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Synthesis method of citalopram intermediate

A technology for citalopram and intermediates, applied in the field of preparation of citalopram intermediate 4--1--1-hydroxybutyl)-3-benzonitrile, can solve the problem of high overall cost and unfavorable industrial production , low yield and other problems, to achieve the effect of strong operability, short synthetic route, and cheap and easy-to-obtain raw materials

Active Publication Date: 2020-08-14
福建海西新药创制股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A class of solvent carbon tetrachloride and heavy metal silver nitrate are used in the middle, and extremely dangerous tert-butyllithium is used in the last step, and the yield is low. The intermediate is purified by column chromatography, and the overall cost is high, which is not conducive to industrial production

Method used

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  • Synthesis method of citalopram intermediate
  • Synthesis method of citalopram intermediate
  • Synthesis method of citalopram intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Synthesis of 4-(dimethylamino)-1-(4-fluorophenyl)butan-1-one hydrochloride

[0042] Add 4-chloro-1-(4-fluorophenyl)butan-1-one (20.1g, 0.1 mmol), dimethylamine (40% aqueous solution, 20mL) and ethanol (100mL) into a 250mL three-necked flask in sequence . The reaction was refluxed for 16 h, cooled to room temperature, concentrated under reduced pressure, then added water, and extracted with ethyl acetate. The organic phase was washed again with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was dissolved in acetone, fed with hydrogen chloride gas, stirred for 1 h, and then filtered with suction to obtain the hydrochloride of formula II (21.3 g, 86.9%).

Embodiment 2

[0043] Example 2 Synthesis of 4-(dimethylamino)-1-(4-fluorophenyl)butane-1-one

[0044] Add 4-chloro-1-(4-fluorophenyl)butan-1-one (20.1g, 0.1 mmol), dimethylamine hydrochloride (16.3g, 0.2mol), carbonic acid Potassium (27.6 g, 0.2 mol) and DMF (100 mL). Reacted at 80°C for 16h, cooled to room temperature, added saturated brine, and extracted with ethyl acetate. The organic phase was washed again with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was dissolved in acetone, fed with hydrogen chloride gas, stirred for 1 h, and then filtered with suction to obtain the hydrochloride of formula II. The hydrochloride salt of formula II was dissolved in water, and was extracted with aqueous sodium bicarbonate until no gas was generated, dried, concentrated and used (20.5 g, 83.4%).

Embodiment 3

[0045] Example 3 Synthesis of 5-chloro-2-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)benzoic acid

[0046] -78°C, under nitrogen protection, carefully drop n-butyl lithium (2.5M / hexane, 0.11mol) into 5-chloro-2-bromobenzoic acid (11.8g, 0.05mol) in anhydrous THF (100 mL ,44.0mL). After the dropwise incubation for 1 h, a solution of 4-(dimethylamino)-1-(4-fluorophenyl)butan-1-one (10.5 g, 0.05 mol) in THF (20 mL) was added dropwise. After the addition, it was raised to -60°C for 2 h, and then saturated ammonium chloride (100 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, washed once with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with dichloromethane to obtain a white solid (15.3 g, 83.5%).

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Abstract

The invention provides a preparation method of a citalopram intermediate 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl) benzonitrile. The method provided by the invention has the advantages of cheap and easily available raw materials, short reaction steps, high yield, simple post-treatment, easy operation and the like, reduces the cost, has certain technical advantages,and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to the citalopram intermediate 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxy The preparation method of methyl) benzonitrile. The information provided is intended only to aid the reader's understanding. Neither the information provided nor the references cited are admitted as prior art to the present invention. Each reference cited is incorporated herein in its entirety and may be used for any purpose. Background technique [0002] Citalopram (Citalopram), developed by the Danish company LUNDBECK, is a selective serotonin reuptake inhibitor (SSRI), which can selectively inhibit the 5-HT transporter and block the presynaptic membrane to 5-HT. Reuptake prolongs and increases the action of 5-HT, resulting in an antidepressant effect. [0003] 4-(4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile is an impor...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/34C07C253/14C07C255/59
CPCC07C221/00C07C227/02C07C213/00C07C29/147C07C213/02C07C253/14C07C225/16C07C229/38C07C215/34C07C33/46C07C255/59Y02P20/55
Inventor 王如勇郑建加冯岩康心汕
Owner 福建海西新药创制股份有限公司
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