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

A technology for escitalopram oxalate and an intermediate is applied in the field of preparation of an intermediate S-configuration diol of escitalopram oxalate with high optical purity, and can solve the problem of no splitting effect, poor reproducibility, and poor yield. The rate is only 20.3%, etc., to achieve the effect of high resolution efficiency, high optical purity and high product yield

Active Publication Date: 2022-04-15
BEIJING MEDISAN TECH +1
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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 s-configuration diol of high optical purity escitalopram oxalate intermediate
  • Preparation method of s-configuration diol of high optical purity escitalopram oxalate intermediate
  • Preparation method of s-configuration diol of high optical purity escitalopram oxalate intermediate

Examples

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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 (85.0 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 oil, 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 , standi...

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 escitalopram oxalate intermediate S-configuration diol, comprising: (1) preparing racemic diol (4-(4-dimethylamino-1-p-fluorobenzene Base-1-hydroxybutyl)-3-(hydroxymethyl) benzyl cyanide) hydrobromide basification to obtain free racemic diol; (2) free racemic diol with D-(+)- Chiral resolution and crystallization of di-p-toluoyl tartaric acid in isopropanol by static resolution to obtain the crude product of the S-configuration diol of the escitalopram oxalate intermediate, and the crude product was carried out in an organic solvent The escitalopram oxalate intermediate with high optical purity was obtained through recrystallization and purification. The method of the invention has high resolution efficiency and high product yield, and the prepared diol intermediate has high optical purity and can meet the needs 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 Patents(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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