CN112279817B - Preparation method of high-purity pramipexole dihydrochloride - Google Patents
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Abstract
The invention provides a preparation method of high-purity pramipexole dihydrochloride, which comprises the following steps: (a) Taking (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole as a raw material, taking tetrahydrofuran as a solvent, reacting in the presence of a reducing agent, and adding dilute hydrochloric acid to terminate the reaction after the reaction is finished; (b) Adding sodium hydroxide solution to regulate pH, adding extractant to extract, adding alcohol reagent, dropping concentrated hydrochloric acid to form salt, cooling to crystallize, filtering and stoving to obtain pramipexole dihydrochloride monohydrate. (c) Refining the pramipexole dihydrochloride monohydrate obtained in the step (b) through a ternary system of water, alcohol reagents and ester reagents, filtering and drying to obtain a pramipexole dihydrochloride finished product. The novel synthesis method of pramipexole dihydrochloride has the advantages of simple reaction steps, high safety, high yield, purity reaching more than 99.95 percent and stable water content, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of high-purity pramipexole dihydrochloride.
Background
Pramipexole hydrochloride is a drug for treating parkinsonism, belongs to a selective non-ergot dopamine receptor agonist, is successfully developed by Boehringer Ingelheim (Boehringer Ingelheim) in Germany, is the dopamine receptor agonist with the largest dosage currently prescribed globally, is approved by the FDA in the United states for treating idiopathic parkinsonism for the first time in 1997, can relieve symptoms and signs of patients, can be used singly or in combination with levodopa, has the trade name Mirapex sold in the United states, is the drug approved for parkinsonism for the first time in the past 6 years by the FDA, is marketed in China in 2007, has the trade name of forest for treating the signs and symptoms of idiopathic parkinsonism, and is singly (without levodopa) or in combination with levodopa.
Pramipexole dihydrochloride is chemically named as S (-) -2-amino-6-n-propylamino-4, 5,6, 7-tetrahydrobenzothiazole dihydrochloride, and the synthesis method thereof only needs to be provided at present:
1. the document J.Med.chem.1987,30-494-498 discloses a preparation method of pramipexole hydrochloride, which takes (-) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole as a raw material, reacts with propionic anhydride in tetrahydrofuran of triethylamine, the obtained solution is extracted by ethyl acetate, dried by MgSO4, distilled off under reduced pressure and washed by acetone, and (-) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole is obtained, reacts with tetrahydrofuran solution of borane under the protection of N2 in tetrahydrofuran, free alkali is refined by ethyl acetate, salified in methanol, and refined by methanol once after salifying, thus obtaining pramipexole hydrochloride.
The method has the defects that the borane is colorless and extremely toxic gas, is inflammable, explosive, easy to hydrolyze, poor in stability, difficult to store and transport and low in reaction safety, and the pramipexole hydrochloride prepared by the method has low yield and no crystal water, and in addition, the preparation method of the tetrahydrofuran solution of the borane is complex, so that the method is not suitable for industrial production.
2. The preparation method of the patent CN201710706979.8 comprises the following steps: 2.11g of (S) - (-) -2-amino-6-n-propylamino-4, 5,6, 7-tetrahydrobenzothiazole were added, followed by 30ml of acetone. Cooling to 0-5 deg.c in ice bath, and then dropping 3ml concentrated hydrochloric acid in half an hour. The reaction was continued for 1 hour at the end of the dripping. The filter cake was washed with 10ml of acetone. The filter cake was air-dried at 60℃for 1 hour to give 2.53g of crude pramipexole.
15ml of an aqueous 85% (W/W) ethanol solution was added first, the temperature was raised to reflux, and 17ml of an aqueous 85% (W/W) ethanol solution was added to completely dissolve the whole. 0.3g of activated carbon is added, and the mixture is stirred for half an hour with heat preservation. And (5) hot filtering. The filtrate is naturally cooled to 35 ℃ to separate out seed crystals, and then the crystallization is continued for 1 hour at 35 ℃. Cooling to 0 ℃ by ice bath, and continuing to keep the temperature at 0 ℃ for crystallization for 1 hour. The filter cake was filtered off with suction and washed with 10ml of absolute ethanol. Then, the mixture was air-dried at 50℃for 2 hours to obtain 2.27g of a white powdery solid, the content of which was 99.95% by HPLC, and the yield was 75.17%.
The method involves salification and refining, adopts ethanol-water refining, and has high purity but lower yield.
