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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 unfavorable industrialized production, the price of isoeugenol methyl ether is relatively expensive, and the synthetic cost of tofisopam is improved.

Active Publication Date: 2010-09-08
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] Put 1,2-dichloroethane (30ml) and anhydrous aluminum trichloride (16.3g, 122.2mmol) into the reaction flask, cool down to 5°C in an ice-water bath, and then add propionyl chloride (8.8g, 95.1mmol) dropwise 1,2-dichloroethane (20ml) solution, 1,2-dimethoxybenzene (10.0g, 72.4mol) in dichloroethane (30ml) solution, after reacting at 5°C for 3h, pour into ice water (40g) was stirred for 1h, then the layers were separated, and the aqueous layer was extracted with 1,2-dichloroethane (20ml). The organic layers were combined, washed with 10% NaOH aqueous solution (20ml), and then washed with water (20ml×2) until nearly neutral, dried with anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain 13.9g of the crude product of the target compound, with a yield of 98.9% %.

Embodiment 2

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

[0034] Put 1,2-dichloroethane (30ml) and anhydrous aluminum trichloride (48.9g, 366.6mmol) into the reaction flask, cool down to 5°C in an ice-water bath, and then add propionic anhydride (12.4g, 95.1mmol) dropwise 1,2-dichloroethane (20ml) solution, 1,2-dimethoxybenzene (10.0g, 72.4mol) in dichloroethane (30ml) solution, after reacting at 5°C for 3h, pour into ice water (40g) was stirred for 1h, then the layers were separated, and the aqueous layer was extracted with 1,2-dichloroethane (20ml). The organic layers were combined, washed with 10% NaOH aqueous solution (20ml), and then washed with water (20ml×2) until nearly neutral, dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain 12.4g of the crude product of the target compound, with a yield of 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 the reaction flask, and react at 60°C After 12 hours, the solvent was evaporated under reduced pressure, water (90ml) and toluene (150ml) were added to the concentrated solution and stirred at room temperature for 0.5h, then the layers were separated, and the aqueous layer was extracted with toluene (50ml×2). The organic layers were combined, washed with saturated saline solution (50ml×3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the remaining oil was continuously distilled under reduced pressure to collect fractions at 120-125°C / 1mmHg to obtain 39.3g of the title compound. Yield 87.6%.

[0038] 1 HNMR (CDCl 3 ( 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, and in particular relates to the preparation of an anxiolytic drug tofisopam, more specifically 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 (Lvzhuo) derivatives, these compounds generally have anxiolytic, antidepressant, antispasmodic , muscle relaxation and neuroprotective properties. [0003] In this class of compounds, the compound 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzo Diazepine (Lv Zhuo) (formula Ⅱ), common name is Tofisopam (Tofisopam), the effect is similar to diazepam (stable), but basically has no sedative, anticonvulsant and muscle relaxation effects, and is different from traditional benzodiazepines. Compared with diazepines, the side effects of sleepymen ...

Claims

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Application Information

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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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