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Method for synthesizing (+/-)-9-O-demethyl-alpha-dihydrotetrabenazine

A technology of dihydrotetrabenazine and -9-O-, applied in the field of drug synthesis, can solve the problems of inability to be widely used in industry, poor repeatability, low conversion rate and the like, and achieves reasonable step design, high conversion rate, and economical cost effect

Active Publication Date: 2011-03-16
JIANGSU INST OF NUCLEAR MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its synthetic route is as follows figure 1 As shown, in the process of actual operation, the synthesis method of the prior art not only has low conversion rate and low yield, but also has poor repeatability, and cannot be widely used in industry

Method used

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  • Method for synthesizing (+/-)-9-O-demethyl-alpha-dihydrotetrabenazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The synthetic steps of (±)-9-O-desmethyl-α-dihydrotetrabenazine are as follows:

[0030] Add sodium hydride and hexamethylphosphoric triamide to xylene, add N-methylaniline dropwise after heating to 90°C, and stir for 15 minutes; add (±)-α-dihydrobutylbenzene dropwise to the above reaction mixture After the addition of the xylene suspension of nazine is completed, the reaction suspension is continuously stirred at 90°C for 48 hours; an aqueous sodium hydroxide solution is slowly added to the above reaction suspension, and the water phase is separated, and the water phase is neutralized by aqueous hydrochloric acid to After the pH value was 7, it was extracted with ether, and the organic phase was concentrated under reduced pressure to obtain a light brown solid; the above light brown solid was purified by column chromatography to obtain the compound (±)-9-O-desmethyl-α-dihydrobutanol benazine. The column chromatography purification steps are as follows: Weigh the silic...

Embodiment 2

[0033] The synthetic steps of (±)-9-O-desmethyl-α-dihydrotetrabenazine are as follows:

[0034] Add sodium hydride and hexamethylphosphoric triamide to xylene, add N-methylaniline dropwise after heating to 100°C, and stir for 20 minutes; add (±)-α-dihydrobutylbenzene dropwise to the above reaction mixture After the addition of the xylene suspension of nazine is completed, the reaction suspension is continuously stirred at 100° C. for 50 h; an aqueous sodium hydroxide solution is slowly added to the above reaction suspension, and the water phase is separated, and the water phase is neutralized by aqueous hydrochloric acid to After the pH value was 9, it was extracted with ether, and the organic phase was concentrated under reduced pressure to obtain a light brown solid; the above light brown solid was purified by column chromatography to obtain the compound (±)-9-O-desmethyl-α-dihydrobutanol benazine. The column chromatography purification steps are as follows: Weigh the silic...

Embodiment 3

[0037] The synthetic steps of (±)-9-O-desmethyl-α-dihydrotetrabenazine are as follows:

[0038] Add sodium hydride and hexamethylphosphoric triamide to xylene, add N-methylaniline dropwise after heating to 95°C, and stir for 18 minutes; add (±)-α-dihydrobutylbenzene dropwise to the above reaction mixture After the addition of the xylene suspension of nazine is completed, the reaction suspension is continuously stirred at 95°C for 49 hours; an aqueous sodium hydroxide solution is slowly added to the above reaction suspension, and the water phase is separated, and the water phase is neutralized by aqueous hydrochloric acid to After the pH value was 8, it was extracted with ether, and the organic phase was concentrated under reduced pressure to obtain a light brown solid; the above light brown solid was purified by column chromatography to obtain the compound (±)-9-O-desmethyl-α-dihydrobutanol benazine. The column chromatography purification steps are as follows: Weigh the silic...

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Abstract

The invention discloses a method for synthesizing (+ / -)-9-O-demethyl-alpha-dihydrotetrabenazine, which comprises the following steps of: adding sodium hydride and hexamethylphosphoramide into dimethylbenzene, heating to the temperature of between 90 and 100 DEG C, dripping N-methylaniline, and stirring for 15 to 20 minutes; dripping dimethylbenzene suspension of (+ / -)-alpha-dihydrotetrabenazine into the mixed solution, after dripping, continuously stirring the reaction suspension at the temperature of between 90 and 100 DEG C for 48 to 50 hours; slowly adding aqueous solution of sodium hydroxide into the reaction suspension, separating out an aqueous phase, neutralizing the aqueous phase by using aqueous solution of hydrochloric acid until the pH value is 7 to 9, extracting by using diethyl ether, concentrating an organic phase under reduced pressure to obtain a light brown solid; and purifying the light brown solid by using column chromatography technology to obtain the target product. By optimizing the reaction conditions of the prior art and improving posttreatment and purification technology, the method has the advantages of low preparation cost, high repeatability and high yield.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method of (±)-9-O-desmethyl-α-dihydrotetrabenazine. Background technique [0002] The type 2 vesicular monoamine transporter is a membrane protein located on the membrane of intracytoplasmic vesicles in neurons and plays a key role in the reuptake of monoamine transmitters. Therefore, radionuclide imaging studies using type 2 vesicular monoamine transporter as the target can reflect the changes of monoamine transmitters in the nervous system. So far, a series of imaging agents for type 2 vesicular monoamine transporter have been developed at home and abroad, and they are basically diffracted substances of dihydrotetrabenazine (DTBZ). (±)-9-O-desmethyl-α-dihydrotetrabenazine ((±)-9-O-DM-α-DTBZ) is a synthetic type 2 vesicular monoamine transporter imaging agent such as 11 C-DTBZ and 18 An important intermediate compound of F-FP-DTBZ. in 11 The research on C-DTBZ has ...

Claims

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Application Information

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IPC IPC(8): C07D455/06
Inventor 刘春仪陈正平李晓敏唐婕
Owner JIANGSU INST OF NUCLEAR MEDICINE
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