3. The preparation method of the patent CN201310105277.6 comprises the following steps: adding 40.00g of initial raw materials into a 1000ml three-port reaction bottle, adding 160.0ml of tetrahydrofuran, adding 19.85g of sodium bicarbonate, stirring and heating to 50 ℃, dropwise adding 29.22g of propionic anhydride, controlling the temperature to be 1 hour, stirring and reacting for 0.5 hour after the dropwise adding is finished, cooling to 5+/-5 ℃, adding 26.82g of sodium borohydride, dropwise adding 118.4ml of boron trifluoride diethyl etherate solution, controlling the dropwise adding to be 1 hour, keeping the temperature and stirring for 1 hour after the dropwise adding is finished, naturally heating to room temperature and stirring for 1.5 hours, and refluxing and stirring for reacting for 1.5 hours; cooling to 10+ -5deg.C, dropwise adding 120.0ml of water, adding 100.0ml of concentrated hydrochloric acid after 20 min, heating and refluxing for 1 hr, cooling to 15+ -5deg.C, adjusting pH to be more than 11 with sodium hydroxide solution, layering, extracting water layer with appropriate amount of ethyl acetate for 2 times, mixing organic layers, washing 3 times with saturated saline, adding 150ml of saturated saline into the organic layers, dropwise adding 16ml of hydrochloric acid under stirring to precipitate hydrochloride of the product, filtering the precipitated solid, drying at 60deg.C to obtain 35.25g of pramipexole monohydrochloride with yield of 60.20% and HPLC content of more than 99.8%.
Adding 20.0g of the obtained solid into a reaction bottle, adding 100ml of absolute ethyl alcohol, dropwise adding 13.5ml of concentrated hydrochloric acid, stirring for reaction for 30min, distilling to remove solvent and redundant acid, adding 8ml of water and 60ml of absolute ethyl alcohol, heating for dissolving, filtering, adding 60ml of absolute ethyl alcohol, stirring, cooling for crystallization, crystallizing at 5-15 ℃ for 2 h, filtering, drying to obtain 21.50g of pramipexole dihydrochloride monohydrate, wherein the yield is 87.8%, and the HPLC content is 99.9%.
The method firstly forms monohydrochloride and then forms dihydrochloride hydrate, has complex process and lower total yield.
4. The preparation method of the patent CN201310684092.5 comprises the following steps:
(1) Preparation of (S) - (-) -2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole
(S) - (-) -2, 6-diamino-4, 5,6, 7-tetrahydrobenzothiazole (42.3 g,0.25 mol) was added to methanol (500 mL), cooled with stirring to-20℃and n-propanal (26.75 g,0.46 mol) was added dropwise at a temperature of-15 to-20 ℃. After the addition, the mixture was stirred at the temperature for 1.5 hours, 80mL of a methanol solution of NaBH4 (6.65 g,0.18 mol) was added dropwise at a temperature of-15 to-20℃and the mixture was stirred at the natural temperature for 2 hours after the addition. Then cooling to below 0 ℃, dropwise adding 70mL of concentrated hydrochloric acid to adjust the pH to 2-3, evaporating methanol, dissolving the residue in 150mL of water, adjusting the pH to 7 with 25% sodium hydroxide solution, stirring and crystallizing for 2 hours at 0 ℃, filtering to obtain a white scaly solid, refining twice with a mixed solvent of ethanol and water (volume ratio of 5:1), and air-drying to obtain a white powdery solid (S) - (-) -2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole (33.5 g, 63.5%).
(2) Preparation of pramipexole dihydrochloride monohydrate
(S) - (-) -2-amino-6-propylamino-4, 5,6, 7-tetrahydrobenzothiazole (33.5 g,0.16 mol) obtained in (1) was added to acetone (300 mL), 13mL of concentrated hydrochloric acid was added dropwise with stirring at-5 to 0 ℃ to adjust ph=1, and then the reaction was stirred at that temperature for 2 hours. The mixture was filtered and the filter cake was washed with acetone to give a white powdery solid which was then recrystallized from 90% ethanol and air dried at 50 ℃ to give pramipexole dihydrochloride monohydrate (43.6 g, 90.3%).
The method uses acetone as solvent, and concentrated hydrochloric acid to form salt, and has low yield and multiple refining.
The pramipexole dihydrochloride synthesis method in the prior art has the following defects: 1) The reaction condition is harsh, the reaction safety is low, the reaction needs to be carried out under the protection of inert gas, the post-treatment is complex, and the solvent needs to be removed, so that the product yield is low; 2) Multiple recrystallization is needed, the yield is low, the intermediate treatment process is complex, the process is complex, and the method is not suitable for industrial production; 3) The reaction yield is low and the purity is not high; 4) The recrystallization by adopting a single polar solvent such as acetone, ethanol and the like can cause crystallization water loss, and the water content is unqualified.
In view of the shortcomings of the prior art, it is very necessary to develop a new synthesis method of pramipexole dihydrochloride, which has the advantages of simple reaction steps, high safety, high yield, high purity and stable water content, and is suitable for industrial production.
