Preparation method of citalopram intermediate

A technology of time and volume ratio, applied in the field of preparation of citalopram intermediates, can solve the problems of poor reaction selectivity and difficulty in obtaining

Inactive Publication Date: 2016-02-03
SUN YAT SEN UNIV +1
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Problems solved by technology

[0008] The technical problem to be solved in the present invention is to overcome the poor reaction selectivity of 4-fluorophenylmagnesium bromide Grignard reagent and 5-cyanophthalide in tetrahydrofuran and toluene solvent, it is difficult to obtain 4-(4 -(Dimethylamino)-1-(4-fluorophenyl)-1

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  • Preparation method of citalopram intermediate

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specific Embodiment approach

[0048] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0049] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0050] The synthetic route is as follows:

[0051]

Embodiment 14

[0052] Preparation of embodiment 14-fluorophenylmagnesium bromide Grignard reagent

[0053] 2-Methyltetrahydrofuran as solvent:

[0054]

[0055] reaction process:

[0056] At room temperature, Mg scraps (5.37g, 220.90mmol, 1.10equiv.) and iodine particles (539.3mg, 2.12mmol, 0.01equiv.) were suspended in 2-methyltetrahydrofuran (200mL), and the reaction mixture was evacuated and replaced with nitrogen four times. The reaction mixture was heated to 30°C, BFB (35.07g, 200.40mmol) diluted in 2-methyltetrahydrofuran (100mL) was added dropwise to the reaction mixture, the addition was completed after 85min, and the reaction mixture was reacted at 30°C under nitrogen protection for 0.5h.

[0057] Post-reaction processing:

[0058] The reaction mixture was sampled under nitrogen protection, and saturated NH 4 Cl solution (2 mL) was used to quench the reaction, and 5 drops of the 2-methyltetrahydrofuran layer were diluted with chromatographic acetonitrile / purified water 1.5 mL ...

Embodiment 2

[0085] Preparation of Example 2 (5-cyano-2-(4-fluorobenzoyl) phenyl) magnesium bromide

[0086] 2-Methyltetrahydrofuran as solvent:

[0087]

[0088] reaction process:

[0089] At room temperature, the formula (I) (24.11g, 151.50mmol) was suspended in 2-methyltetrahydrofuran (241mL), the reaction mixture was evacuated and replaced with nitrogen 4 times, the reaction mixture was cooled to -20°C, and the formula (V) Grignard reagent ( 200mmol, dissolved in 300mL 2-methyltetrahydrofuran) was added dropwise to the above reaction mixture, and the dropwise addition was completed after 140min. The reaction mixture was stirred and reacted at -20°C under the protection of nitrogen for 1h and 2h, respectively, and samples were sent for inspection.

[0090] Post-reaction processing:

[0091] Sampling with saturated NH 4 The Cl solution was used to quench the reaction, and the 2-methyltetrahydrofuran layer was taken for HPLC detection. The reaction mixture was cooled to -20°C and u...

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Abstract

The invention provides a preparation method of a citalopram intermediate, and belongs to the technical field of pharmaceuticals. In the method, 2-methyltetrahydrofuran is taken as a reaction solvent. Under the protection of nitrogen, a 4-fluorophenylmagnesium bromide solution Grignard reagent, 5-cyanophthalein and a N,N-dimethylpropyl magnesium chloride Grignard reagent are taken as raw materials. A reaction is carried out to synthesize 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrilehydrobromide. The method is characterized by high yield and high purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a citalopram intermediate, belonging to the technical field of pharmacy. Background technique [0002] Citalopram is a 5-hydroxytryptamine reuptake inhibitor, has antidepressant activity, has been on the market for many years, and it is a well-known antidepressant. Citalopram was first disclosed in DE 2,657,013, corresponding to US Patent 4,136,193. This patent describes a process for the preparation of citalopram. According to the described method, the corresponding 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuranonitrile and 3-(N,N-Dimethylamino)propyl chloride was reacted to prepare citalopram. [0003] 4-(4-(Dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile hydrobromide [0004] [0005] It is an important intermediate in the synthesis of Citalopram. Therefore efficient synthesis of 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl) benzonitr...

Claims

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Application Information

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IPC IPC(8): C07C255/59C07C253/30
Inventor 杨凤智漆春辉肖毅杨丽珍鲁桂
Owner SUN YAT SEN UNIV
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