CN104004044A - Highly pure fluticasone propionate preparation method - Google Patents
Highly pure fluticasone propionate preparation method Download PDFInfo
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- CN104004044A CN104004044A CN201310058297.2A CN201310058297A CN104004044A CN 104004044 A CN104004044 A CN 104004044A CN 201310058297 A CN201310058297 A CN 201310058297A CN 104004044 A CN104004044 A CN 104004044A
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Abstract
The invention discloses a highly pure S-fluoromethyl-6alpha,9alpha-difluoro-11beta-hydroxy-16alpha-methyl-17alpha-propionooxo-3-androsterone-1,4-diene-17beta-benzothiodiazole (fluticasone propionate) preparation method. The method is characterized in that various highly-pure intermediates of fluticasone propionate are prepared in order to obtain highly pure fluticasone propionate; and post-treatment and purification of the intermediates obtained in each step are carried out in order to obtain the highly pure fluticasone propionate. The method has the advantages of simple operation, high purity and low quantity of impurities, common and cheap reagents, and suitableness for the large-scale industrial production.
Description
Technical field
The invention belongs to organic chemical synthesis technical field, relate to the high purity preparation of each step intermediate of fluticasone propionate, thereby prepare the method for high purity fluticasone propionate.
Background technology
Patent US4335121, WO01/62722 (US2002/0133032), CN200610161627[1] .0, CN200710044880[1] patent such as .2 all described the synthetic of fluticasone propionate, but thereby neither one patent relates to the method that each purifying that walks intermediate obtains high purity fluticasone propionate of describing in detail, the crude product purity dealing according to the present invention can reach more than 99%, single main impurity is no more than 0.2%, a recrystallization just can reach single main impurity and be no more than 0.1% limit requirement, and yield is 80%～98%.
Summary of the invention
Problem to be solved by this invention is that each walks highly purified intermediate preparation fluticasone propionate, thereby obtains highly purified fluticasone propionate, this method is simple to operate, and the product purity obtaining is high, and impurity number is few, agents useful for same is common cheap, is suitable for scale suitability for industrialized production.
Method of the present invention comprises the following steps:
(1) purifying of the first step product: the first step crude product dissolves with inorganic base aqueous solution, stir, through filtering or using again reagent a extraction with reagent a extraction or first filtration, then directly drip acid or add reagent b, dripping acid separates out product again, filter, be washed to neutrality, dry and obtain high-purity compound [2]; Reagent dosage be crude product (gram): mineral alkali (mol ratio be take crude product mole number as benchmark): water (milliliter)=1:(1～1.8): (10～100);
Compound [2]
(2) purifying of second step product: second step crude product dissolves with inorganic base aqueous solution, stir, through filtering or using again reagent a extraction with reagent a extraction or first filtration, then directly drip acid or add reagent b, dripping acid separates out product again, filter, be washed to neutrality, dry and obtain high-purity compound [3]; Reagent dosage be crude product (gram): mineral alkali (mol ratio be take crude product mole number as benchmark): water (milliliter)=1:(1～1.8): (10～100);
Compound [3]
(3) the 3rd step purifying: after completion of the reaction, in reaction solution, add mineral alkali and water, stir, then drip product is separated out, filtration drying, obtains high-purity compound [4], or the 3rd step crude product dissolves with reagent c, with inorganic base aqueous solution extraction, then concentrated evaporate to dryness obtains high-purity compound [4] again; Reagent dosage be crude product (gram): mineral alkali (mol ratio be take crude product mole number as benchmark): water (milliliter)=1:(1～1.8): (10～500);
Compound [4]
(4) the 4th steps: compound [4], in alcoholic solvent, stirs under nitrogen protection, reacts with mineral alkali, then dilute with water, uses reagent a abstraction impurity removal, and water drips acid, filter, obtain high-purity compound [5], or compound [4] is in alcoholic solvent, under nitrogen protection, react with mineral alkali, then drip acid and drip, filtration obtains the 4th step crude product, and this crude product dissolves with inorganic base aqueous solution, removes by filter impurity, filtrate is dripped acid, refilters, the dry high-purity compound [5] that obtains; Reagent dosage crude product (gram): alcohol (milliliter): water (milliliter)=1:(5～100): (50～500);
Compound [5]
(5) the 5th step purifying: the 5th step crude product dissolves with reagent d, add mineral alkali, dripping water makes entirely molten, add discoloring agent to stir, then filter, filtrate drips water or filtrate is splashed in water product is separated out, and after filtering drying, with ethanol or propyl carbinol recrystallization, obtains high-purity compound [1] (fluticasone propionate); Reagent dosage ratio be crude product (gram): reagent d(milliliter): mineral alkali (gram): discoloring agent (gram % or milliliter): water (below crystallization water, milliliter)=1:(20～300): (1～3): (1%～10%): (1～300); Recrystallization ratio of reagents be compound [1] (gram): alcohol (milliliter)=1:(30～150);
Compound [1].
