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Process for synthesizing 5-cyanophthalide

A technology for the synthesis of cyanophthalide and 5-cyanophthalide, which is applied in the field of synthesis of 5-cyanophthalide, can solve the problems of long cycle time, complicated post-processing, harsh conditions, etc., achieve short reaction process, safe and mild reaction conditions, The effect of little pollution

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 above-mentioned synthetic processes have a long cycle time and harsh conditions, or many experimental processes involve strong acid or strong alkali conditions, highly toxic reagents (such as sodium cyanide, potassium cyanide), low yield, complex post-treatment and other problems

Method used

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  • Process for synthesizing 5-cyanophthalide
  • Process for synthesizing 5-cyanophthalide
  • Process for synthesizing 5-cyanophthalide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] In a 100 ml three-necked flask, under the protection of nitrogen, 50 ml of N,N-dimethylacetamide solvent, 6.4 g (30 mmol) of 5-bromophthalide, 2.5 g (6 mmol, 0.2 equivalent) of three Potassium ferrocyanide hydrate, 68 mg (0.3 mmol, 0.3 mol%) palladium acetate catalyst, 3.5 g sodium carbonate (33 mmol, 1.1 equivalent), stirred and reacted at 100°C for 1 hour under the protection of nitrogen to complete the reaction. The solvent N,N-dimethylacetamide was recovered under reduced pressure, the residue was then added with 50 ml of water, stirred at room temperature for 1 hour, filtered and washed with water, and finally the filtrate was recrystallized with acetic acid to obtain white needle-like crystals of 5-cyano. Phthalide, yield 94%, purity 98% (HPLC), melting point 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

[0020] In a 100 ml three-necked flask, under the protection of nitrogen, add 50 ml of N,N-dimethylacetamide solvent, 6.4 g (30 mmol) of 5-bromophthalide, 2.8 g (6.6 mmol, 0.22 equivalent) of three Potassium ferrocyanide hydrate, 340 mg (1.5 mmol, 5 mol%) palladium acetate catalyst, 3.18 g sodium carbonate (30 mmol, 1.0 equivalent), stirred and reacted at 120°C for 2 hours under the protection of nitrogen, and the reaction was terminated. The solvent N,N-dimethylacetamide was recovered by pressure, the residue was then added with 50 ml of water, stirred at room temperature for 1 hour, filtered, washed with water, and finally the filtrate was recrystallized with acetic acid to obtain white needle-like crystals of 5-cyanophthalide , The yield is 95%, the purity is 99%, and the melting point is 201~202℃.

Embodiment 3

[0022] In a 100 ml three-necked flask, under the protection of nitrogen, add 50 ml of N,N-dimethylacetamide solvent, 6.4 g (30 mmol) of 5-bromophthalide, 3.1 g (7.5 mmol, 0.25 equivalent) of three Sodium ferrocyanide hydrate, 0.15 millimoles (0.5 mol%) bis(dibenzylidenepyruvate) palladium catalyst, 3.18 g sodium carbonate (30 millimoles, 1.0 equivalent), stirred at 120°C under nitrogen for reaction 3 After hours, the reaction was completed and the solvent N,N-dimethylacetamide was recovered under reduced pressure. The residue was then added with 50 ml of water, stirred at room temperature for 1 hour, filtered and washed with water, and finally the filtrate was recrystallized with acetic acid to obtain white needle-like crystals. 5-cyanophthalide, 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, which comprises the following steps: adopting N, N-dimethylacetamide as reacting solvent and 0.1-5% palladium complex as catalyst; making 0.5-2% alkaline metal carbonate as alkaline; reacting 5, 4-difluobromobenzene and ferrocyanide with molar rate at 1: 0.15-0.3 to react under 100-150 Deg C for 1-6h; filtering; decompressing the filtrate; fractioning to obtain the product. The invention shortens reacting flow path, which is simple to feed and dispose without poison in the whole course.

Description

Technical field [0001] The invention relates to a preparation method of pharmaceutical intermediates, in particular to a synthesis process of 5-cyanophthalide. Background technique [0002] The chemical name of 5-Cyano-phthalide (5-Cyano-phthalide) is 1,3-dihydro-1-oxo-5-isobenzofuran nitrile, which is the key to the synthesis of antidepressant citalopram (Citalopram) body. Therefore, how to efficiently and greenly synthesize 5-cyanophthalide has attracted great attention. The synthesis of 5-cyanophthalide has been reported in some literatures. For example, documents WO 00 112 044 and 2000-03-09 reported that 5-carboxyl group was prepared by using phthalic acid and paraformaldehyde as starting materials under the action of fuming sulfuric acid. Phthalide is prepared by the reaction of thionyl chloride, amidation of ammonia and dehydration of sulfolane. Literature "Chemical and Biological Engineering" 2006, Vol.23, No.6, 17-18 and "Chinese Journal of Pharmaceutical Industry" 2004,...

Claims

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Application Information

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