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The preparation method of tafluprost

A technology of tafluprost and compound, applied in the field of pharmacy, can solve the problems of high content of excessive reduction impurities, high content of trans-isomer impurities, low yield and the like

Active Publication Date: 2021-01-12
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these synthetic methods have the problems of high excessive reduction impurity content, high trans isomer impurity content, and low yield (all between 38-47%)

Method used

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  • The preparation method of tafluprost
  • The preparation method of tafluprost
  • The preparation method of tafluprost

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation of formula 2 compound

[0035] Add 50.0 g of the compound of formula 1 into a four-necked reaction flask filled with 500 mL of anhydrous tetrahydrofuran, and lower the temperature to -70°C±10°C. Under nitrogen protection, DIBAL-H solution (245.6g, 2.8eq) was slowly added dropwise. After dropping, keep the temperature and continue to stir the reaction for 1h, keep at -70°C±10°C, slowly add methanol (9.45g, 8.0eq) dropwise, stir for 0.5h, and quench the reaction. The above mixture was added to 1000 mL of water, and then 1000 mL of ethyl acetate was added, and stirred overnight until the organic phase became clear. Extract and separate the liquids, combine the organic phases; wash the organic phase with saturated brine, let stand to separate the liquids; add silica gel to the organic phase to mix the sample, and separate by column chromatography: prepare n-heptane / triethylamine (17.0kg / 36.5g) Punch the column; the receiving bucket collects 4L each time. ...

Embodiment 2

[0037] The preparation of formula 3 compound

[0038] Add 33.0 g of the compound of formula 2 into a four-necked reaction flask filled with 500 mL of anhydrous tetrahydrofuran, cool down to 5±5° C., and add NaHMDS solution (359.7 g, 8.0 eq) dropwise under nitrogen protection. After dropping, keep the temperature at 5°C±5°C and continue stirring for 1h. The temperature was lowered to -20±5°C, and 160 mL of a tetrahydrofuran solution of 33.0 g of the compound of formula SM2 was slowly added dropwise into the system. After dropping, the temperature of the reaction solution was raised to 0±5°C and stirred for 1 h. The reaction solution was poured into 495 g of ice-water mixture, stirred to quench the reaction, 330 mL of ethyl acetate was added, and stirred for liquid separation. The organic phase was extracted once with water, and the aqueous phases were combined; the aqueous phase was extracted twice with ethyl acetate, and the organic phase was discarded. Add 330 mL of ethyl ...

Embodiment 3

[0040] The preparation of formula 4 compound

[0041] 16.99 g of 1,8-diazabicycloundec-7-ene and 18.99 g of 2-iodopropane were successively added to an acetone solution of 33.0 g of the compound of formula 2, heated under reflux at 55±5°C and stirred. The reaction solution was cooled to room temperature, 460 mL of dichloromethane and 138 mL of water were added, and stirred to dissolve. Extract and separate, and keep the organic phase. Concentrate the organic phase under reduced pressure to a small volume, add silica gel to mix the sample to make sand, and separate by column chromatography. The column fractions of the samples were collected, combined and concentrated to obtain 35.0 g of the crude product as a light yellow oily liquid, with a purity of 99.4%, a trans isomer content of 0.34%, and a yield of 93.2%.

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Abstract

The invention discloses a preparation method of Tafluprost. The preparation method comprises the following steps: adopting a compound of formula 1 as a raw material, and carrying out the steps of DIBAL-H reduction, a Wittig reaction and an esterification reaction, wherein alkaline amino acids are adopted for refining after the Wittig reaction. According to the preparation method disclosed by the invention, the total mass yield of the three-step reaction can reach 70%, the technology is stable, a prepared Tafluprost product is colorless or faint yellow thick oily liquid, and the purity reaches up to more than 99%.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to tafluprost (5Z)-7-[(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxy- A preparation method of 1-buten-1-yl]-3,5-dihydroxycyclopentyl]-5-heptenoic acid isopropyl ester. Background technique [0002] Tafluprost (Tafluprost) is a new type of prostaglandin analog developed and produced by Japan Santen Co., Ltd. It is mainly used for the treatment of open-angle glaucoma or ocular hypertension in patients with elevated intraocular pressure. The mechanism of lowering intraocular pressure is to promote the outflow of aqueous humor through the uveal sclera, thereby reducing intraocular pressure. The 15th hydroxyl group in the traditional prostaglandin analog structure is an essential functional group for prostaglandin receptor agonists to exert physiological activity. Tafluprost replaces this functional group with 2 F atoms. As an isopropyl ester, it can be Corneal esterase rapidly hydrolyzes to the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/10C07C69/736
CPCC07C51/367C07C67/10C07D307/935C07C69/736C07C59/68
Inventor 李鹏飞徐镜人阴启明周崴海吴川刘欢宋亚郝秀斌倪海华
Owner YANGTZE RIVER PHARM GRP CO LTD
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