Process for producing pramipexole midbody 2,6-diamino-4,5,6,7-tetrahydrochysene-benzothiazole

A technology of benzothiazole and diamino, applied in the field of chemistry, can solve the problems of high cost, difficult removal, and low process yield, and achieve the effects of mild reaction time, reduced separation steps, and flexible and convenient operation

Active Publication Date: 2012-12-05
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method only considers the protective effect on the amino group, but does not take into account the influence of the protective group on the reactivity and reaction yield.
The activity of phthaloyl group is low, and phthaloyl group is difficult to remove as a protecting group, which leads to low yield (about 20%) of the process and high cost
In addition, the process includes independent reaction steps, each step requires different conditions, solvents and other temperatures, and when dissociating the protecting group phthaloyl group of the amino group, it is necessary to use a highly toxic solvent such as benzene, which requires Using batch operation and multiple separation steps, compared with continuous operation, this means longer processing time, lower yield, and more discharge streams, which are not suitable for industrial production of products.
[0008] Patent US4731374 also describes a preparation method of pramipexole, using acetic anhydride, acetyl chloride, etc. to protect the amino group, the reaction activity and reaction yield are high, but the bromination process is carried out after the acetyl group is used to protect the amino group, because the acetyl group The hydrogen atom on the α-methyl group has high activity, so it is easy to be replaced by bromine. In addition, its steric hindrance is small, and acetamidocyclohexanone is prone to double substitution, and there are many side reactions

Method used

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  • Process for producing pramipexole midbody 2,6-diamino-4,5,6,7-tetrahydrochysene-benzothiazole
  • Process for producing pramipexole midbody 2,6-diamino-4,5,6,7-tetrahydrochysene-benzothiazole
  • Process for producing pramipexole midbody 2,6-diamino-4,5,6,7-tetrahydrochysene-benzothiazole

Examples

Experimental program
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Effect test

Embodiment 1

[0048] Preparation of 4-Benzamidocyclohexanol. Dissolve 203.60 g (1.767 mol) of trans-4-aminocyclohexanol in 1000 ml of pyridine. The reaction liquid was heated to 110° C. with an oil bath, and 400.00 g (1.770 mol) of benzoic anhydride was added to the reaction liquid. Continue to stir for 3 hours after the reaction liquid is clarified, pour the reaction liquid into a beaker and stand for crystallization, filter and separate the product 4-benzamidocyclohexanol, and dry to obtain 356.00 g of white product with a yield of 91.9%.

Embodiment 2

[0050] Preparation of 4-Benzamidocyclohexanone. Dissolve 61ml of concentrated sulfuric acid in 270ml of water, then add 62.00g of chromium trioxide to obtain an oxidizing solution, and cool it for later use. Dissolve 160.00 g (0.730 mol) of 4-benzamidocyclohexanol in a mixed solution of 1000 ml glacial acetic acid and 1000 ml chloroform, and stir until clear. Then the prepared oxidizing solution (aqueous sulfuric acid solution of chromium trioxide) is dropped into the reaction solution, and the reaction temperature is strictly controlled between 25°C and 35°C. After the dropwise addition, the stirring reaction was continued for 3 hours. 160ml of water was added to the reaction solution, stirred thoroughly, and then the chloroform layer was separated. The aqueous layer was extracted twice with 200 ml of chloroform. The chloroform layers were combined, washed with 800 ml of water, the chloroform layer was separated, dried over anhydrous magnesium sulfate, filtered and distill...

Embodiment 3

[0052] Preparation of 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole. 236.0 g (1.087 mol) of 4-benzamidocyclohexanone were dissolved in 500 ml HAc and 125 ml HBr. Under the conditions of avoiding light and cooling in an ice-water bath, and keeping the temperature between 5 °C and 15 °C, 177.28 g (1.108 mol) of bromine was added dropwise, and the reaction was continued for 1.5 h with stirring after dropping. At this time, 165.0 g (2.17 mol) of thiourea was added, the mixture was heated to 90° C., and refluxed for 3 h. 200ml of 20% hydrochloric acid was added, and the reaction was refluxed for 24h. Then the reaction solution was cooled to about 10°C, neutralized with a saturated KOH solution, and kept in an ice-water bath. The product 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole was isolated by washing with cold water followed by drying. 104.2 g of a white product was obtained, with a yield of 57.2%.

[0053] The obtained 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole can be res...

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Abstract

The invention relates to a novel preparation method for a pramipexole intermediate. The preparation method is as follows: formacyl is used as a protecting group of amino, and 4-amino cyclohexanol reacts with benzoic anhydride to obtain 4-benzoyl cyclohexanol; and after a product obtained by oxidation, bromine substitution, cyclization by amido thiourea, and hydrolysis of the 4-benzoyl cyclohexanol reacts with propionic aldehyde, the reactant is reduced by sodium borohydride to obtain pramipexole. The method has the advantages of high yield, better reaction activity and reaction yield compared with phthalyl, an easy industrialized production.

Description

technical field [0001] The invention belongs to the field of chemistry, and specifically relates to a preparation method of a compound of formula (1), the chemical name is 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole, and the compound is a compound used in the preparation of Intermediate of Pramipexole. The present invention also relates to the synthesis of pramipexole. [0002] Background technique [0003] (S)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, commonly known as pramipexole, as two molecules of hydrochloride (Mirapexin [TM]) It is marketed as a dopamine agonist in early and advanced Parkinson's disease, to stimulate dopamine receptors in the brain. [0004] Early patents EP186087, EP207969, WO0222590, etc. disclose several synthetic methods of compounds with structural formula (1) including pramipexole. The typical synthetic reaction route of pramipexole is as follows: first, bromine and 4-acetamido-cyclohexanone are reacted in glacial acetic ac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/82C07D277/60
CPCY02P20/55
Inventor 叶文润梁柱颜伟伟孙化富罗杰
Owner CHONGQING PHARMA RES INST
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