Feature of the present invention:
(a) in step (1), (2), (3), (4), (5), all use mineral alkali, mineral alkali used comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, Quilonum Retard, sodium bicarbonate, saleratus, lithium bicarbonate.
(b) step (1), (2), (3), (4), (5) service temperature are-10 ℃～50 ℃, and churning time is 20 minutes to 8 hours.
(c) in step (1), (2) operation, with reagent a, extract and add reagent b, wherein reagent a comprises toluene, ethyl acetate, methyl acetate, propyl acetate, ethyl formate, propyl formate, methyl propionate, propyl propionate, methylene dichloride, ethylene dichloride, trichloromethane; Reagent b comprises methyl alcohol, tetrahydrofuran (THF), acetone.
(d) in step (3) operation, with reagent c, dissolve, wherein reagent c comprises ethyl acetate, methyl acetate, propyl acetate, ethyl formate, propyl formate, methyl propionate, propyl propionate, methylene dichloride, ethylene dichloride, trichloromethane.
(e) in step (5) operation, with reagent d, dissolve, add discoloring agent, wherein reagent d comprises methyl alcohol, tetrahydrofuran (THF), acetone, acetonitrile, DMF, N, N N,N-DIMETHYLACETAMIDE; Discoloring agent comprises gac, Periodic acid, sodium periodate, hydrogen peroxide, hypochlorous acid, clorox; Alcohol comprises methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol.
(f) in step (1), (2), (4) operation, drip acid, wherein acid comprise hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid with and different concns or multiple mixing acid wherein.
For clearer explanation the present invention, enumerate following instance, but it is without any restrictions to scope of the present invention.The quality of the product of producing according to the present invention can reach international standard requirement; The present invention is simple to operate, and the product purity obtaining is high, and impurity number is few, and agents useful for same is common cheap, is suitable for scale suitability for industrialized production.
Embodiment
Example 1
By 5 grams of the first crude product solids (12.61mmol) that are oxidized out with fluorine compound, join in flask, add water-soluble 0.9 gram of sodium hydroxide solution with 150ml, stirring at room makes to dissolve for 2 hours, and decompress filter cleans filter cake and filter flask with a small amount of water, merging filtrate and washing lotion, in flask, add methyl alcohol 50ml, stirring at room 20 minutes, drip 2M hydrochloric acid, making pH is 2～4, stirs decompress filter 2 hours, filter cake washes with water to neutrality, in 70 ℃ dry, obtain 4.9 grams, HPLC purity 99.7%.
Example 2
By 5 grams of second step crude product solids (11.05mmol), join in flask, add water-soluble 0.8 gram of sodium hydroxide solution with 200ml, stirring at room makes to dissolve for 2 hours, and decompress filter cleans filter cake and filter flask with a small amount of water, merging filtrate and washing lotion, in flask, add methyl alcohol 80ml, stirring at room 20 minutes, drips 2M hydrochloric acid, and making pH is 2～4, stir 2 hours, decompress filter, filter cake washes with water to neutrality, in 70 ℃ dry, obtain 5.0 grams of solids, HPLC purity 99.6%.
Example 3
By 5 grams of the 3rd step crude products, join in reaction flask, add ethyl acetate 150ml, stirring at room makes to dissolve, then uses 3% aqueous sodium hydroxide solution 5 * 50ml extraction, then uses 2 * 50ml washing, with anhydrous sodium sulfate drying, be evaporated to dryly, add water stirring at room, after dispersible solid, decompress filter, in 75 ℃ dry, obtain 4.8 grams, HPLC purity 99.4%.
Example 4
Above-mentioned example 3 is processed to the solid obtaining and get 5 grams, in flask, add methyl alcohol 30ml, 2.5 grams, salt of wormwood, nitrogen protection, 30 ℃ are reacted 6 hours, cooling is room temperature, add water 70ml, with 2M hydrochloric acid adjustment pH value to 2～4, stirring at room 2 hours, decompress filter, be washed to neutrality, dry in 65 ℃, obtain 4.4 grams of crude products, this crude product is put in flask, add 1.3 grams, salt of wormwood, add water 400ml, stirring at room 3 hours, make to dissolve, decompress filter, with a small amount of water washing filter cake and filter flask, merging filtrate and washing lotion are in flask, add methyl alcohol 50ml, stir 30 minutes, with 2M hydrochloric acid adjustment pH value to 2～4, stirring at room 2 hours, decompress filter, be washed to neutrality, dry in 65 ℃, obtain 4.2 grams of solids, HPLC purity 99.3%.
