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Preparation of pramipexole

A technology of pramipexole hydrochloride and benzothiazole, which is applied in the direction of organic chemistry, can solve the problems of low reaction safety and difficult preparation of raw materials, and achieve the effects of mild reaction conditions, improved reaction safety, and easy control

Inactive Publication Date: 2010-04-28
姜能桥 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to provide a kind of preparation method of pramipexole hydrochloride with simple and easy to obtain raw materials and high reaction safety in order to overcome the shortcomings of the above-mentioned method that the raw materials are not easy to obtain and the reaction safety is low

Method used

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  • Preparation of pramipexole
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Examples

Experimental program
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[0009] The preparation method of pramipexole hydrochloride provided by the invention can be represented by following reaction equation 1:

[0010]

[0011] Reaction Equation 1

[0012] In the first step reaction of reaction equation 1, the (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole, NaBH 4 and BF 3 The molar ratio is 1:4:6-1:10:13, preferably 1:6:8-1:9:11.

[0013] Described tetrahydrofuran (THF) is used as solvent, and its volume consumption is NaBH 4 4-10 times the weight (volume / weight).

[0014] The inert gas refers to any gas that does not react chemically with reactants or products, such as nitrogen, one or more of the gases of group zero in the periodic table, preferably nitrogen.

[0015] During the reaction, (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole, NaBH 4 and BF 3 The order of addition is preferably, first NaBH 4 Added into tetrahydrofuran, and then added (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole and ...

Embodiment 1

[0022] This embodiment is used to illustrate the preparation method of pramipexole hydrochloride of the present invention.

[0023] (1) Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0024] 0.325 M NaBH 4 Add to the three-necked flask that fills 60 milliliters of anhydrous THF, pass into N 2 Under gas protection, at a temperature of 2°C and under constant stirring, add 0.05 mole (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole, mix well and then add 100 mL of 5 mol / L BF 3 Diethyl ether solution (0.5 mole BF 3 ). Then the temperature was raised to 10° C., and reacted for 1.5 hours under constant stirring, and then the reaction mixture was heated to 45° C., reacted for 4.5 hours under constant stirring, and then cooled at 2° C. for 18 minutes.

[0025]To the above reacted mixture was added 200 ml of 20% hydrochloric acid solution, and then THF was evaporated. Dissolve the residue in 600 ml of water, adjust the pH to 12.5 with 0.5 ...

Embodiment 2

[0029] This embodiment is used to illustrate the preparation method of pramipexole hydrochloride of the present invention.

[0030] (1) Preparation of (S)-(-)2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole

[0031] 0.40 M NaBH 4 Add to the three-necked flask that fills 120 milliliters of anhydrous THF, pass into N 2 Under gas protection, at a temperature of 4°C and under constant stirring, add 0.05 mole (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrobenzothiazole, mix well and then add 70 mL of 6 mol / L BF 3 Ether solution (0.42 mole BF 3 ). Then the temperature was raised to 30° C. and reacted for 2.5 hours under constant stirring, then the reaction mixture was heated to 55° C., reacted for 2.5 hours under constant stirring, and then cooled at 5° C. for 10 minutes.

[0032] To the above reacted mixture was added 350 ml of 22% hydrochloric acid solution, and THF was evaporated. The residue was then dissolved in 600 ml of water, adjusted to pH 10.5 with 0.5 mol / L NaO...

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Abstract

This invention relates to a method to prepare pramipexole hydrochloride, which includes the contact reaction between (S)-(-) 2-amino-6-propylamido-4, 5, 6, 7-tetrahydrobenzothiazole and hydrogen chloride. To prepare (S)-(-) 2-amino-6-propylamido-4, 5, 6, 7-tetrahydrobenzothiazole, (-) 2-amino-6-propionamido-4, 5, 6, 7-tetrahydrobenzothiazole reacts with NaBH4 and BF3 in tetrahydrofuran under the protection of inert gas and then (S)-(-) 2-amino-6-propylamido-4, 5, 6, 7-tetrahydrobenzothiazole is separated from the mixture. The preparation method of (S)-(-)2-amino-6-propylamido-4, 5, 6, 7-tetrahydrobenzothiazole dihydrochloride from the hydroboration reduction and salt formation of (-)2-amino-6-propionamido-4, 5, 6, 7-tetrahydrobenzothiazole as raw materials provided in this invention has the advantages of simple and easily obtainable raw materials and soft reaction conditions, and operation is thus easy to control and the reaction security is promoted.

Description

technical field [0001] The present invention relates to the preparation method of pramipexole hydrochloride represented by following structural formula (1), [0002] Structural formula (1): [0003] Background technique [0004] The chemical name of pramipexole hydrochloride is (S)-(-)-2-amino-6-(propylamino)-4,5,6,7-tetrahydrobenzothiazole dihydrochloride, where (S) represents Pramipexole hydrochloride is in the S configuration, (-) means that pramipexole hydrochloride is L-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. At present, its synthesis methods mainly include: [0005] J.Med.Chem.1987,30,494-498 discloses a kind of preparation method of pramipexole hydrochloride, this method is with (-) 2-amino-6-propionylamino-4,5,6,7-tetrahydrochloride Hydrobenzothiazole is used as raw material, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/60C07D277/82
CPCC07D277/82
Inventor 姜能桥尹先清
Owner 姜能桥
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