solids; Solid is separated out complete back separation, washing, the dry 2-amino-6-of (S)-(-) third amino-4 that gets; 5,6, the 7-tetrahydro benzothiazol.The volume of said hydrochloric acid soln (L) is NaBH
4Weight (kg) 10-15 doubly, the concentration of said hydrochloric acid soln is 15-37wt%, adds behind the hydrochloric acid at 40 ℃ of reaction 30min.The concentration of said sodium hydroxide solution is 20-30wt%, add-on to reaction solution pH be 11-12.Said separation can be adopted known method, like vacuum filtration, mechanical centrifugal; Said washing can be adopted known method, and like drip washing, immersion, washings can select one or more in tap water, the ethanol, is preferably water; Said drying can adopt known method and technology, like seasoning, heat drying, forced air drying, vacuum-drying etc.
The preparation method of pramipexole two hydrochloric acid monohydrates of the present invention can adopt any method of the prior art with the 2-amino-6-of (S)-(-) third amino-4,5,6, the HCl reaction in 7-tetrahydro benzothiazol and the concentrated hydrochloric acid.These many documents there is description more, for example the description of Chinese patent CN1834092 etc.Reaction equation is following:
The contriver is in process of the test; What adopt is following method: with the above-mentioned solid product that obtains (S)-(-) 2-amino-6-third amino-4,5,6; The 7-tetrahydro benzothiazol is dissolved in the solvent, adds concentrated hydrochloric acid solution and carries out prepared in reaction pramipexole dihydrochloride monohydrate.
In the 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 the solid product that obtains of washing, drying.Said solvent is selected from one or more in liquid alcohol, the liquid ketone, and methyl alcohol, ethanol, propyl alcohol, butanols etc. are preferably arranged.The volumetric usage of said solvent (L) is the 2-amino-6-of (S)-(-) third amino-4,5,6, and the 6-12 of 7-tetrahydro benzothiazol weight (kg) is (volume/weight) doubly.
In order to make the 2-amino-6-of (S)-(-) third amino-4,5,6, the 7-tetrahydro benzothiazol transforms into (S)-(-)-2-amino-6-(third amino)-4; 5,6,7-tetrahydro benzothiazol dihydrochloride, (S)-(-) 2-amino-6-third amino-4; 5,6, the mol ratio of 7-tetrahydro benzothiazol and concentrated hydrochloric acid was at least 1: 2, and the increase of concentrated hydrochloric acid consumption can improve the 2-amino-6-of (S)-(-) third amino-4; 5,6, the conversion rate of 7-tetrahydro benzothiazol, still; Because contain water in the concentrated hydrochloric acid, and two hydrochloric acid, one water pramipexole solubleness in water is bigger, so concentrated hydrochloric acid consumption mol ratio is very serious greater than 2.6 back yields declines, so select the 2-amino-6-of (S)-(-) third amino-4; 5,6, the mol ratio of the hydrogenchloride in 7-tetrahydro benzothiazol and the concentrated hydrochloric acid is 1:2.01-1:2.6.
In the aforesaid method, in order further to improve the purity of final product, can the pramipexole of gained be added gac and carry out removal of impurities, gac is best at 50 ℃ of left and right sides impurity-eliminating effects.
In the aforesaid method, separation can be adopted known method, like vacuum filtration, centrifugal, the press filtration of machinery etc.; Said washing can be adopted known method, and like drip washing, immersion, the washing solutions employed can be selected from one or more in water, methyl alcohol, ethanol and the Virahol, is preferably 95% ethanol; Said drying can adopt known method and technology, like seasoning, heat drying, forced air drying, vacuum-drying, infrared drying etc.
The present invention is with (-) 2-amino-6-propionamido-4,5,6; The 7-tetrahydro benzothiazol is a raw material, makes pramipexole as reductive agent through reduction with Peng Qinghuana and iodine, makes its dihydrochloride monohydrate by the pramipexole salify again; Preparing method's of the present invention raw material simply and easily obtains; Reaction conditions is gentle, 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 the ee value is 100%, and molar yield is 87-93%.
Embodiment
To describe the present invention in more detail by embodiment below, following explanation only is in order to explain the present invention, its content not to be limited.Reaction raw materials of the present invention all can have been bought on market, and (-) 2-amino-6-propionamido-4,5,6 wherein, 7-tetrahydro benzothiazol come can be through buying the commercially available prod or according to J.Med.Chem.1987, and 30, the method preparation that 494-498 provides.
