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Method for preparing tartrate

A technology of tartrate and toluoyl tartrate, which is applied in the field of drug synthesis, can solve problems such as racemization and refining failure, and achieve the effects of simple operation, improved refining rate, high purity and yield

Active Publication Date: 2014-11-05
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

US2009099375A1 chooses isopropanol as the refining solvent. Due to the low solubility of tartrate in isopropanol, the amount of isopropanol in the refining process of this patent is as high as 14 times, and high temperature refluxing at 80°C is required to dissolve tartrate, and tartrate is in Reflux at high temperature can easily cause racemization and make refining fail
The total yield of the patent is only 73%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 20.0g of compound (I) hydrobromide, 80ml of dichloromethane, 10g of 30% sodium hydroxide, and 20ml of water, and stir to react. After standing still, the water layer was separated, the organic layer was washed with water, and dichloromethane was evaporated to obtain 19.9 g of compound (I) oil. Add 60ml of isopropanol, 0.2g of water, stir, add 9.1g of D-DTTA at 40°C, stir and crystallize, the crystallization temperature is 20°C. Cool down, filter with suction, wash with isopropanol, and dry to obtain 12.0 g of crude compound (Ⅲ), with an optical purity (HPLC) of 93%, and a yield of 88.2%. 12.0g of crude compound (Ⅲ) was heated and dissolved in 9ml of methanol, the temperature was controlled at 40°C, 36ml of isopropanol was added dropwise for 2 hours, the temperature was lowered, filtered with suction, washed with isopropanol, and dried to obtain the fine product of compound (Ⅲ) 10.6g, optical purity (HPLC) 99.95%, purification rate 95.0%, total yield 83.8%.

Embodiment 2

[0031] Add 20.0g of compound (I) hydrobromide, 60ml of dichloromethane, 8g of 30% sodium hydroxide, and 16ml of water, and stir to react. After standing still, the water layer was separated, the organic layer was washed with water, and dichloromethane was evaporated to obtain 18.8 g of compound (I) oil. Add 80ml of isopropanol, 0.2g of water, stir, add 9.5g of D-DTTA at 20°C, stir and crystallize, the crystallization temperature is 30°C. Cool down, filter with suction, wash with isopropanol, and dry to obtain 12.5 g of crude compound (Ⅲ), with an optical purity (HPLC) of 90%, and a yield of 88.9%. Heat and dissolve 12.5g of compound (Ⅲ) crude product in 6.3ml of methanol, control the temperature at 50°C, add 25ml of isopropanol dropwise for 4 hours, cool down, filter with suction, wash with isopropanol, and dry to obtain compound (Ⅲ) The fine product is 10.8g, the optical purity (HPLC) is 99.90%, the refining rate is 96.0%, and the total yield is 85.4%.

Embodiment 3

[0033] Add 20.0 g of compound (I) hydrobromide, 100 ml of dichloromethane, 12 g of 30% sodium hydroxide, and 24 ml of water, and stir to react. After standing still, the water layer was separated, the organic layer was washed with water, and dichloromethane was evaporated to obtain 20.2 g of compound (I) oil. Add 100ml of isopropanol, 1.0g of water, stir, add 10.0g of D-DTTA at 30°C, stir and crystallize, the crystallization temperature is 40°C. Cool down, filter with suction, wash with isopropanol, and dry to obtain 10.5 g of crude compound (Ⅲ), with an optical purity (HPLC) of 98.8%, and a yield of 82.5%. 10.5g of crude compound (Ⅲ) was heated and dissolved in 10.5ml of methanol, controlled temperature at 30°C, 42ml of isopropanol was added dropwise for 3h, cooled down, filtered with suction, washed with isopropanol, dried to obtain compound (Ⅲ) The fine product is 10.1g, the optical purity (HPLC) is 99.97%, the refining rate is 97.5%, and the total yield is 80.1%.

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Abstract

The invention belongs to the field of medicament synthesis, and particularly relates to a method for preparing tartrate. The method comprises the following steps of: dissolving an (RS)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile (I) oily matter into isopropyl alcohol; adding water; controlling temperature; stirring and adding D-(+)-Di-para-toluoyl-tartaric acid (D-DTTA) (II); after a reaction liquid becomes transparent, continuing to stir to crystallize, filtrating, washing and drying to obtain a crude (S)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile hemi-D-(+)-Di-para-toluoyl-tartaric acid (III) product; heating the crude (S)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl) benzonitrile hemi-D-(+)-Di-para-toluoyl-tartaric acid (III) product in methanol to melt; controlling temperature; dropwise adding isopropyl alcohol to crystallize; decreasing temperature, carrying out suction filtering, washing and drying to obtain the fine product. The method is easy to operate, and the prepared tartrate is high in purity and yield.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of tartrate. Background technique [0002] Citalopram is clinically used for the treatment of depression. It was developed by Swiss Lundbeck Company and first launched in 1989. While citalopram is a racemic enantiomer, the effect of the R enantiomer is only 1 / 100 of that of the S enantiomer. Therefore, the citalopram of the S enantiomer, namely escitalopram oxalate, was first marketed in the United States in 2002. Based on the consideration of curative effect and safety, tartrate with high optical purity becomes the key to prepare escitalopram oxalate. [0003] The resolution and purification method provided by WO2006106531A1 has a very low yield. Due to the low solubility of tartrate in isopropanol, the solubility in methanol is very high. In addition to adding isopropanol in the resolution, 1.5 times the amount of methanol was added, resulting in a very lo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C255/59C07C253/30C07C69/78C07C67/28
Inventor 翟吉胜郑忠辉赵春燕于磊窦国华
Owner SHANDONG XINHUA PHARMA CO LTD
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