Disclosure of Invention
The applicant of the invention discovers that in the process of salifying and refining pramipexole, compared with pramipexole hydrochloride refined by a monobasic or dibasic system, the pramipexole hydrochloride obtained by refining the pramipexole hydrochloride by a ternary system of water, an alcohol reagent and an ester reagent has the advantages of high yield, high purity, stable water content, improved water proportion in the ternary system, obvious reduction of the yield, overhigh proportion of the alcohol and the ester, gradual reduction of the content of crystal water and no compliance with pharmacopoeia standards.
The invention discloses a preparation method of high-purity pramipexole dihydrochloride, which comprises the following steps:
(a) Taking (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole as a raw material, taking tetrahydrofuran as a solvent, reacting in the presence of a reducing agent, and adding dilute hydrochloric acid to terminate the reaction after the reaction is finished;
(b) Adding sodium hydroxide solution, regulating pH to 12-14, adding extractant for extraction, then adding alcohol reagent, dropwise adding concentrated hydrochloric acid to form salt, cooling for crystallization, filtering and drying to obtain pramipexole dihydrochloride monohydrate.
(c) Refining the pramipexole dihydrochloride monohydrate obtained in the step (b) through a ternary system of water, alcohol reagents and ester reagents, filtering and drying to obtain a pramipexole dihydrochloride finished product.
Further, the reducing agent in the step (a) is any one of sodium borohydride-boron trifluoride diethyl ether or sodium borohydride-sulfuric acid, preferably sodium borohydride-boron trifluoride diethyl ether.
Further, the extractant in the step (b) is any one of ethyl acetate, isopropyl acetate and methyl tertiary butyl ether, preferably ethyl acetate, the alcohol reagent in the step (b) and the step (c) is any one of methanol, ethanol and isopropanol, preferably methanol, and the ester reagent in the step (c) is any one of ethyl acetate and isopropyl acetate, preferably ethyl acetate.
Further, in the step (a), the (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole: the volume ratio of tetrahydrofuran is as follows: 1:3-10.
Further, in the step (b), the (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole: the volume ratio of the alcohol reagent is 1:0.5-10.
Further, in the step (b), the (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole: the molar ratio of the concentrated hydrochloric acid is 1:2-4, and the crystallization temperature in the step (b) is 0-20 ℃.
Further, in the step (c), the (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole: water: alcohol reagent: the volume ratio of the ester reagent is as follows: 1:0:1:1-1:3:10:30.
Further, in the step (a), the (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole: sodium borohydride: the molar ratio of boron trifluoride diethyl etherate is as follows: 1:2:2.4-1:4:4.8.
Further, in the step (a), the (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole: sodium borohydride: the molar ratio of sulfuric acid is: 1:3:1.2-1:8:5.
The specific process comprises the following steps:
the reaction formula:
the novel synthesis method of pramipexole dihydrochloride has the advantages of simple reaction steps, high safety, high yield, purity reaching more than 99.95 percent and stable water content, and is suitable for industrial production.
Drawings
FIG. 1 is a liquid chromatogram of pramipexole dihydrochloride in example 1
FIG. 2 is a liquid chromatogram of pramipexole dihydrochloride in example 5
FIG. 3 is a liquid chromatogram of pramipexole dihydrochloride in example 7
Detailed Description
The invention is further illustrated by the following examples, which are not intended to be limiting.
Example 1
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 300ml of tetrahydrofuran and 20g of sodium borohydride were added to a reaction flask. 94.5g of boron trifluoride is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dropwise addition. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, extracting with ethyl acetate, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 2V methanol, dropwise adding 0.75V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 60.3g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 89.9%, and the purity is 99.92%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 25g of water and 250ml of methanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 500ml of ethyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.2g of water: 6.0%, yield 96.4% and purity 100%.
Example 2
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 400ml of tetrahydrofuran and 24g of sodium borohydride were added to a reaction flask. 113.4g of boron trifluoride is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dropwise addition. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, extracting with ethyl acetate, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 2V methanol, dropwise adding 0.8V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 61.5g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 91.7%, and the purity is 99.91%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 15g of water and 150ml of methanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 300ml of ethyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.5g of water: 6.0%, yield 97% and purity 99.99%.
Example 3
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 500ml of tetrahydrofuran and 22g of sodium borohydride were added to a reaction flask. 104g of boron trifluoride is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dropwise addition. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, extracting with ethyl acetate, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 2V methanol, dropwise adding 0.8V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 61.1g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 91.1%, and the purity is 99.91%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 5g of water and 100ml of methanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 200ml of ethyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.8g of water: 5.9%, yield 97.6% and purity 99.98%.
Example 4
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 500ml of tetrahydrofuran and 32g of sodium borohydride were added to a reaction flask. 104g of boron trifluoride is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dropwise addition. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, extracting with ethyl acetate, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 5V methanol, dropwise adding 1.4V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 61g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 90.9%, and the purity is 99.91%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 5g of water and 100ml of methanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 200ml of ethyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.7g of water: 5.9%, yield 97.4% and purity 99.98%.