Embodiment 1
(1) (S)-(-) 2-amino-6-third amino-4,5,6, the preparation of 7-tetrahydro benzothiazol
With (-) 2-amino-6-propionamido-4,5,6; (227.33g 1mol) joins in the THF (1362ml) the 7-tetrahydro benzothiazol, stirs to make its dissolving; Add Peng Qinghuana (94.68g then fast; 2.5mol) stir, be cooled to-5 ℃ then, slowly drip I down at-5～0 ℃ then
2(253.8g is 1mol) with THF 725ml (I
2Mass concentration be 35%) solution, drip to finish, slowly be warming up to 35 ℃, insulation reaction 8h; Be cooled to then below 10 ℃, drip earlier tap water 45ml, avoid reaction too fierce, drip massfraction then and be 37% hydrochloric acid 946.8ml and slowly be warming up to 40 ℃ then; Keep 30min, the method with underpressure distillation reclaims THF then, and after recovery finished, surplus solution was regulated pH=12 with 30% sodium hydroxide solution; Separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use the B suction filtration; Water 600ml washing 2 times, 40 ℃ of air blast dry white solid (S)-(-) 2-amino-6-third amino-4,5; 6,7-tetrahydro benzothiazol (198.64g, molar yield 94%).
The preparation of (2) two hydrochloric acid one water pramipexole
With the 2-amino-6-of (S)-(-) third amino-4,5,6 that obtains in (1), 7-tetrahydro benzothiazol (198.64g; 0.94mol) be dissolved in the 1390ml absolute ethyl alcohol, add needle-use activated carbon 42g, be warming up to 50 ℃; Stir 30min, filter, filtrating is cooled to below 10 ℃; And to keep below 10 ℃ dripping massfraction be 37% concentrated hydrochloric acid 198ml, stirs 10h, suction filtration; Filter cake is with 95% ethanol 200ml washing 2 times, and 40 ℃ of vacuum-dryings get product two hydrochloric acid one water pramipexoles (256.48g, molar yield 90.27%).
Embodiment 2
(1) (S)-(-) 2-amino-6-third amino-4,5,6, the preparation of 7-tetrahydro benzothiazol
With (-) 2-amino-6-propionamido-4,5,6; (227.33g 1mol) joins in the THF (2270ml) the 7-tetrahydro benzothiazol, stirs to make its dissolving; Add Peng Qinghuana (37.83g then fast; 1mol) stir, be cooled to-30 ℃ then, slowly drip I down at-30～-5 ℃ then
2(101.52g is 0.40mol) with THF 253.8ml (I
2Mass concentration be 40%) solution, drip to finish, slowly be warming up to 40 ℃, insulation reaction 6h; Be cooled to then below 10 ℃, drip earlier water 18ml, avoid reaction too fierce, drip massfraction then and be 37% hydrochloric acid 454ml and slowly be warming up to 40 ℃ then; Keep 30min, the method with underpressure distillation reclaims THF then, and after recovery finished, surplus solution was regulated pH=12 with 30% sodium hydroxide solution; Separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use the B suction filtration; Water 600ml washing 2 times, 40 ℃ of air blast dry white solid (S)-(-) 2-amino-6-third amino-4,5; 6,7-tetrahydro benzothiazol (197.64g, molar yield 93.52%).
The preparation of (2) two hydrochloric acid one water pramipexole
With the 2-amino-6-of (S)-(-) third amino-4,5,6 that obtains in (1), 7-tetrahydro benzothiazol (197.64g) is dissolved in the 1380ml absolute ethyl alcohol; Add gac 40g, be warming up to 50 ℃, stir 30min, filter; Filtrating is cooled to below 10 ℃, and to keep below 10 ℃ dripping massfraction be 37% concentrated hydrochloric acid 200ml, stirs 10h, suction filtration; Filter cake is with 95% ethanol 200ml washing 2 times, and 40 ℃ of vacuum-dryings get product two hydrochloric acid one water pramipexoles (250.28g, molar yield 88.54%).
Embodiment 3
(1) (S)-(-) 2-amino-6-third amino-4,5,6, the preparation of 7-tetrahydro benzothiazol
With (-) 2-amino-6-propionamido-4,5,6; (227.33g 1mol) joins in the THF (1362ml) the 7-tetrahydro benzothiazol, stirs to make its dissolving; Add Peng Qinghuana (94.68g then fast; 2.5mol) stir, be cooled to-30 ℃ then, slowly drip I down at-30～-20 ℃ then
2(253.8g is 1mol) with THF 725ml (I
2Mass concentration be 35%) solution, drip to finish, slowly be warming up to 35 ℃, insulation reaction 8h; Be cooled to then below 10 ℃, drip earlier water 45ml, avoid reaction too fierce, drip massfraction then and be 37% hydrochloric acid 946.8ml and slowly be warming up to 40 ℃ then; Keep 30min, the method with underpressure distillation reclaims THF then, and after recovery finished, surplus solution was regulated pH=12 with 30% sodium hydroxide solution; Separate out a large amount of solids, be cooled to below 10 ℃, stir 30min, use the B suction filtration; Water 600ml washing 2 times, 40 ℃ of air blast dry white solid (S)-(-) 2-amino-6-third amino-4,5; 6,7-tetrahydro benzothiazol (206.41g, molar yield 97.67%).
