Synthesis method of 9-demethyl-(+)-alpha-dihydrotetrabenazine

Abstract

The invention relates to a synthesis method of 9-demethyl-(+)-alpha-dihydrotetrabenazine. The synthesis method comprises the following steps: 9-benzyloxy-(+)-alpha-dihydrotetrabenazine serves as a raw material and experiences reactions for at least 10min in a polar protonic solvent at room temperature under the catalysis of hydrobromic acid to obtain the reaction liquid of a crude product of 9-demethyl-(+)-alpha-dihydrotetrabenazine, wherein the polar protonic solvent is at least one of C1-C10 monohydric alcohols. The synthesis method has the advantages of relatively low preparation cost, relatively mild reaction conditions, relatively short reaction time, relatively simple reaction operation and relatively high reaction yield, facilitates the large-scale industrial production of 9-demethyl-(+)-alpha-dihydrotetrabenazine and lays a foundation for the large-scale industrial production of a development drug 11C-(+)-alpha-DTBZ and a development drug 18F-FP-(+)-alpha-DTBZ.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of 9-desmethyl-(+)-α-dihydrotetrabenazine. Background technique

[0002] Vesicular monoamine transporter type II (VMAT2) is a membrane protein located on the membrane of intracytoplasmic vesicles in neurons and plays a key role in the reuptake of monoamine transmitters. Molecular cloning technology identification shows that VMAT2 is mainly distributed in the central nervous system and pancreatic tissue of humans and mammals. Changes in VMAT2 are associated with various diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), diabetes, etc. In recent years, using VMAT2 as a target to conduct radioactive tracer imaging for early diagnosis, grading, differential diagnosis, and curative effect monitoring of related diseases has become one of the hot spots in nuclear medicine research. So far, the VMAT2 imaging...

Examples

Embodiment 1

[0043] The synthetic method of present embodiment 9-demethyl-(+)-α-dihydrotetrabenazine comprises the following steps:

[0044] Dissolve 1mmol of 9-benzyloxy-(+)-α-dihydrotetrabenazine in 5mL of methanol, add 2mmol of hydrobromic acid dropwise under stirring, and react at room temperature for 0.5h to obtain 9-desmethyl-(+ )-alpha-dihydrotetrabenazine crude product reaction solution;

[0045] It also includes the following steps of separation and purification treatment:

[0046](1) concentrating the reaction solution of the crude 9-desmethyl-(+)-α-dihydrotetrabenazine under reduced pressure to obtain a solid;

[0047] (2) Dissolving the solid in a mixed solvent of dichloromethane / ethyl acetate / methanol (volume ratio 1:1:0.05), standing still and crystallizing to obtain crystals;

[0048] (3) Dissolve the crystals in water, adjust the pH value to 7-9 with aqueous sodium hydroxide solution, extract with ether, and concentrate the organic phase under reduced pressure to obtain 9...

Embodiment 2

[0054] The synthetic method of present embodiment 9-demethyl-(+)-α-dihydrotetrabenazine comprises the following steps:

[0055] Dissolve 1mmol of 9-benzyloxy-(+)-α-dihydrotetrabenazine in 5mL of ethanol, add 5mmol of hydrobromic acid dropwise under stirring, and react for 1h at room temperature to obtain 9-desmethyl-(+) -The reaction liquid of α-dihydrotetrabenazine crude product;

[0056] It also includes the following steps of separation and purification treatment:

[0057] (1) concentrating the reaction solution of the crude 9-desmethyl-(+)-α-dihydrotetrabenazine under reduced pressure to obtain a solid;

[0058] (2) Dissolving the solid in a mixed solvent of dichloromethane / ethyl acetate / methanol (volume ratio 0.8:1.2:0.04), standing still and crystallizing to obtain crystals;

[0059] (3) Dissolve the crystals in water, adjust the pH value to 7-9 with potassium hydroxide aqueous solution, extract with ether, and concentrate the organic phase under reduced pressure to ob...

