Method for purifying tafluprost

A technology of tafluprost and purification method, which is applied in chemical instruments and methods, organic chemistry, pharmaceutical formulations, etc., and can solve problems such as low yield, long manufacturing process, and low practicability

Active Publication Date: 2021-05-28
ASAHI GLASS CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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  • Method for purifying tafluprost
  • Method for purifying tafluprost
  • Method for purifying tafluprost

Examples

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[0095] Hereinafter, reference examples, examples, and test examples are given to describe the present invention in detail, but the present invention is not limited thereto.

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

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-hydroxyl-2-oxo Tetrahydrofuran (1200 g) was added to heterobicyclo[3.3.0]octan-3-one (280 g) for dissolution, 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 product (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 1 more hour. The above-mentioned reduced product (286 g) dissolved in ...

reference example 2

[0101] Reference example 2: Synthesis of tafluprost crude product

[0102]

[0103] Under a nitrogen atmosphere, the tafluprost acid (120 g) obtained in Reference Example 1 was charged into a 5 L flask, and dissolved in acetone (600 mL) while stirring. Cool to 5°C, add 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (160mL) dropwise while keeping below 5°C, and then drop while keeping below 5°C After adding 2-iodopropane (146 mL), it was stirred at 30°C until the conversion rate of the reaction was above 95%. Ethyl acetate (1800 mL) and 5% citric acid aqueous solution (900 mL) were added to the reaction mixture for liquid separation, 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 below 40° C., thereby obtaining a crude product of tafluprost (132 g, yield 100%; HPLC purity: 95.5%, α-chain trans-isomer conte...

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Abstract

The purpose of the present invention is to provide a simple and efficient method for purifying tafluprost that can be scaled up in proportion. The present invention relates to the method for purifying tafluprost, which comprises a step for purifying a crude product of tafluprost by silica gel column chromatography and collecting a component containing tafluprost by HPLC analysis. In addition, the present invention also relates to a method for producing tafluprost, which comprises 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 2440mPa·s at 25°C, is a very viscous difluoroprostaglandin F 2α derivative. Tafluprost has an unstable chemical structure including 2 double bonds, unsaturated fatty acid ester sites, and 4 asymmetric centers, and has the hydroxyl and hydrogen atoms at the C15 position existing in other prostaglandin derivatives replaced by 2 It has a structure substituted with fluorine atoms, so it has remarkable fat-soluble specificity among prostaglandin derivatives. As a prostaglandin derivative, although it has high chemical stability, it also has the property of decomposing at high temperature. In addition, tafluprost has...

Claims

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Application Information

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IPC IPC(8): C07C67/56C07C67/54C07C69/736A61K31/215A61P27/02A61P27/06
CPCC07C67/56C07C67/54C07C69/736C07C2601/08A61P27/02A61P27/06C07C405/00A61K31/5575
Inventor 小西克彦森信明松村靖
Owner ASAHI GLASS CO LTD
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