The preparation of (2) two hydrochloric acid one water pramipexole
With the 2-amino-6-of (S)-(-) third amino-4,5,6 that obtains in (1), 7-tetrahydro benzothiazol (206.41g; 0.9767mol) be dissolved in the 1340ml absolute ethyl alcohol, add gac 35g, be warming up to 50 ℃; Stir 30min, filter, filtrating is cooled to below 5 ℃; And to keep below 5 ℃ dripping massfraction be 37% concentrated hydrochloric acid 165ml, stirs 10h, suction filtration; Filter cake is with 95% ethanol 200ml washing 2 times, and 40 ℃ of vacuum-dryings get product two hydrochloric acid one water pramipexoles (295.22g, molar yield 92.51%).
Embodiment 4
(1) (S)-(-) 2-amino-6-third amino-4,5,6, the preparation of 7-tetrahydro benzothiazol
With (-) 2-amino-6-propionamido-4,5,6; 7-tetrahydro benzothiazol 1mol joins in the THF (1800ml), stirs and makes its dissolving, adds Peng Qinghuana 5mol then fast and stirs; Being cooled to-10 ℃ then, is 30% I then-10～10 ℃ of slow down dropping mass concentrations
2Tetrahydrofuran solution (I
2Content 2mol), drip and finish, slowly be warming up to 50 ℃, insulation reaction 4h is cooled to below 10 ℃ then; Drip earlier water 45ml, avoid reaction too fierce, drip massfraction then and be 37% hydrochloric acid 1906.8ml and slowly be warming up to 40 ℃ then, keep 30min; Method with underpressure distillation reclaims THF then, and after recovery finished, surplus solution was regulated pH=11 with 20% sodium hydroxide solution, separates out a large amount of solids; Be cooled to below 10 ℃, stir 30min, use the B suction filtration, water 600ml washing 2 times; 40 ℃ of air blast dry white solid (S)-(-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol (molar yield 93.25%).
The preparation of (2) two hydrochloric acid one water pramipexole
With the 2-amino-6-of (S)-(-) third amino-4,5 that obtains in (1), 6; The 7-tetrahydro benzothiazol is dissolved in the anhydrous butanols of 1400ml, adds gac 35g, is warming up to 50 ℃; Stir 30min, filter, filtrating is cooled to below 5 ℃; And keep below 5 ℃ by the mol ratio with pramipexole be the minim of 2.6:1 to add massfraction be 37% concentrated hydrochloric acid, stir 0.5h, suction filtration; Filter cake is with 95% ethanol 200ml washing 2 times, and 40 ℃ of vacuum-dryings get product two hydrochloric acid one water pramipexoles (295.22g, molar yield 92.67%).
Embodiment 5
(1) (S)-(-) 2-amino-6-third amino-4,5,6, the preparation of 7-tetrahydro benzothiazol
With (-) 2-amino-6-propionamido-4,5,6; 7-tetrahydro benzothiazol 1mol joins in the THF (1400ml), stirs and makes its dissolving, adds Peng Qinghuana 3mol then fast and stirs; Being cooled to-5 ℃ then, is 40% I then-5～0 ℃ of slow down dropping mass concentration
2Tetrahydrofuran solution (I
2Content 1.25mol), drip and finish, slowly be warming up to 20 ℃, insulation reaction 12h is cooled to below 10 ℃ then; Drip earlier water 45ml, avoid reaction too fierce, drip massfraction then and be 15% hydrochloric acid 1700ml and slowly be warming up to 40 ℃ then, keep 30min; Method with underpressure distillation reclaims THF then, and after recovery finished, surplus solution was regulated pH=12 with 20% sodium hydroxide solution, separates out a large amount of solids; Be cooled to below 10 ℃, stir 30min, use the B suction filtration, water 600ml washing 2 times; 40 ℃ of air blast dry white solid (S)-(-) 2-amino-6-third amino-4,5,6,7-tetrahydro benzothiazol (molar yield 96.16%).
