Preparation method of tafluprost

A technology of tafluprost and compound, applied in the field of medicinal chemistry, can solve the problems of low product purity, low yield of fluorination step, low conversion rate of target fluorinated product, etc., and achieve the effects of reducing preparation cost and improving economic benefit

Active Publication Date: 2021-03-09
西安国康瑞金制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main reason for the low yield of this fluorination step or the low purity of the product is that there will be the generation of by-products of ω side chain double bond addition during fluorination,

Method used

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  • Preparation method of tafluprost
  • Preparation method of tafluprost
  • Preparation method of tafluprost

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] 1-Bromo-3-phenoxypropan-2-one (15mmol) was dissolved in 100ml of dichloromethane, cooled to 0°C in an ice-water bath, BAST (5.6ml, about 30mmol) was slowly added, and the mixture was heated at 0 Stir for 1 hour at °C, then heat to 50°C and stir for an additional 5 hours. After the reaction was completed, cool to room temperature, slowly pour the reaction solution into a saturated sodium bicarbonate solution at 0°C, separate the organic phase and the aqueous phase, extract the aqueous phase once with dichloromethane, combine the organic phases, wash with saturated brine, and anhydrous After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and recrystallized from ethanol to obtain 3.63 g of (3-bromo-2,2-difluoropropoxy)benzene with a yield of 96.5% and a purity of 98.9%. Mass spectrum m / z: theoretical value 249.9805; found value: 249.9833.

[0029] (3-Bromo-2,2-difluoropropoxy)benzene (10 mmol) and KI (11 mmol) were added to a...

Embodiment 2

[0033]

[0034](3-Bromo-2,2-difluoropropoxy)benzene (10 mmol) and KI (11 mmol) were added to a mixed solution of acetone (50 ml) and acetonitrile (50 ml) under nitrogen atmosphere. A solution of triethylphosphate (2ml, about 12mmol) in acetone (10ml) and acetonitrile (10ml) was slowly added dropwise at room temperature over 30 minutes. After dropping, the reaction mixture was stirred at room temperature for 15 hours, then filtered through celite on a glass filter, and the solvent was distilled off under reduced pressure, then dichloromethane (50ml) was added to dissolve, washed with saturated brine, and dried over anhydrous sodium sulfate. Afterwards, dichloromethane solution of (2,2-difluoro-3-phenoxypropyl) diethyl phosphate was obtained and set aside.

[0035] Sodium hydride (60% dispersion in mineral oil, 12 mmol) was dispersed in tetrahydrofuran (20 mL) under a nitrogen atmosphere to form a suspension, cooled to 0° C. in an ice-water bath, and the (2,2- Difluoro-3-phe...

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Abstract

The invention provides a preparation method of tafluprost. According to the method, a fluorinated raw material is obtained at first, and then, HWE reaction is carried out to form double bonds; and therefore, the double bond addition side reaction during fluorination can be avoided. Therefore, the method disclosed by the invention can be used for obtaining the fluorinated product with high yield and high purity, so that the preparation cost of the tafluprost can be reduced, and the economic benefit of the tafluprost can be improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a new preparation method of tafluprostaglandin. Background technique [0002] Lafluprost (Lafluprost, also known as tafluprost, chemical name is (5Z)-7-[(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4- Phenoxy-1-buten-1-yl]-3,5-dihydroxycyclopentyl]-5-heptenoic acid isopropyl ester), is a new type of PGF 2 Derivatives, as a selective PG receptor agonist, are used to reduce the elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. They have high safety and small adverse reactions. They are a new generation of anti-glaucoma prostaglandin drugs . The drug was jointly developed and marketed by Asahi Glass Co., Ltd. and Santen Pharmaceutical Co., Ltd., and its patent protection in China expired in 2017. Therefore, the process development of its API has a high market value. [0003] The synthetic method of tafluprostaglandin is main...

Claims

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Application Information

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IPC IPC(8): C07D307/935
CPCC07D307/935Y02P20/55
Inventor 张铧镔王培文严捷
Owner 西安国康瑞金制药有限公司
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