Example 5
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 300ml of tetrahydrofuran and 40g of sodium borohydride were added to a reaction flask. 50g of sulfuric acid is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dripping. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, extracting with ethyl acetate, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 2V methanol, dropwise adding 0.75V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 60g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 89.4%, and the purity is 99.92%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 25g of water and 250ml of ethanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 500ml of ethyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.3g of water: 6.0%, yield 96.6% and purity 99.97%.
Example 6
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 350ml of tetrahydrofuran and 41g of sodium borohydride were added to a reaction flask. 55g of sulfuric acid is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dripping. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, adding isopropyl acetate, extracting, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 2V methanol, dropwise adding 0.75V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 60.5g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 90.2%, and the purity is 99.91%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 25g of water and 250ml of isopropanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 500ml of isopropyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.5g of water: 6.1%, yield 97.0% and purity 99.98%.
Example 7
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 360ml of tetrahydrofuran and 42g of sodium borohydride were added to the reaction flask. 54g of sulfuric acid is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dripping. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, adding methyl tert-butyl ether for extraction, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 2V methanol, dropwise adding 0.75V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 60.8g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 90.6%, and the purity is 99.93%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 25g of water and 250ml of methanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 500ml of ethyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.8g of water: 5.9%, yield 97.6% and purity 99.97%.
Example 8
50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 400ml of tetrahydrofuran and 60g of sodium borohydride were added to a reaction flask. 95g of sulfuric acid is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the completion of the dripping. After cooling to room temperature, dilute hydrochloric acid was added to terminate the reaction. Adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, extracting with ethyl acetate, and layering. Concentrating the organic layer until the residual solvent is 4-5V, adding 6V methanol, dropwise adding 1.0V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization. After filtration and drying, 60.3g of pramipexole dihydrochloride monohydrate is obtained, the molar yield is 89.9%, and the purity is 99.92%.
50g of pramipexole dihydrochloride monohydrate is added into a reaction bottle, 25g of water and 400ml of methanol are added, the mixture is stirred uniformly, then the temperature is raised for dissolution, mechanical impurities are removed by filtration, and 800ml of ethyl acetate is slowly added for crystallization. Filtering and drying to obtain 48.8g of water: 5.9%, yield 97.6% and purity 99.97%.
The applicant of the invention discovers that in the process of salifying and refining pramipexole, the obtained pramipexole hydrochloride is refined by a ternary system of water, alcohol reagent and ester reagent, and has the advantages of high yield, high purity, stable water content, improved water proportion in the ternary system, obviously reduced yield, overhigh alcohol and ester proportion, gradually reduced content of crystal water and no compliance with pharmacopoeia standards. Compared with a monobasic or dibasic system, the ternary system is refined, the yield and purity of the obtained pramipexole dihydrochloride are high, and the water content of the pramipexole dihydrochloride is more stable.
The purity, yield and water content of the solvent used for refining pramipexole dihydrochloride are compared as follows:
the test comparison shows that when the pramipexole dihydrochloride is refined in a binary system of water and alcohol, water and ester, the yield is relatively low, the water content is not in accordance with the requirements, when the pramipexole dihydrochloride is refined in a system of acetone or methyl tertiary butyl ether, the yield and the water content are not good, the content and the purity of finished products obtained when the pramipexole dihydrochloride is refined in a ternary system of water, alcohol and ester are relatively high, and the water content meets the requirements of pharmacopoeia.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (1)
1. A preparation method of high-purity pramipexole dihydrochloride is characterized in that 50g of (S) -2-amino-6-propionylamino-4, 5,6, 7-tetrahydrobenzothiazole, 400ml of tetrahydrofuran and 24g of sodium borohydride are added into a reaction bottle, 113.4g of boron trifluoride is added dropwise at the temperature of 10 ℃, and the temperature is raised to reflux reaction for 2 hours after the dropwise addition; cooling to room temperature, adding dilute hydrochloric acid to terminate the reaction, adding 20% sodium hydroxide aqueous solution, adjusting pH to 14, adding ethyl acetate for extraction, and layering; concentrating the organic layer until the residual solvent is 4-5V, adding 2V methanol, dropwise adding 0.8V concentrated hydrochloric acid to form salt, and cooling to 10 ℃ for crystallization; filtering and drying to obtain 61.5g of pramipexole dihydrochloride monohydrate, wherein the molar yield is 91.7% and the purity is 99.91%; adding 50g of pramipexole dihydrochloride monohydrate into a reaction bottle, adding 15g of water and 150ml of methanol, uniformly stirring, heating to dissolve, filtering to remove mechanical impurities, and slowly adding 300ml of ethyl acetate for crystallization; filtering and drying to obtain 48.5g of water: 6.0%, yield 97% and purity 99.99%.
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