The preparation of (2) two hydrochloric acid one water pramipexole
With the 2-amino-6-of (S)-(-) third amino-4,5 that obtains in (1), 6; The 7-tetrahydro benzothiazol is dissolved in the anhydrous butanols of 2200ml, adds gac 35g, is warming up to 50 ℃; Stir 30min, filter, filtrating is cooled to below 15 ℃; And keep below 15 ℃ by the mol ratio with pramipexole be the minim of 2.1:1 to add massfraction be 37% concentrated hydrochloric acid, stir 20h, suction filtration; Filter cake is with 95% ethanol 200ml washing 2 times, and 40 ℃ of vacuum-dryings get product two hydrochloric acid, one water pramipexoles (molar yield 89.97%).
Claims (10)
1. the preparation method of a pramipexole is characterized in that may further comprise the steps: with (-) 2-amino-6-propionamido-4,5,6, and 7-tetrahydro benzothiazol, NaBH
4And I
2In solvent, carry out reduction reaction, the post-reaction treatment reaction solution gets the 2-amino-6-of (S)-(-) third amino-4,5,6,7-tetrahydro benzothiazol.
2. preparation method according to claim 1 is characterized in that: (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4And I
2Temperature of reaction be 20～50 ℃, the reaction times is 4～12 hours; (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol: NaBH
4: I
2Mol ratio be 1: 1: 0.4～1: 5: 2, NaBH wherein
4With I
2Mol ratio greater than 2:1.
3. preparation method according to claim 2 is characterized in that: (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol, NaBH
4And I
2Temperature of reaction be 35-40 ℃, the reaction times is 6-10 hour; (-) 2-amino-6-propionamido-4,5,6,7-tetrahydro benzothiazol: NaBH
4: I
2Mol ratio be 1: 2.5: 1～1: 3: 1.25, NaBH wherein
4With I
2Mol ratio greater than 2:1.
4. preparation method according to claim 1 is characterized in that, reactant adds by following method: earlier with (-) 2-amino-6-propionamido-4,5,6, and 7-tetrahydro benzothiazol and NaBH
4Join in the solvent, and then drip I down at-30～10 ℃
2Tetrahydrofuran solution, I
2Concentration in THF is 30-40wt%.
5. preparation method according to claim 4 is characterized in that: drip I down at-5～0 ℃
2Tetrahydrofuran solution, I
2Concentration in THF is 30-35wt%.
6. preparation method according to claim 1 is characterized in that: solvent for use is a THF, and the volume of THF (L) is (-) 2-amino-6-propionamido-4,5,6, and the 5-10 of 7-tetrahydro benzothiazol weight (kg) doubly.
7. preparation method according to claim 1 is characterized in that, the treatment process of reaction solution is: reaction solution is cooled to below 10 ℃; Add hydrochloric acid remaining borine and Peng Qinghuana decomposition are finished, the solvent of underpressure distillation recovery part then, remaining reaction solution add sodium hydroxide solution and also are cooled to below 10 ℃; Separate out a large amount of solids, solid is separated out complete back separation, washing, the dry 2-amino-6-of (S)-(-) third amino-4,5 that gets; 6, the 7-tetrahydro benzothiazol.
8. preparation method according to claim 7 is characterized in that: in the treating processes of reaction solution, the concentration of hydrochloric acid is 15-37wt%, and the volume of hydrochloric acid soln (L) is NaBH
4Weight (kg) 10-15 doubly, add hydrochloric acid after, at 40 ℃ of reaction 30min; The concentration of sodium hydroxide solution is 20-30wt%, add-on to reaction solution pH be 11-12.
9. the preparation method of a pramipexole dihydrochloride monohydrate is characterized in that may further comprise the steps: the pramipexole that will make according to the preparation method of the described pramipexole of claim 1 in the presence of solvent with concentrated hydrochloric acid react the pramipexole dihydrochloride monohydrate.
10. preparation method according to claim 9 is characterized in that: the mol ratio of pramipexole and concentrated hydrochloric acid is 1: 2.01～2.6; Said solvent is one or more in the pure and mild ketone, and the volumetric usage of solvent (L) is the 2-amino-6-of (S)-(-) third amino-4,5,6, and the 6-12 of 7-tetrahydro benzothiazol weight (kg) doubly; Temperature of reaction is 5-15 ℃, and the reaction times is 0.5-20h.
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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 |
| CN104031002A (en) * | 2014-06-09 | 2014-09-10 | 福建科瑞药业有限公司 | Process for synthesizing pramipexole |
| 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 |
| CN104230846A (en) * | 2014-09-05 | 2014-12-24 | 杭州华东医药集团新药研究院有限公司 | Method for 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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| CN1834092A (en) * | 2005-03-15 | 2006-09-20 | 姜能桥 | Prepn. of pramipexole |
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 |
| 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 |
| 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 |
| CN104230846A (en) * | 2014-09-05 | 2014-12-24 | 杭州华东医药集团新药研究院有限公司 | Method for preparing pramipexole intermediate |
| 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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