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

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

Inactive Publication Date: 2009-02-04
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 in the synthesis of antidepressant citalopram (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 WO 00 112 044, 2000-03-09 reported that phthalic acid and paraformaldehyde were used as starting materials to prepare 5-carboxyphthalide under the action of oleum. Phthalide is prepared by thionyl chloride acyl chloride, ammonia amidation and sulfolane dehydration. Literature "Chemical and Biological Engineering" 2006, Vol.23, No.6, 17-18 and "Chinese...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/88
Inventor 徐方羲林旭锋
Owner ZHEJIANG UNIV
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