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Preparation method of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole

A technology of cyclohexanone and bromosuccinimide, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of endangering the health of operators, unfavorable industrial production, and high requirements for production equipment, so as to reduce waste and improve production Efficiency and shortening of the reaction steps

Inactive Publication Date: 2015-01-28
ANHUI WANBANG MEDICAL TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are three problems in this route: (1) after the amino group is protected with phthalic anhydride, the protecting group will be removed at last, which will produce a large amount of industrial by-products, and the atom utilization rate is low; During oxidation, strong oxidizing and corrosive raw materials such as potassium dichromate and concentrated sulfuric acid are used, which have high requirements for production equipment; (3) bromine is used for bromination reaction, because bromine is a highly toxic chemical and has Strong corrosiveness, which seriously endangers the health of operators and is not conducive to industrial production;
Compared with the synthesis route 1, this route avoids the steps of protecting and deprotecting groups on phthalic anhydride, but potassium dichromate, concentrated sulfuric acid, bromine, etc. are also used in the oxidation reaction and bromination reaction. Strong oxidizing, corrosive, and highly toxic raw materials also have the disadvantages described in Synthetic Route 1

Method used

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  • Preparation method of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole
  • Preparation method of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole
  • Preparation method of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Synthesis of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole

[0028] (1) Dissolve 9.3g (0.06mol) of acetamidocyclohexanone in 90ml of acetic acid and place it in a 150mL three-necked flask connected with a reflux device, heat up to 50°C under stirring conditions, and add N-bromosuccinyl 10.7g of amine, and keep the temperature at 50-60°C for 3 hours. The end point of the reaction is controlled by TLC. After the reaction of acetamidocyclohexanone is complete, add 9.12g (0.12mol) of thiourea, raise the temperature to 115°C, keep the temperature at 115~120°C for reflux reaction for 3 hours, and slowly cool down to room temperature under stirring. The solid was precipitated, filtered with suction, the filter cake was washed with water and methanol, and dried to obtain 9.2 g of 2-amino-6-acetamido-4,5,6,7-tetrahydrobenzothiazole (compound of formula B), yield 72.7% ;

[0029] (2) Put 9.2g (0.04354mol) of 2-amino-6-acetamido-4,5,6,7-tetrahydrobenzothiazole in ...

Embodiment 2

[0031] Example 2: Synthesis of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole

[0032] (1) Dissolve 9.3g (0.06mol) of acetamidocyclohexanone in 90ml of acetic acid and place it in a 150mL three-necked flask connected with a reflux device, heat up to 50°C under stirring conditions, and add N-bromosuccinyl 10.7g of amine, and keep the temperature at 50-60°C for 3 hours. The end point of the reaction is controlled by TLC. After the reaction of acetamidocyclohexanone is complete, add 9.12g (0.12mol) of thiourea, raise the temperature to 115°C, keep the temperature at 115~120°C for reflux reaction for 3 hours, and slowly cool down to room temperature under stirring. The solid was precipitated, filtered with suction, the filter cake was washed with water and methanol, and dried to obtain 9.5 g of 2-amino-6-acetamido-4,5,6,7-tetrahydrobenzothiazole (compound of formula B), yield 75.1% ;

[0033] (2) Put 9.5g (0.050mol) of 2-amino-6-acetamido-4,5,6,7-tetrahydrobenzothiazole in a...

Embodiment 3

[0035] Embodiment three: (6S)-2, the synthesis of 6-diamino-4,5,6,7-tetrahydrobenzothiazole

[0036](1) Dissolve 9.3g (0.06mol) of acetamidocyclohexanone in 90ml of acetic acid and place it in a 150mL three-necked flask connected to a reflux device, heat up to 50°C under stirring, and add N-bromosuccinyl 10.7g of amine, and keep the temperature at 50-60°C for 3 hours. The end point of the reaction is controlled by TLC. After the reaction of acetamidocyclohexanone is complete, add 9.12g (0.12mol) of thiourea, raise the temperature to 115°C, keep the temperature at 115~120°C for reflux reaction for 3 hours, and slowly cool down to room temperature under stirring. The solid was precipitated, filtered with suction, the filter cake was washed with water and methanol, and dried to obtain 9.1 g of 2-amino-6-acetamido-4,5,6,7-tetrahydrobenzothiazole (compound of formula B), yield 87.0% ;

[0037] (2) Put 9.1g (0.0431mol) of 2-amino-6-acetamido-4,5,6,7-tetrahydrobenzothiazole in a ...

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Abstract

The invention discloses a preparation method of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (formula I). The compound is an intermediate of a drug pramipexole hydrochloride (formula II) for treating Parkinson's diseases. The formula I and formula II are shown in the description. The preparation method comprises the steps of taking 4-acetamino cyclohexanone as an initial raw material; then subjecting 4-acetamino cyclohexanone to bromination and condensation cyclization with N-bromobutanimide and urea in glacial acetic acid; removing acetyl by hydrolysis; and then carrying out alkaline aqueous solution ionization and L-(+)-tartaric acid resolution to obtain a target compound. Compared with an original preparation method, the preparation method provided by the invention omits use of strong oxidizing and corrosive reagents such as potassium dichromate, concentrated sulfuric acid and bromine, changes two reaction steps of sodium hydroxide ionization and chiral resolution into a one-pot method, thereby reducing operation steps and increasing yield.

Description

technical field [0001] The present invention relates to a preparation method of a pharmaceutical intermediate, specifically a preparation method of (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole, which is a synthetic anti-Parkinson's The key intermediate of the disease drug pramipexole hydrochloride. Background technique [0002] (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole is a key intermediate of the anti-Parkinson's disease drug pramipexole hydrochloride. Pramipexole hydrochloride was first developed by Boehringer-Ingelheim in Germany, and it was first launched in the United States in May 1997. The trade name is Mirapex / Mirapex, and the specifications are 0.375mg, 0.75mg, 1.5mg, and 3mg. Currently reported preparation (6S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole methods mainly contain the following: [0003] (1) Synthetic route 1: [0004] [0005] This route uses 4-aminocyclohexanol as the starting material to protect the amino group through phthalic anhy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/82
CPCC07D277/82
Inventor 陶春蕾陈国祥王鹏飞
Owner ANHUI WANBANG MEDICAL TECH
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