Embodiment 3

[0065] The synthetic method of present embodiment 9-demethyl-(+)-α-dihydrotetrabenazine comprises the following steps:

[0066] Dissolve 1mmol of 9-benzyloxy-(+)-α-dihydrotetrabenazine in 5mL of methanol, add 20mmol of hydrobromic acid dropwise under stirring, and react at room temperature for 1.5h to obtain 9-desmethyl-(+ )-alpha-dihydrotetrabenazine crude product reaction solution;

[0067] It also includes the following steps of separation and purification treatment:

[0068] (1) concentrating the reaction solution of the crude 9-desmethyl-(+)-α-dihydrotetrabenazine under reduced pressure to obtain a solid;

[0069] (2) Dissolving the solid in a mixed solvent of dichloromethane / ethyl acetate / methanol (volume ratio 1.2:0.8:0.06), standing still and crystallizing to obtain crystals;

[0070] (3) Dissolve the crystals in water, adjust the pH value to 7-9 with aqueous sodium carbonate solution, extract with ether, and concentrate the organic phase under reduced pressure to ob...

technical field

[0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of 9-desmethyl-(+)-α-dihydrotetrabenazine. Background technique

[0002] Vesicular monoamine transporter type II (VMAT2) is a membrane protein located on the membrane of intracytoplasmic vesicles in neurons and plays a key role in the reuptake of monoamine transmitters. Molecular cloning technology identification shows that VMAT2 is mainly distributed in the central nervous system and pancreatic tissue of humans and mammals. Changes in VMAT2 are associated with various diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), diabetes, etc. In recent years, using VMAT2 as a target to conduct radioactive tracer imaging for early diagnosis, grading, differential diagnosis, and curative effect monitoring of related diseases has become one of the hot spots in nuclear medicine research. So far, the VMAT2 imaging...

Examples

Embodiment 1

[0043] The synthetic method of present embodiment 9-demethyl-(+)-α-dihydrotetrabenazine comprises the following steps:

[0044] Dissolve 1mmol of 9-benzyloxy-(+)-α-dihydrotetrabenazine in 5mL of methanol, add 2mmol of hydrobromic acid dropwise under stirring, and react at room temperature for 0.5h to obtain 9-desmethyl-(+ )-alpha-dihydrotetrabenazine crude product reaction solution;

[0045] It also includes the following steps of separation and purification treatment:

[0046](1) concentrating the reaction solution of the crude 9-desmethyl-(+)-α-dihydrotetrabenazine under reduced pressure to obtain a solid;

[0047] (2) Dissolving the solid in a mixed solvent of dichloromethane / ethyl acetate / methanol (volume ratio 1:1:0.05), standing still and crystallizing to obtain crystals;

[0048] (3) Dissolve the crystals in water, adjust the pH value to 7-9 with aqueous sodium hydroxide solution, extract with ether, and concentrate the organic phase under reduced pressure to obtain 9...

Embodiment 2

[0054] The synthetic method of present embodiment 9-demethyl-(+)-α-dihydrotetrabenazine comprises the following steps:

[0055] Dissolve 1mmol of 9-benzyloxy-(+)-α-dihydrotetrabenazine in 5mL of ethanol, add 5mmol of hydrobromic acid dropwise under stirring, and react for 1h at room temperature to obtain 9-desmethyl-(+) -The reaction liquid of α-dihydrotetrabenazine crude product;

[0056] It also includes the following steps of separation and purification treatment:

[0057] (1) concentrating the reaction solution of the crude 9-desmethyl-(+)-α-dihydrotetrabenazine under reduced pressure to obtain a solid;

[0058] (2) Dissolving the solid in a mixed solvent of dichloromethane / ethyl acetate / methanol (volume ratio 0.8:1.2:0.04), standing still and crystallizing to obtain crystals;

[0059] (3) Dissolve the crystals in water, adjust the pH value to 7-9 with potassium hydroxide aqueous solution, extract with ether, and concentrate the organic phase under reduced pressure to ob...

Embodiment 3

[0065] The synthetic method of present embodiment 9-demethyl-(+)-α-dihydrotetrabenazine comprises the following steps:

[0066] Dissolve 1mmol of 9-benzyloxy-(+)-α-dihydrotetrabenazine in 5mL of methanol, add 20mmol of hydrobromic acid dropwise under stirring, and react at room temperature for 1.5h to obtain 9-desmethyl-(+ )-alpha-dihydrotetrabenazine crude product reaction solution;

[0067] It also includes the following steps of separation and purification treatment:

[0068] (1) concentrating the reaction solution of the crude 9-desmethyl-(+)-α-dihydrotetrabenazine under reduced pressure to obtain a solid;

[0069] (2) Dissolving the solid in a mixed solvent of dichloromethane / ethyl acetate / methanol (volume ratio 1.2:0.8:0.06), standing still and crystallizing to obtain crystals;

[0070] (3) Dissolve the crystals in water, adjust the pH value to 7-9 with aqueous sodium carbonate solution, extract with ether, and concentrate the organic phase under reduced pressure to ob...

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