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Preparation method of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizidine-2-ketone

A technology of dimethoxy and methyl, applied in the field of chemistry, can solve problems such as easy polymerization, unfavorable industrial production, and many reaction steps

Active Publication Date: 2011-07-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route has many reaction steps, some reaction conditions are harsh and complicated to operate, the reagents used are expensive (such as palladium / carbon, etc.), and the total yield is low, so it is not conducive to industrial production
[0007] The synthetic method of TBZ reported by Osbond etc. (Osbond, J.Chem.Soc.1961,4711) adopts expensive and flammable aluminum tetrahydrogen lithium as reducing agent, and key intermediate is difficult for preparation, and total yield is low, therefore also not suitable for Industrial production
[0008] Szantay et al. reported that from 6,7-dimethoxy-3,4-dihydroisoquinoline and 3-isobutyl-3-butene- The method for synthesizing TBZ from 2-ketone, the disadvantage of this method is that the preparation yield of 3-isobutyl-3-buten-2-one is very low, easy to polymerize, and very toxic, which is not conducive to industrial production
The shortcoming of this method is that when utilizing 5-methyl-2-hexanone to carry out Mannich reaction to prepare 3-dimethylaminomethyl-5-methyl-hexane-2-one, the reaction yield is extremely low (only 16% ), and need to be separated and purified by column chromatography
In addition, methyl iodide, which is highly toxic and expensive, is also used, so this method is not suitable for industrial production
[0010] In summary, the existing method for preparing TBZ has long reaction steps, complicated process, high cost and potential environmental protection hazards

Method used

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  • Preparation method of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizidine-2-ketone
  • Preparation method of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizidine-2-ketone
  • Preparation method of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizidine-2-ketone

Examples

Experimental program
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Effect test

Embodiment 1

[0021] (1) Preparation of 3-dimethylaminomethyl-5-methyl-hexane-2-one

[0022] Under ice bath, add aqueous sodium hydroxide solution (1 equivalent) dropwise to ethyl 2-isobutylacetoacetate (3.06 g), after the addition is complete, stir at room temperature until the reaction is complete (TLC detection), then add 38% formaldehyde solution in turn (1.63ml) and Me 2 NH.HCl (1.33 g). After the addition, stir at room temperature until the reaction is complete (TLC detection). Add sodium hydroxide aqueous solution dropwise under ice bath, after the addition is complete, stir at room temperature for a period of time, extract with ethyl acetate, dry the extract with anhydrous sodium sulfate overnight, filter, evaporate the solvent, and distill under reduced pressure to obtain a colorless and transparent Liquid 3-dimethylaminomethyl-5-methyl-hexane-2-one (yield 50.1%). 1 H NMR (300MHz, CDCl 3 ): δ0.90(d, 3H, J=5.7Hz), 0.95(d, 3H, J=8.8Hz), 1.16-1.25(m, 1H), 1.42-1.57(m, 2H), 2.15(s,...

Embodiment 2

[0026] (1) Preparation of 3-diethylaminomethyl-5-methyl-hexane-2-one

[0027] Under ice bath, add aqueous potassium hydroxide solution (1 equivalent) dropwise to ethyl 2-isobutylacetoacetate (3.06 g), after the addition is complete, stir at room temperature until the reaction is complete (TLC detection), then add 38% formaldehyde solution in turn (1.63ml) and Et 2 NH.HCl (1.80 g). After the addition, stir at room temperature until the reaction is complete (TLC detection). Add sodium hydroxide aqueous solution dropwise under ice bath to alkalinize, after adding, stir at room temperature for a period of time, extract with ethyl acetate, dry the extract with anhydrous sodium sulfate overnight, filter, evaporate the solvent, and distill under reduced pressure to obtain Color transparent liquid 3-diethylaminomethyl-5-methyl-hexane-2-one (yield 52.5%).

[0028] (2) preparation of tetrabenazine

[0029] Mix 6,7-dimethoxy-3,4-dihydroisoquinoline (1.38 g) with ethanol (20 ml), add ...

Embodiment 3

[0031] Preparation of tetrabenazine

[0032] Mix 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (147.88 g) with ethanol (1000 ml), and add 3-diethylaminomethyl-5-methanol dropwise under stirring at room temperature Base-hexane-2-one (129.35 g), after the addition was completed, stirred at room temperature, a solid precipitated out, filtered with suction, and washed with water to obtain a light yellow solid crude product. After recrystallization, an off-white solid product-tetrabenazine (65% yield) was obtained, and the HPLC purity was above 99%.

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Abstract

The invention relates to a novel preparation method of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] quinolizidine-2-ketone. The technological method is economic, simple, convenient and high in total yield, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of chemistry, in particular to 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a] The preparation method of quinozin-2-one (tetrabenazine). Background technique [0002] Tetrabenazine (Tetrabenazine, TBZ) was listed in Switzerland in the late 1950s, initially for the treatment of schizophrenia. After a period of clinical use, it was found that TBZ is a dopamine receptor blocking drug. TBZ has been tested and found to have a wider range of uses, especially in hyperkinesia. In 2008, TBZ became the first drug approved by the FDA for the treatment of Huntington's disease in the United States. TBZ mainly reduces the supply of monoamines, such as serotonin, dopamine and norepinephrine, by reversibly inhibiting the monoamine transporter 2 (VMAT 2) in the central nervous system to produce pharmacological activity. In addition to inhibiting VMAT 2, TBZ also has certain antagonistic effects on pre...

Claims

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Application Information

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IPC IPC(8): C07D455/06
Inventor 孙宏斌温小安
Owner CHINA PHARM UNIV
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