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Synthesis method of key intermediate 17-beta-carboxylic acid derivative of fluticasone derivative
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A technology of carboxylic acid derivatives and synthesis methods, applied in the direction of steroids, organic chemistry, etc., can solve the problems of high raw material synthesis cost, low overall yield, long reaction time, etc., and achieve short reaction time and good reaction selectivity , the effect of simple operation
Active Publication Date: 2013-05-01
ZHEJIANG UNIV OF TECH +1
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[0003] Currently propionic acid (furoic acid) fluticasone and its analogues key intermediates 17-β carboxylic acids (I) and (II) are generally obtained from (V) and (VI) by periodic acid oxidation (WO2004001369, CN100497367C, WO2008115069 ), the synthesis cost of raw materials used in this method is relatively high; there are also reports in the literature that (Ⅴ) and (Ⅵ) are used to obtain (Ⅰ), (Ⅱ) (WO2004052912, J. Org. Chem., 1986, 51, 2315-2328 ) but the reaction time is long and the yield is low; Chinese patent (CN1244593C) adopts hydrogenperoxide to oxidize flumetasone 21-acetate to obtain 17-beta carboxylic acid (I); Chinese patent (CN101838301) reports from (Ⅲ), (Ⅳ ) through iodine, replacement, hydrolysis, and oxidation to obtain (I) and (II), the route is cumbersome, the cost is high, and the overall yield is low
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Embodiment 1
[0041] Add 1.5g (37.5mmol) of NaOH and 15ml of water into a 100ml three-neck flask equipped with a thermometer, stir to dissolve and cool down to -5°C, slowly add 1.5g (9.3mmol) of bromine dropwise, and control the temperature below 0°C for half an hour After the dropwise addition, 20ml of 1,4-dioxane and 9β,11β-epoxy-17α-hydroxyl-16α-methyl-pregna-1,4-diene-3,20-dione 1.0g ( 2.8mmol) was stirred and reacted at 5°C for 4h, after the reaction was completed, 1.9g NaHSO was added 3 and 19ml of water, stir for half an hour, adjust the pH value to neutral with concentrated sulfuric acid, remove dioxane under reduced pressure, adjust the pH value to 2~3 with concentrated sulfuric acid, add 10ml of water, white solid precipitates, filter, and dry the filter cake 0.8 g of 9β,11β-epoxy-17αhydroxyl-16αmethyl-pregna-1,4-dien-3-one-17β-carboxylic acid was obtained with a yield of 80%.
[0044] Add 2.0g (50.0mmol) of NaOH and 20ml of water into a 100ml three-necked flask equipped with a thermometer, stir to dissolve and cool down to -5°C, slowly add 2.0g (12.4mmol) of bromine dropwise, and control the temperature below 0°C for half an hour After the dropwise addition, 20ml of 1,4-dioxane and 9β,11β-epoxy-17α-hydroxyl-16α-methyl-pregna-1,4-diene-3,20-dione 1.0g ( 2.8mmol) was stirred and reacted at 8°C for 4h, after the reaction was completed, 2.6g NaHSO was added 3 and 26ml of water, stirred for half an hour, adjusted the pH value to neutral with concentrated sulfuric acid, removed dioxane under reduced pressure, adjusted the pH value to 2~3 with concentrated sulfuric acid, white solid precipitated, filtered, and dried the filter cake to obtain 9β, 11β - Epoxy-17α-hydroxy-16α-methyl-pregna-1,4-dien-3-one-17β-carboxylic acid 0.85g, yield 85%.
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Abstract
The invention discloses a synthesis method of a key intermediate 17-beta-carboxylic acid derivative of a fluticasone derivative. The synthesis method of the key intermediate 17-beta-carboxylic acid derivative of the fluticasone derivative comprises the following steps: taking a compound shown as a formula (III) or a formula (IV) as a raw material; and under actions of strong alkali and a hypohalite oxidant, correspondingly preparing the 17-beta-carboxylic acid derivative shown as a formula (I) or a formula (II). The used oxidant is cheap, easy to obtain and low in environment pollution; and the synthesis method is good in reaction selectivity, high in yield, simple in posttreatment and easy to separate a synthesized product, and is applicable to industrial production.
Description
(1) Technical field [0001] The present invention relates to a synthesis method of fluticasone propionic acid (furoic acid) and its analog key intermediates 17-beta carboxylic acid (I) and (II). (2) Background technology [0002] Fluticasonepropionate (Fluticasonepropionate) is a new type of glucocorticoiddrug developed by Glaxo Wellcome, Germany. Compared with other glucocorticoids, this drug has strong curative effect and weak adverse reactions. Fluticasone furoate ( fluticasone furoate), developed by GlaxoSmithKline (GSK), a new drugnasal spray that was launched in the United States in April 2007, with a trade name of Veramyst. Compared with fluticasone propionate, fluticasone furoate has higher receptor affinity and prolonged duration of action. [0003] Currently propionic acid (furoic acid) fluticasone and its analogues key intermediates 17-β carboxylic acids (I) and (II) are generally obtained from (V) and (VI) by periodic acid oxidation (WO2004001369, CN100497367...
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