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Methods of preparing intermediate of fluticasone propionate

A technology of fluticasone propionate thioacid and intermediates, which is applied in the field of preparation of fluticasone propionate thioacid intermediates, and can solve the problems that impurities are difficult to be removed, affected, and reduce the quality of the final product.

Inactive Publication Date: 2017-08-29
AMPHASTAR NANJING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the impurities produced in this process are difficult to remove, thus affecting (or reducing) the quality (or purity) of the final product

Method used

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  • Methods of preparing intermediate of fluticasone propionate
  • Methods of preparing intermediate of fluticasone propionate
  • Methods of preparing intermediate of fluticasone propionate

Examples

Experimental program
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preparation example Construction

[0045]According to an embodiment of the present invention, the preparation method of the fluticasone propionate thioacid intermediate comprises: processing 17.-[( N,N-dimethylformamide)mercapto]carbonyl compounds (such as compounds 4,17.-[(N,N-dimethylformamide)mercapto]carbonyl-6.,9.-difluoro-11. -Hydroxy-16.-methyl-3-oxo-17.-oxopropoxyandrost-1,4-diene or its derivatives), the amide from the 17.-[(N,N- Cleavage from dimethylformamide) mercapto] carbonyl compounds; processing the solution to separate the water-soluble fraction; and adding acid to the water-soluble fraction to obtain fluticasone propionate thioacid intermediates (such as compounds 1, 6., 9.-Difluoro-11.-hydroxy-16.-methyl-3-oxo-17.-oxopropoxyandrost-1,4-diene-17.-thioformate or its derivatives things). The amide can be cleaved from the 17.-[(N,N-dimethylformamide)mercapto]carbonyl compound by hydrolysis. The amide may comprise, for example, (CH 3 )2NCOOH. Treatment of the solution removes impurities follo...

example 1

[0065] Compound 2, 6.,9.-Difluoro-11.-hydroxy-16.-methyl-3-oxoandrost-1,4-diene-17.-carboxylic acid, was prepared as follows.

[0066] 36.2 g of periodic acid was dissolved in 72 ml of water to obtain a periodic acid solution. The periodic acid solution was added dropwise to a stirred suspension composed of 30 g of fluticasone and 150 ml of tetrahydrofuran at a temperature of 0° C. to 10° C. to obtain a reaction solution. After the dropwise addition (or approximately) of the periodic acid solution was completed, the reaction solution was continued to be stirred for 2 hours. The THF was then distilled off (at least most of the THF was distilled off), cooled to 0°C to 10°C and held in this temperature range for 2 hours, then filtered to obtain the filtered product. The filtered product was washed with water and dried at 50° C. to obtain 28.3 g of a final product with a purity of 99.5% (ie, the final product contained 99.5 wt% of compound 2 based on the total mass of the final p...

example 2

[0071] Compound 3, 6.,9.-Difluoro-11.-hydroxy-16.-methyl-3-oxo-17.-oxopropoxyandrost-1,4-diene-17, was prepared as follows .-carboxylic acid.

[0072] At a temperature of 0° C. to 10° C., 40 ml of triethylamine was added to the suspension containing compound 2 (composed of 50 g of compound 2 with a purity of 99.5 wt % and 250 ml of ethyl ketone) to obtain a reaction solution. Then 45.6 ml of propionyl chloride was added to the reaction solution. After the addition was complete (or substantially complete), the reaction solution was stirred for 1 hour. Then 50ml of diethylamine was added, and stirring was continued for 2 hours to obtain a reaction mixture. Afterwards, 2M hydrochloric acid was added to acidify the reaction mixture to a pH of about 1 to 2 and to produce a precipitated product. The precipitated product was filtered, washed with water and dried at 50° C. to obtain 54.5 g of a final product with a purity of 99.2% (that is, the final product contained 99.2 wt% of c...

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Abstract

A method of preparing a thioic acid intermediate of fluticasone propionate includes: treating a 17beta-[(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 17beta-[(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.

Description

technical background [0001] The structure of fluticasone propionate is shown below: [0002] [0003] 6.,9.-Difluoro-11.-hydroxy-16.-methyl-3-oxo-17.-oxopropoxyandrost-1,4-diene-17.-thiocarbamate (Compound 1) is used as an intermediate (or a key or important intermediate) in the synthesis of fluticasone propionate. The structure of compound 1 is shown below: [0004] [0005] Fluticasone propionate can be synthesized by oxidation of flumetasone to compound 1 and reaction of compound 1 to fluticasone propionate. The synthesis route of the aforementioned synthesis is mainly as follows: [0006] [0007] Dimethylaminothioformyl chloride can be used as a vulcanizing agent in the above reaction method. Its sulfurized product can be decomposed by reflux to obtain diethylamine, thioacid and compound 1. However, this method is polluting, in part because it consumes large quantities of reactants. In addition, very low yields were obtained with diethylamine. Although die...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J31/00C07J5/00C07J3/00
CPCC07J3/005C07J5/0076C07J31/006C07J41/0038
Inventor 邱银华吴征远刘勇陈松张昊宁
Owner AMPHASTAR NANJING PHARMA
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