Preparation process of key intermediate 5-cyanphthalide of antidepressant drug citalopram

A technology for citalopram and antidepressants, applied in the field of pharmaceutical intermediate preparation, can solve the problems of complex post-processing, harsh conditions, long cycle time, etc., and achieve the effects of short reaction process flow, simple material feeding and post-processing

Inactive Publication Date: 2007-05-16
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction process of the above-mentioned synthetic processes has a long cycle time and harsh conditions, or many experimental processes involve strong acid or strong alkali conditions, low yield, complex post-processing and other problems

Method used

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  • Preparation process of key intermediate 5-cyanphthalide of antidepressant drug citalopram
  • Preparation process of key intermediate 5-cyanphthalide of antidepressant drug citalopram
  • Preparation process of key intermediate 5-cyanphthalide of antidepressant drug citalopram

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] In a 100 ml three-necked flask, 50 ml of toluene, 6.4 g (30 mmol) of 5-bromophthalide, 1.18 g (36 mmol, 1.2 equivalents) of sodium cyanide, 0.573 g (3 mmol) of sodium cyanide were added successively under nitrogen protection. , 0.1 equivalent) cuprous iodide, 1 gram of potassium iodide (6 mmol, 0.2 equivalent), 2.64 grams of N, N'-dimethylethylenediamine (30 mmol, 1.0 equivalent), under nitrogen protection at 110 ° C Stir the reaction for 30 hours, end the reaction, recover the solvent toluene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization with ethanol to obtain white needle-shaped crystals of 5-cyanobenzene Phthale, the yield is 90%, the purity is 98% (HPLC), and the melting point is 200-202°C. 1 HNMR (CDCl 3 , ppm): 5.51(2H, s), 7.55(1H, s), 7.55(1H, s), 8.05(1H, d, J=2.5Hz).

Embodiment 2

[0019] In a 100 ml three-necked flask, 60 ml of ethylbenzene, 6.4 g (30 mmol) of 5-bromophthalide, 1.6 g (39 mmol, 1.3 equivalents) of sodium cyanide, 0.573 g (3 mg) of sodium cyanide were added successively under nitrogen protection. mol, 0.1 equivalent) cuprous iodide, 1 gram of potassium iodide (6 mmol, 0.2 equivalent), 2.64 grams of N, N'-dimethylethylenediamine (30 mmol, 1.0 equivalent), under nitrogen protection at 130 Stir the reaction at ℃ for 24 hours, end the reaction, recover the solvent ethylbenzene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization from ethanol to obtain white needle-shaped crystals of 5-cyanide phenylphthalide, the yield is 85%, the purity is 99%, and the melting point is 201-202°C.

Embodiment 3

[0021] In a 100 ml three-necked flask, 50 ml of toluene, 6.4 g (30 mmol) of 5-bromophthalide, 1.18 g (36 mmol, 1.2 equivalents) of sodium cyanide, 0.7 g (4.5 mmol) of sodium cyanide were added successively under nitrogen protection. , 0.15 equivalents) cuprous iodide, 1.5 grams of potassium iodide (9 mmoles, 0.3 equivalents), 2.64 grams of N, N'-dimethylethylenediamine (30 mmoles, 1.0 equivalents), under nitrogen protection at 100 ° C Stir the reaction for 48 hours, end the reaction, recover the solvent toluene under reduced pressure, then add 50 ml of water to the residue, stir at room temperature for 1 hour, filter, wash with water, and finally the filtrate is separated by recrystallization with ethanol to obtain white needle-shaped crystals of 5-cyanobenzene Phthale, the yield is 91%, the purity is 98%, and the melting point is 200-202°C.

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Abstract

The invention discloses a prapring method of key intermediate of 5-cyanobenzene phthalidyl to prevent depression, which comprises the following steps: adopting alkyl benzene as reacting solvent; making 1.5-3% cuprous iodide, potassium iodide and 1-1.5% N, N'-dimethyldiamine as composite catalyst; reacting 5-brobenzene phthalidyl and sodium cyanide with molar rate at 1: 1.0-2.0 protected by nitrogen at 100-150 Deg C for 20-48h; filtering; decompressing the filtrate; fractioning to obtain the product. The invention shortens reacting flow path, which is simple to feed and dispose.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation process of a key intermediate of citalopram, an antidepressant, 5-cyanophthalide. Background technique [0002] The chemical name of 5-cyanophthalide (5-Cyano-phthalide) is 1,3-dihydro-1-oxo-5-isobenzofuranonitrile, which is the key intermediate for the synthesis of antidepressant citalopram. body. Therefore, how to efficiently synthesize 5-cyanophthalide has attracted great attention. The synthesis of 5-cyanophthalide has been reported in some literatures. For example, the document WO00112044, 2000-03-09 reported that 5-carboxyphthalide was prepared by using phthalic acid and paraformaldehyde as starting materials under the action of oleum. It can be prepared by thionyl chloride chlorination, amidation of ammonia and dehydration of sulfolane. Literature "Chemical and Biological Engineering" 2006, Vo1.23, No.6, 17-18 and "Chinese Journal of...

Claims

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Application Information

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IPC IPC(8): C07D307/88
Inventor 徐方羲林旭锋
Owner ZHEJIANG UNIV
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