Synthetic method for tetrabenazine and intermediate of tetrabenazine

A synthesis method and technology of tetrabenazine are applied in the field of synthesis of tetrabenazine and intermediates thereof, and can solve the problems of difficult removal of impurities and poor purity, and achieve the effects of increased selectivity, readily available raw materials, and simple operation.

Inactive Publication Date: 2018-02-16
北京恒瑞康达医药科技发展有限公司
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Problems solved by technology

The intermediate preparation process of this method is similar to WO 080582612, and a large amount of isomer impurities 1-(dimethylamino)-6-methyl-3-heptanone and diaminomethyl substituted products wil...

Method used

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  • Synthetic method for tetrabenazine and intermediate of tetrabenazine
  • Synthetic method for tetrabenazine and intermediate of tetrabenazine
  • Synthetic method for tetrabenazine and intermediate of tetrabenazine

Examples

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Effect test

example 1

[0039] Preparation of 3-dimethylaminomethyl-5-methyl-2-hexanone (intermediate)

[0040]Add dimethylamine hydrochloride (41g, 0.5mol), paraformaldehyde (29.5g, 1mol), 5-methyl-2-hexanone (210ml, 1.5mol) into 500ml methanol, add 0.1N hydrochloric acid ( 12mol / L, 4.2ml, 0.05mol), heated to react. The reaction temperature was controlled at 55-60° C., and the reaction was carried out for 24 hours. Remove the solvent under reduced pressure, add 300ml of water, now under acidic conditions, extract the unreacted raw materials with n-hexane, adjust the pH value of the aqueous phase to about 7-9 with dilute sodium hydroxide solution, extract with 100ml of n-hexane, and then adjust the pH value of the aqueous phase to about 7-9, re-extract 100ml, repeat 5-6 times, combine the organic phases and concentrate under reduced pressure, and rectify the residue under reduced pressure, collect 2mmHg, 75±1°C fractions, and obtain 31.6g of refined intermediates, with a yield of 37.1% (GC %>98%). ...

example 2

[0042] Synthesis of Tetrabenazine

[0043] The intermediate (3-dimethylaminomethyl-5-methyl-2-hexanone, 30g, 0.175mol) and 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (39.8g, 0.175mol) was added to 300ml of water, a catalyst (TEBAC, 4.0g, 0.018mol, 0.1N) was added, and the reaction was heated. The temperature is controlled at 50-60°C, and the reaction time is 24h. Stop stirring, cool down to room temperature, filter the solid, and wash twice with 100 ml of water to obtain 41.5 g of crude tetrabenazine as an off-white solid, with a yield of 81.3%. Recrystallized from absolute ethanol to obtain 40.6 g of refined tetrabenazine, with a total yield of 73.3% and an HPLC purity of >99.5%.

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Abstract

This study illustrates a simple and efficient method for the synthesis of tetrabenazine and its intermediates. First, take paraformaldehyde, dimethylamine hydrochloride, and 5-methyl-2-hexanone as raw materials to synthesize the key intermediate 3-dimethylaminomethyl-5-methyl-2-hexanone; secondly, to The crude product is effectively optimized by a simple chemical purification operation to obtain a key intermediate with higher purity; finally, using water as a solvent under the action of a catalyst, the purified key intermediate and 6,7-dimethoxy-3,4 ‑ Dihydroisoquinoline hydrochloride condensation to obtain tetrabenazine crude product, recrystallization can obtain tetrabenazine product, HPLC purity greater than 99.5%. The method uses simple chemical raw materials to obtain key intermediates with high purity through synthesis and purification, thereby further obtaining tetrabenazine products with good purity; the method has easy-to-obtain raw materials, simple operation, no need for special equipment, and high yield , get tetrabenazine with high purity.

Description

technical field [0001] This study illustrates a simple and efficient method for the synthesis of tetrabenazine and its intermediates. Background technique [0002] The invention belongs to the field of organic chemical synthesis, and relates to a preparation method of tetrabenazine and an intermediate thereof. [0003] Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by progressive involuntary movements, neuropsychiatric disorders, and cognitive impairment. There are currently no effective treatments that can delay or stop the progression of the disease. The treatment of HD is mainly focused on symptomatic therapy, with the aim of reducing the impact of the disease on the individual's abilities, mainly improving motor function, in order to obtain a favorable impact on their quality of life. [0004] Tetrabenazine (TBZ) was first synthesized in 1956 and was first approved by Switzerland for the treatment of neurasthenia and schizoph...

Claims

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Application Information

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IPC IPC(8): C07D455/06C07C221/00C07C225/06
CPCC07D455/06C07C221/00C07C225/06
Inventor 牛永涛李政宇
Owner 北京恒瑞康达医药科技发展有限公司
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