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Industrial preparation method for pramipexole and its dihydrochloride monohydrate

A technology of amino and tetrahydro, applied in the direction of organic chemistry, can solve problems such as harsh reaction conditions, difficult preparation, damage to reaction equipment, etc., and achieve the effects of mild reaction conditions, high reaction safety, and safe reaction process

Active Publication Date: 2012-05-09
山东富创医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006]2. Chinese patent CN1834092 improves the above method, using NaBH4 and BF3 to generate on-site Borane, but the ether solution of boron trifluoride decomposes with water and has a pungent smell, and ether is highly flammable, the reaction conditions are harsh and the requirements for equipment are very high, and it is not suitable for industrial production
[0008]3. Chinese patent CN101676272 uses sodium borohydride and lithium aluminum hydride as a reducing agent for reduction, the conditions are relatively mild, but the reaction needs to be carried out under reflux, and the reaction time is very long. Tetrahydrofuran as a solvent has a low boiling point and is highly corrosive to organic parts other than polytetrafluoroethylene. It is easy to cause running, popping, dripping, and leaking. Tetrahydrofuran has the risk of explosion in the reflux state, so the requirements for equipment and workshops are very high.
Damage to the reaction equipment, high requirements on the plant and equipment
Moreover, Zn(BH4)2 is difficult to prepare and not easy to store
Also not suitable for industrialization

Method used

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  • Industrial preparation method for pramipexole and its dihydrochloride monohydrate
  • Industrial preparation method for pramipexole and its dihydrochloride monohydrate
  • Industrial preparation method for pramipexole and its dihydrochloride monohydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0034] Add (-)2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole (227.33g, 1mol) into tetrahydrofuran (1362ml), stir to dissolve, then add boron quickly Sodium hydride (94.68g, 2.5mol) was stirred, then cooled to -5°C, and then slowly added dropwise at -5 to 0°C 2 (253.8g, 1mol) and tetrahydrofuran 725ml (I 2 The mass concentration of the solution is 35%). After dropping, slowly raise the temperature to 35°C, keep the temperature for 8 hours, then cool to below 10°C, first add 45ml of tap water dropwise to avoid excessive reaction, and then add dropwise the 946.8ml of hydrochloric acid, then slowly raise the temperature to 40°C, keep it for 30min, then recover tetrahydrofuran by vacuum distillation, after recovery, adjust the pH of the remaining solution to 12 with 30% sodium hydroxide solution, precipitate a large amount of solids, cool down to below 10°C , stirred for 30 minutes...

Embodiment 2

[0038] (1) Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0039] Add (-)2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole (227.33g, 1mol) into tetrahydrofuran (2270ml), stir to dissolve, and then quickly add boron Sodium hydride (37.83g, 1mol) was stirred, then cooled to -30°C, and then slowly added dropwise at -30~-5°C 2 (101.52g, 0.40mol) and tetrahydrofuran 253.8ml (I 2 The mass concentration is 40%) solution, after dropping, slowly heat up to 40°C, keep warm for 6 hours, then cool to below 10°C, first add 18ml of water dropwise to avoid excessive reaction, then add dropwise hydrochloric acid with a mass fraction of 37% 454ml, then slowly raised the temperature to 40°C, kept for 30min, and then recovered tetrahydrofuran by vacuum distillation. After recovery, the remaining solution was adjusted to pH=12 with 30% sodium hydroxide solution, and a large amount of solids were precipitated, cooled to below 10°C, and stirred 30min, filter ...

Embodiment 3

[0043] (1) Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0044] Add (-)2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole (227.33g, 1mol) into tetrahydrofuran (1362ml), stir to dissolve, then add boron quickly Sodium hydride (94.68g, 2.5mol) was stirred, then cooled to -30°C, and then slowly added dropwise at -30 to -20°C 2 (253.8g, 1mol) and tetrahydrofuran 725ml (I 2 The mass concentration is 35%) solution, after dropping, slowly heat up to 35°C, keep the temperature for 8 hours, then cool to below 10°C, first add 45ml of water dropwise to avoid excessive reaction, then add dropwise hydrochloric acid with a mass fraction of 37% 946.8ml, then slowly heated up to 40°C, kept for 30min, and then recovered tetrahydrofuran by vacuum distillation. After the recovery, the remaining solution was adjusted to pH = 12 with 30% sodium hydroxide solution, a large amount of solids were precipitated, and the temperature was lowered to below 10°C. Sti...

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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 [0001] The invention relates to an industrial preparation method of pramipexole and its dihydrochloride monohydrate, belonging to the technical field of drug synthesis. Background technique [0002] Pramipexole is used in early and advanced Parkinson's disease as a dopamine agonist that stimulates dopamine receptors in the brain. In practice, pramipexole dihydrochloride monohydrate is preferred as the compound for treating Parkinson's disease. The chemical name of pramipexole dihydrochloride monohydrate is (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole dihydrochloride Monohydrate, wherein (S) means that pramipexole hydrochloride is in S configuration, and (-) means that pramipexole hydrochloride is left-handed. Pramipexole hydrochloride can be used as a pharmaceutical raw material to prepare a drug for treating Parkinson's disease. Pramipexole hydrochloride must be in S configuration and L-rotational to have a medical effect. [0003] At p...

Claims

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Application Information

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IPC IPC(8): C07D277/60
Inventor 宫庆创司志现
Owner 山东富创医药科技有限公司
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