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Preparation method of high-optical-purity escitalopram oxalate intermediate S-configuration diol

A technology for escitalopram oxalate and intermediates, which is applied in the field of preparation of high-purity escitalopram oxalate intermediates S-configuration diol, can solve the problem of poor reproducibility, yield of only 20.3%, There are no problems such as resolution effects, and the effects of high product yield, high optical purity, and high resolution efficiency are achieved

Active Publication Date: 2019-07-09
BEIJING MEDISAN TECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

CN 102796065A discloses a method for the resolution of isopropanol solvent system, and obtains an intermediate with high optical purity after three crystallizations, but the yield is only 20.3%
[0005] In the synthesis research of escitalopram oxalate, the present inventors found that the resolution methods of the diol intermediates disclosed in the literature all have certain problems in varying degrees; for example, the resolution method disclosed in US4943590 has a Not good, especially the reproducibility after the amplification reaction is not good, resulting in the resolution efficiency of the diol intermediate is not high, under the experimental conditions disclosed in this document and the situation of prolonging the reaction time, there is no resolution effect, and only external results are obtained. Racemic intermediate B, indicating that the resolution method disclosed in this document does not have resolution efficiency
With the synthetic method disclosed in CN 102190600A, the optical purity and yield of diol intermediates cannot meet the needs of industrial production

Method used

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  • Preparation method of high-optical-purity escitalopram oxalate intermediate S-configuration diol
  • Preparation method of high-optical-purity escitalopram oxalate intermediate S-configuration diol
  • Preparation method of high-optical-purity escitalopram oxalate intermediate S-configuration diol

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Example 1 (S)-(4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)benzocyanide) D-(+)- Preparation of di-p-methylbenzoyl tartrate

[0026] (1) At room temperature, (RS)-4-(4-(dimethylaminopropyl)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-hydroxymethylbenzonitrile hydrogen Bromate (85.0g, 0.2mol) was added to 200ml of an aqueous solution containing 12.0g of NaOH, dichloromethane (200ml) was added, and stirred for 0.5 hour; the liquid was left to separate, and the aqueous phase was extracted twice with dichloromethane (50ml). Combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, remove residual methylene chloride with isopropanol (20ml) to obtain an oily substance, add isopropanol (200ml) and heat to 70 ° C, after completely dissolving, Add D-(+)-di-p-methylbenzoyl tartaric acid (40.0g, 0.1mol), after completely dissolved, stop stirring, naturally cool down to 20-25°C, add a little seed crystal (1‰) at 60°C...

Embodiment 2

[0029] Example 2 (S)-(4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)benzocyanide) D-(+)- Preparation of di-p-methylbenzoyl tartrate

[0030] (1) At room temperature, (RS)-4-(4-(dimethylaminopropyl)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-hydroxymethylbenzonitrile hydrogen Bromate (85.0 g, 0.2 mol) was added to 200 ml of an aqueous solution containing 12.0 g of NaOH, dichloromethane (200 ml) was added, and stirred for 0.5 hour; standing for liquid separation, the aqueous phase was extracted twice with dichloromethane (50 ml), Combine the organic phases, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, remove residual methylene chloride with isopropanol (20ml) to obtain an oily substance, add isopropanol (300ml) and heat to 70 ° C, after completely dissolving, Add D-(+)-di-p-methylbenzoyl tartaric acid (40.0g, 0.1mol), after completely dissolved, stop stirring, naturally cool down to 20-25°C, add a little seed crystal (1‰) at 60°...

Embodiment 3

[0033] Example 3 (S)-(4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)benzocyanide) D-(+)- Preparation of di-p-methylbenzoyl tartrate

[0034] (1) At room temperature, (RS)-4-(4-(dimethylaminopropyl)-1-(4-fluorophenyl)-1-hydroxybutyl)-3-hydroxymethylbenzonitrile hydrogen Bromate (85.0 g, 0.2 mol) was added to 200 ml of a solution containing 12.0 g of NaOH, dichloromethane (200 ml) was added, and stirred for 0.5 hours. Stand for liquid separation, extract the aqueous phase twice with dichloromethane (50ml), combine the organic phases, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and remove residual dichloromethane with isopropanol (20ml) to obtain an oily Add isopropanol (400ml) and heat to 70°C. After it is completely dissolved, add D-(+)-di-p-methylbenzoyl tartaric acid (40.0g, 0.1mol). After it is completely dissolved, stop stirring and let it cool down naturally. To 20-25°C, add a little seed crystal (1‰) at 60°C, stan...

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Abstract

The invention discloses a preparation method of an escitalopram oxalate intermediate S-configuration diol. The preparation method comprises the following steps: (1) carrying out hydrobromic acid salinization on racemic diol (4-(4-dimethylamino-1-p-fluorophenyl-1-hydroxybutyl)-3-(hydroxymethyl)benzonitrile) to obtain free racemic diol; and (2) carrying out chiral resolution on the free racemic diolby using (+)-di-p-toluoyl-D-tartaric acid in isopropanol by adopting a standing resolution mode, and conducting crystallization to obtain an escitalopram oxalate intermediate S-configuration diol crude product, and carrying out recrystallization refining on the crude product in an organic solvent to obtain the escitalopram oxalate intermediate with high optical purity. The method disclosed by theinvention is high in resolution efficiency and high in product yield, and the prepared diol intermediate is high in optical purity and can meet the requirements of industrial production.

Description

technical field [0001] The invention relates to a preparation method of an escitalopram oxalate intermediate, in particular to a preparation method of an S-configuration diol of an escitalopram oxalate intermediate with high optical purity, and belongs to the field of preparation of an escitalopram oxalate intermediate. Background technique [0002] Escitalopram is the antidepressant citalopram (ie S(+)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisophenyl The S configuration in the molecule of furan-5-nitrile oxalate), the S configuration isomer is more than 100 times more active than the R configuration isomer, and it has a higher selectivity for 5-HT reuptake inhibition. Reduce the dosage of medicine and reduce side effects. Escitalopram oxalate was jointly developed by Denmark Lundbeck Pharmaceutical Company (Lundbeck) and American Forest Laboratory (Forest Laboratory). It was listed in Europe and America in 2002 for the treatment and maintenance of severe d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/59C07C253/30C07C253/34C07C67/52C07C69/76
CPCC07C253/30C07C253/34C07C67/52C07B2200/07C07C255/59C07C69/76
Inventor 李元珍喻海宁瑞勃
Owner BEIJING MEDISAN TECH
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