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Preparation method for tofisopam intermediate

A kind of technology of tofisopam and intermediates, applied in directions such as oxidative preparation of carbonyl compounds, organic chemistry, etc., can solve problems such as isoeugenol methyl ether being more expensive, unfavorable for industrialized production, and improving the synthesis cost of tofisopam

Active Publication Date: 2013-04-24
ZHEJIANG APELOA KANGYU PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The raw material isoeugenol methyl ether price that these methods use is more expensive, accounts for very large proportion in the raw material cost of tofisopam, thereby has improved the synthetic cost of tofisopam, is unfavorable for industrialized production

Method used

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  • Preparation method for tofisopam intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Preparation of 1-(3,4-dimethoxyphenyl)-1-propanone

[0031] 1,2-Dichloroethane (30ml) and anhydrous aluminum trichloride (16.3g, 122.2mmol) were put into the reaction flask, the ice-water bath was cooled to 5°C, and propionyl chloride (8.8g, 95.1mmol) was added dropwise in turn 1,2-dichloroethane (20ml) solution, 1,2-dimethoxybenzene (10.0g, 72.4mol) solution in dichloroethane (30ml), reacted at 5°C for 3h, poured into ice water (40 g), stirred for 1 h, and then allowed to stand for layers, and the aqueous layer was extracted with 1,2-dichloroethane (20 ml). The organic layers were combined, washed with 10% NaOH aqueous solution (20ml), then washed with water (20ml×2) until nearly neutral, dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 13.9g of crude target compound in a yield of 98.9 %.

Embodiment 2

[0033] Preparation of 1-(3,4-dimethoxyphenyl)-1-propanone

[0034] 1,2-Dichloroethane (30ml) and anhydrous aluminum trichloride (48.9g, 366.6mmol) were put into the reaction flask, the ice water bath was cooled to 5°C, and propionic anhydride (12.4g, 95.1mmol) was added dropwise in turn 1,2-dichloroethane (20ml) solution, 1,2-dimethoxybenzene (10.0g, 72.4mol) solution in dichloroethane (30ml), reacted at 5°C for 3h, poured into ice water (40 g), stirred for 1 h, and then allowed to stand for layers, and the aqueous layer was extracted with 1,2-dichloroethane (20 ml). The organic layers were combined, washed with 10% NaOH aqueous solution (20ml), then washed with water (20ml×2) until nearly neutral, dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 12.4g of crude target compound, yield 88.2 %.

Embodiment 3

[0036] Preparation of 1-(3,4-dimethoxyphenyl)-1-propanol

[0037] Put 1-(3,4-dimethoxyphenyl)-1-propanone (44.4g, 228.6mol), potassium borohydride (6.9g, 127.9mmol) and ethanol (300ml) into a reaction flask, and react at 60°C After 12h, the solvent was evaporated under reduced pressure, water (90ml) and toluene (150ml) were added to the concentrated solution, stirred at room temperature for 0.5h, left to stand for stratification, and the aqueous layer was extracted with toluene (50ml×2). The organic layers were combined, washed with saturated saline solution (50ml×3), dried with anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure, and the remaining oily substance was continuously distilled under reduced pressure to collect 120-125°C / 1mmHg fractions to obtain 39.3g of the target compound, Yield 87.6%.

[0038] 1 HNMR (CDCl 3 )δ: 6.890-6.815(m, 3H), 4.519-4.480(t, 1H), 3.859-3.843(m, 6H), 2.138(s, 1H), 1.795-1.706(m, 2H), 0.913-0.877( t, 3H).

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Abstract

The invention provides a preparation method for a tofisopam intermediate 3-[2-(3,4- dimethoxybenzoyl)-4,5-dimethoxyphenyl]-pentan-2- ketone(I). The method uses 1,2- dimethoxybenzene (III) as original raw material to replace isoeugenol methyl ether(V). The reaction comprises the following steps: reacting 1,2- dimethoxybenzene (III) with a propionylated agent to product a (IIIA) compound; reducing the (IIIA) compound with a reductant to obtain a compound of formula (IV); and reacting 1-(3,4- dimethoxybenzene)-1- propanol (IV) with an oxidant in the present of acids. The raw material of the method of the invention has low price so as to greatly reduce the cost and is suitable for industrially producing tofisopam.

Description

Field of Invention [0001] The invention belongs to the fields of organic chemistry and medicinal chemistry, in particular to the preparation of anxiolytic tofisopam, and more particularly to the preparation of an intermediate of tofisopam. Background of the Invention [0002] Patent documents HU155572, HU179018, HU191698, HU195788, and US20040138209 describe several biologically active 2,3-benzodiazepine (Zozo) derivatives, these compounds generally have anxiolytic, antidepressant, antispasmodic properties , muscle relaxation and neuroprotective properties. [0003] In this class of compounds, compound 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzo Diazepam (Fuzhuo) (formula II), commonly known as Tofisopam (Tofisopam), acts like diazepam (Valium), but basically has no sedative, anticonvulsant and muscle relaxant effects, and traditional benzene Compared with diazepines, the side effects of drowsiness are rare and not obvious. In the treatment of meno...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/84C07C45/29
Inventor 张柯华张永飞胡畏权
Owner ZHEJIANG APELOA KANGYU PHARMA
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