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The purification method of tafluprost

A technology of tafluprost and tafluprost acid, which is applied in the new purification field of tafluprost, can solve the problems of long manufacturing process, low practicability, and low yield, and achieve the effect of inhibiting decomposition

Active Publication Date: 2022-07-19
ASAHI GLASS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the production process of this production method is long and the yield is low, so the practicability is low

Method used

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  • The purification method of tafluprost
  • The purification method of tafluprost
  • The purification method of tafluprost

Examples

Experimental program
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Embodiment

[0095] Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited to these.

[0096] % means mol% in yield, and means mass % unless otherwise specified. The ratios shown in the mixed solvent represent volume ratios unless otherwise specified. In addition, room temperature means the temperature of 15-30 degreeC unless otherwise indicated. below 1 The H-NMR value was measured with a nuclear magnetic resonance apparatus JEOL Ltd. ECP400 (400 MHz). The HPLC apparatus used Shimadzu LC-10ADvp or LC-10A. The GC apparatus used Shimadzu GC-2014ATF.

reference example 1

[0097] Reference Example 1: Synthesis of Tafluprost Acid

[0098]

[0099] Under nitrogen atmosphere, in (1S,5R,6R,7R)-6-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl]-7-hydroxy-2-oxygen Tetrahydrofuran (1200 g) was added and dissolved in heterobicyclo[3.3.0]octan-3-one (280 g), and diisobutylaluminum hydride (1M toluene solution) (2160 mL) was added dropwise at -70°C. After completion of the dropwise addition, the mixture was stirred for 30 minutes, 1N hydrochloric acid was added, and extraction was performed with ethyl acetate. After the organic layers were combined and washed with water, the filtrate was concentrated under reduced pressure to obtain a reduced body (284 g). Under a nitrogen atmosphere, tetrahydrofuran (5030 g) was added to 4-carboxybutyltriphenylphosphonium bromide (1523 g), and sodium bis(trimethylsilyl)amide solution (1M tetrahydrofuran solution) (6684 mL) was added dropwise, Stir for more than 1 hour. The above-mentioned reducing body (286 g) dissolved in ...

reference example 2

[0101] Reference Example 2: Synthesis of Tafluprost Crude Product

[0102]

[0103] Tafluprost acid (120 g) obtained in Reference Example 1 was put into a 5 L flask under a nitrogen atmosphere, and dissolved in acetone (600 mL) with stirring. It was cooled to 5°C, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (160 mL) was added dropwise while keeping the temperature below 5°C, and further dropped while keeping the temperature below 5°C. After adding 2-iodopropane (146 mL), the mixture was stirred at 30° C. until the conversion rate of the reaction was over 95%. Ethyl acetate (1800 mL) and 5% citric acid aqueous solution (900 mL) were added to the reaction mixture, and the layers were separated, and 5% citric acid aqueous solution (900 mL, once), 5% sodium bicarbonate aqueous solution (900 mL, twice), and purified water (900 mL, once) to wash the organic layer. Under reduced pressure, the solvent was distilled off at below 40°C to obtain a crude tafluprost product (132 g, y...

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Abstract

[Subject] The object of the present invention is to provide a simple and efficient purification method of tafluprost that can be scaled up. [Solution] The present invention relates to a method for purifying tafluprost, comprising the steps of purifying a crude product of tafluprost by silica gel column chromatography, and collecting a fraction containing tafluprost by HPLC analysis . In addition, the present invention also relates to a method for producing tafluprost including the aforementioned method for purifying tafluprost.

Description

technical field [0001] The present invention relates to a novel purification method of tafluprost. Background technique [0002] Tafluprost is represented by the following formula: [0003] [0004] Its chemical name is (5Z)-7-(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl]-3,5 -Dihydroxycyclopentyl]-5-heptenoic acid isopropyl ester, with a viscosity of 2440 mPa·s at 25°C, is a very viscous difluoroprostaglandin F 2α derivative. Tafluprost has an unstable chemical structure including two double bonds, unsaturated fatty acid ester moieties, and four asymmetric centers, and the C15 hydroxyl group and hydrogen atom present in other prostaglandin derivatives are replaced by two The structure in which the fluorine atom is substituted, therefore, among the prostaglandin derivatives, it has remarkable specificity of high lipid solubility. Although the prostaglandin derivatives have high chemical stability, they also have the property of being decomposed at high temper...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/56C07C67/54C07C69/736A61K31/215A61P27/02A61P27/06
CPCC07C67/56C07C67/54C07C69/736C07C2601/08A61P27/02A61P27/06C07C405/00A61K31/557
Inventor 小西克彦森信明松村靖
Owner ASAHI GLASS CO LTD
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