Preparation method of high-purity pramipexole

A high-purity, solvent-based technology, applied in the field of preparation of high-purity pramipexole, can solve the problems of low yield, high price, and high production cost, and achieve the effects of simplifying the preparation process, reducing costs, and simple steps

Active Publication Date: 2021-04-06
GUANGDONG HONGSHANHU PHARM CO LTD
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Problems solved by technology

[0005] Method 1: Using (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (referred to as intermediate I) as the starting material, using anhydrous THF as the solvent, adding propionic anhydride Carry out the reaction to obtain (S)-2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole, and then perform a reduction reaction in a THF solution of borane to obtain pramipexole base, Finally, pass into hydrogen chloride gas to form a salt to obtain pramipexole hydrochloride. The total yield is about 45%. Registration requirements (FDA requires at least 3 reaction steps for the synthesis of raw materials), and the reducing reagent borane is a highly toxic chemical reagent, which is expensive and difficult to purchase
[0006] Method 2: Using intermediate I as the starting material, react with n-propionaldehyde in DMF solvent to form a Schiff base, and the reaction product is directly added to sodium triacetoxyborohydride for reduction without separation, and Pralac is prepared by a one-pot method The advantage of this method is that the intermediate product does not need to be separated, the intermediate steps are few, and the operation is simple. The disadvantage is that the price of sodium triacetoxyborohydride is relatively expensive, which makes the production cost higher and the yield of the reduction step is low.
The method for preparing pramipexole in the prior art has less than three steps in the synthetic route, so there are many uncontrollable factors in the product quality, and various materials related to the starting materials need to be provided when the drug is declared, which is difficult to meet the requirements of the declaration

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[0031] The invention provides a kind of preparation method of high-purity pramipexole, comprises the following steps:

[0032] (1) 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, the first solvent and L-(+)-tartaric acid are mixed for a resolution reaction to obtain a product liquid; After cooling down and crystallizing the product liquid, filter and dry in sequence, recrystallize the obtained crystalline product in the first solvent, mix the recrystallized product and the first solvent, add hydrochloric acid until the system dissolves, and use lye to adjust the pH of the system to The value is adjusted to ≥13, followed by filtration and drying to obtain (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole;

[0033] (2) Mix the (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, the second solvent, triethylamine and propionic anhydride for condensation reaction, after the reaction is completed, Use ammonia water to quench the reaction, concentrate the obtained product material liquid, mix...

Embodiment 1

[0060] (1) Synthesis of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (Intermediate I):

[0061]Add 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (100.14g, 0.59mol) into 1500mL of purified water, heat up to 75°C under stirring, add L-(+)-tartaric acid ( 133.24g, 0.89mol), the system was dissolved, kept for 2 hours, cooled to 25°C, stirred and crystallized for 4 hours, filtered with suction, dried, added 1500mL of purified water to the dried product, heated to 77°C with stirring, the system was dissolved, kept warm React for 2 hours, cool down to 25°C, stir and crystallize for 4 hours, suction filter, dry, add 340 mL of purified water to the dry product, add concentrated hydrochloric acid dropwise under stirring until the system dissolves, adjust the pH to ≥13 with 50wt.% NaOH solution, pump Filter and dry to obtain 48.5 g of off-white solid (intermediate I), the yield is 48.4%, HPLC shows that the purity is 99.95%, isomer detection: more than 99.5%;

[0062] (2) Synthesis of ...

Embodiment 2

[0069] (1) Synthesis of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (Intermediate I):

[0070] Add 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (4668.1g, 27.58mol) into 70kg of purified water, stir and begin to heat up to 50°C, add L-(+)- Tartaric acid (6209.2g, 41.37mol), the system was dissolved, heat-retained for 2 hours, cooled to 25°C, stirred and crystallized for 4 hours, suction filtered, dried, and then 70kg of purified water was added, the temperature was raised to 77°C under stirring, the system was dissolved, and heat-preserved for reaction 2h, cooled to 25°C, stirred and crystallized for 4h, filtered with suction, and dried; added 15.9kg of purified water, added concentrated hydrochloric acid dropwise under stirring until the system was dissolved, adjusted the pH to ≥13 with 50wt% NaOH solution, filtered with suction, and dried to obtain White solid (Intermediate I) 2250g, the yield is 48.2%, the purity shown by HPLC is 99.86%, the purity of isomer detection is:...

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Abstract

The invention relates to the technical field of pharmacy, and provides a preparation method of high-purity pramipexole. According to the invention, raceme 2, 6-diamino 4, 5, 6, 7-tetrahydrobenzothiazole is used as an initial raw material, and pramipexole is obtained through a three-step chemical reaction, so the introduction of uncontrollable factors of drug quality is reduced, and the requirements of drug application are better met; the market price of the initial raw materials is low, so that the preparation cost of pramipexole can be greatly reduced; the solvent used in the method is green, environmentally friendly, cheap, easy to obtain and suitable for industrial production, the HPLC purity of the obtained pramipexole can reach 99.86%, and the isomer purity can reach 99.89%.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a preparation method of high-purity pramipexole. Background technique [0002] Pramipexole, chemical name: (S)-2amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, was developed by Boehringer Ingelheim in Germany and approved by FDA on May 10, 1997 Listed for the treatment of idiopathic Parkinson's disease, it was launched in China in 2007 under the trade name Senfulo. The target of pramipexole hydrochloride is the D2 and D3 receptor subtypes of the dopamine system, which has a good protective effect on the dopamine nerve. It is the best choice for the treatment of early Parkinson's disease, and it can also be used for the combination medication. Pramipexole has a broad market prospect because of its low toxicity and side effects, long half-life and high bioavailability. The structural formula of pramipexole is as follows: [0003] [0004] As far as the currently publis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/60
CPCC07D277/60
Inventor 王高华方燕秋徐春霞汪晴
Owner GUANGDONG HONGSHANHU PHARM CO LTD
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