- Fluticasone propionate synthesis method
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The embodiments of the invention provide a fluticasone propionate synthesis method, which comprises: a thioesterification reaction: adding a first intermediate, an first organic alkali, dimethylaminothioformyl chloride, sodium iodide and a first organic solvent into a reaction kettle, carrying out a reaction, adding a polar aprotic solvent and water after the reaction, carrying out cooling crystallizing, filtering, washing, and drying to obtain a second intermediate; an alcoholysis reaction: adding the second intermediate, a first inorganic alkali and a second organic solvent into a reaction kettle, carrying out a reaction, adding water or water and an extracting agent after the reaction, extracting, taking the water phase, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain a third intermediate; and a substitution esterification reaction: adding the third intermediate, a second inorganic alkali and a third organic solvent into a reaction kettle, adding fluorobromomethane, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain fluticasone propionate. According to the embodiments of the invention, the low-cost production can be realized, and the reaction yield and the purity are high.
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Page/Page column 7-15
(2020/02/10)
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- METHODS OF PREPARING INTERMEDIATE OF FLUTICASONE PROPIONATE
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A method of preparing a thioic acid intermediate of fluticasone propionate includes: treating a 17β-[(N,N-dimethyl carbamoyl)thio]carbonyl compound in a solution including an alcohol and an alkali metal hydroxide, an alkaline-earth metal hydroxide, or a mixture thereof to cleave an amide from the 17β-[(N,N-dimethyl carbamoyl)thio]carbonyl compound; treating the solution to separate an aqueous portion; and adding an acid to the aqueous portion to obtain the thioic acid intermediate of fluticasone propionate. A method of preparing fluticasone propionate includes preparing the thioic acid intermediate of fluticasone propionate, and alkylating the thioic acid intermediate of fluticasone propionate to prepare the fluticasone propionate.
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- Improved synthesis of fluticasone propionate
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A novel process for the preparation of fluticasone propionate (1), a corticosteroid, is reported. In this paper, compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H 5IO6 as an oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH2F was replaced by AgNO3 and Selectfluor in decarboxylative fluorination.
- Zhou, Jiadi,Jin, Can,Su, Weike
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p. 928 - 933
(2014/10/16)
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- PROCESS FOR PREPARING FLUTICASONE PROPIONATE/FUROATE
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The present invention relates to an improved process for the preparation of substituted Fluticasone derivatives. The invention also reveals the processes for the purification of Fluticasones and related intermediates to provide the highly pure product.
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- METHOD FOR PREPARATION OF FLUTICASONE PROPIONATE
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Taught is a method for preparing S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (fluticasone propionate). The present method is simple, convenient, and mild, yields highly pure product, and is suitable for use commercially on a large scale.
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Page/Page column 2
(2008/12/05)
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- METHOD FOR THE PREPARATION OF FLUTICASONE PROPIONATE
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Taught is a method for preparing S-fluoromethyl-6α,9α- difluroro-11β-hydroxy-16α-methyl-17α- propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (fluticasone propionate). The present method is simple, convenient, and mild, yields highly pure product, and is suitable for use commercially on a large scale.
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Page/Page column 5
(2010/11/30)
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- Novel crystalline forms of 6alpha, 9alpha -difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17alpha-propionyloxy-androsta-1,4-diene 17beta-carboxylic acid and processes for preparation thereof
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Novel crystalline forms II, III, IV, V, VI, VII and VIII of 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carboxylic acid, a chemical intermediate useful in the preparation of fluticasone propionate, and novel methods of making these forms, substantially free of water, are disclosed.
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Page/Page column 12
(2008/06/13)
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- Convenient synthesis of s-fluoromethyl 6alpha, 9alpha-difluoro-11beta-hydroxy-16alpha-methyl-17alpha-propionyloxy-3-oxoandrosta-1,4-diene-17beta-carbothioate
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The present invention provides a convenient process for the preparation of S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate, a compound of formula 1, comprising (a) treating 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene, a compound of formula 3 with alkali metal carbonate-alcohol system to obtain 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid, a compound of formula 4; (b) reacting the compound of formula 4 with bromofluoromethane to yield the compound of formula 1. The present invention also provides an improved process for preparation of compound of formula 1 comprising (a) reacting 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17-(propionyloxy)androsta-1,4-dien-17β-carboxylic acid, a compound of formula 2, with N,N-dimethylthiocarbamoyl chloride in an inert aprotic solvent in the presence of an iodide catalyst and a base to give a compound of formula 3, (b) reacting the compound of formula 3 with a hydrosulfide reagent and bromofluromethane to obtain a compound of formula 1.
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Page/Page column 8
(2010/02/14)
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- Process for the preparation of steroidal 17 beta-carbothioates
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A novel method for the conversion of steroidal 17β-carboxylic acids to carbothioates such as fluticasone propionate via novel in situ generated 17β-carboxy imidazolyl- or succinimidyl esters.
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- 17.BETA- (ALPHA-HYDROXY) -ESTERS OF ANDROSTANES AS INTERMEDIATES FOR THE PREPARATION FOR THE PREPARATION OF 17Β-FLUORINATED-ANDROSTANE ESTERS
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Process for the preparation of polyhalogenated steroids, in particular of androstanic fluoro derivatives corticosteroids by means of the formation of new androstanic S-hydroxy alkyl or aralkyl-17-carbothioate intermediates.
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- Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods
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This invention discloses a novel method for the conversion of carboxylic acids to carbothioic acids and application of the method to the preparation of androstane carbothiolates, such as fluticasone propionate, which avoids column chromatography.
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- Thiol Esters from Steroid 17β-Carboxylic Acids: Carboxylate Activation and Internal Participation by 17α-Acylates
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The chemistry of the steroid 17β-carboxylic acids derived from 16,17α-disubstituted corticosteroids was investigated with respect to thiol ester formation.Major quantities of 17-spiro byproducts were observed in the reactions of 16-methyl-17α-acyloxy acids, and the degree of 17-ester participation leading to these structures was dependent on the carboxylate activating group used and stereochemistry at C-16.Diethyl phosphate mixed anhydrides of these acids reacted with mercaptide salts to give mixtures of thiol esters with 17-spiro acylthio ortho esters, which predominated and were particularly stable in the case of 16β-methyl substrates; in addition, considerable reversion of 16α-methyl phosphate intermediates to starting acid was experienced.The use of diphenyl chlorophosphate as the activating agent greatly improved yields of thiol esters.Methanolysis of the phosphate adducts derived from 17α-acyloxy acids gave 17-spiro acyl ortho esters as the exclusive products.The reactions of 17α-acetoxy acids with 2-fluoro-N-methylpyridinium tosylate (FMPT) gave novel 17-spiro acyl fluoro ketals 32-35, whereas similar treatment of 17-hydroxy acids led to products of dehydration or of 18-methyl migration, including the novel 13,17-β-lactones 39 and 41.Activation with carbonyldiimidazole followed by addition of mercaptans allowed the preparation of thiol ester products from 17-hydroxy acids, but the method was restricted to use with these substrates.Neighbouring-group participation was not possible for the 16,17-acetonide acid 10, and activation with either cllorophosphate diesters or FMPT followed by reaction with methanethiolate gave high yields of methylthio ester 17.
- Kertesz, Denis J.,Marx, Michael
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p. 2315 - 2328
(2007/10/02)
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