Example 5
By 5.0 grams of the 5th step crude products, put in flask, add tetrahydrofuran (THF) 80ml, 1.5 grams, hydro-oxidation potassium, add water 10ml, be stirred to dissolve, stirring at room 30 minutes, add 2% Periodic acid solution 20ml, stirring at room 1 hour, decompress filter, with a small amount of tetrahydrofuran (THF) washing leaching cake and filter flask, merge washing lotion and filtrate, in flask, room temperature drips water 400ml, dropwises and stirs 3 hours, decompress filter, with the washing of 10% tetrahydrofuran aqueous solution, in 75 ℃ dry, obtain 4.8 grams of solids, HPLC purity 99.46%, single main impurity 0.18%; With after 250ml dehydrated alcohol recrystallization, obtain 4.3 grams of solids, HPLC purity 99.85%, single main impurity 0.07%.
Claims (7)
1. a high purity fluticasone propionate preparation method, the prerequisite synthetic route of present method is that fluorine compound is through peroxidation, propionyl, pass through again N, N-dimethyl sulphide is for formyl chloride acidylate, then alcoholysis, fluoromethylation obtains fluticasone propionate, involved in the present invention to content be mainly this route each step intermediate aftertreatment or purification process; The method comprises the following steps:
(1) purifying of the first step product: the first step crude product dissolves with inorganic base aqueous solution, stir, through filtering or using again reagent a extraction with reagent a extraction or first filtration, then directly drip acid or add reagent b, dripping acid separates out product again, filter, be washed to neutrality, dry and obtain high-purity compound [2]; Reagent dosage be crude product (gram): mineral alkali (mol ratio be take crude product mole number as benchmark): water (milliliter)=1:(1～1.8): (10～100); The consumption of reagent b is 10%～50% of reagent a;
Compound [2]
(2) purifying of second step product: second step crude product dissolves with inorganic base aqueous solution, stir, through filtering or using again reagent a extraction with reagent a extraction or first filtration, then directly drip acid or add reagent b, dripping acid separates out product again, filter, be washed to neutrality, dry and obtain high-purity compound [3]; Reagent dosage be crude product (gram): mineral alkali (mol ratio be take crude product mole number as benchmark): water (milliliter)=1:(1～1.8): (10～100);
Compound [3]
(3) the 3rd step purifying: after completion of the reaction, in reaction solution, add mineral alkali and water, stir, then drip product is used, filtration drying, obtains high-purity compound [4], or the 3rd step crude product dissolves with reagent c, with inorganic base aqueous solution extraction, then concentrated evaporate to dryness obtains high-purity compound [4] again; Reagent dosage be crude product (gram): mineral alkali (mol ratio be take crude product mole number as benchmark): water (milliliter)=1:(1～1.8): (10～500);
Compound [4]
(4) the 4th steps: compound [4], in alcoholic solvent, stirs under nitrogen protection, reacts with mineral alkali, then dilute with water, uses reagent a abstraction impurity removal, and water drips acid, filter, obtain high-purity compound [5], or compound [4] is in alcoholic solvent, under nitrogen protection, react with mineral alkali, then drip acid and drip, filtration obtains the 4th step crude product, and this crude product dissolves with inorganic base aqueous solution, removes by filter impurity, filtrate is dripped acid, refilters, the dry high-purity compound [5] that obtains; Reagent dosage crude product (gram): alcohol (milliliter)=1:(5～100);
Compound [5]
(5) the 5th step purifying: the 5th step crude product dissolves with reagent d, add mineral alkali, dripping water makes entirely molten, add discoloring agent to stir, then filter, filtrate drips water or filtrate is splashed in water product is separated out, and after filtering drying, with propyl carbinol recrystallization, obtains high-purity compound [1] (fluticasone propionate); Reagent dosage ratio be crude product (gram): reagent d(milliliter): mineral alkali (gram): discoloring agent (gram % or milliliter): water (below crystallization water, milliliter)=1:(20～300): (1～3): (1%～10%): (1～300); Recrystallization ratio of reagents be compound [1] (gram): alcohol (milliliter)=1:(30～150);
Compound [1].
2. a kind of high purity fluticasone propionate preparation method according to claim 1, it is characterized in that, in step (1), (2), (3), (4), (5), all use mineral alkali, mineral alkali used comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, Quilonum Retard, sodium bicarbonate, saleratus, lithium bicarbonate.
3. a kind of high purity fluticasone propionate preparation method according to claim 1, step (1), (2), (3), (4), (5) service temperature are-10 ℃～50 ℃, churning time is 20 minutes to 8 hours.
4. a kind of high purity fluticasone propionate preparation method according to claim 1, in step (1), (2) operation, with reagent a, extract and add reagent b, wherein reagent a comprises toluene, ethyl acetate, methyl acetate, propyl acetate, ethyl formate, propyl formate, methyl propionate, propyl propionate, methylene dichloride, ethylene dichloride, trichloromethane; Reagent b comprises methyl alcohol, tetrahydrofuran (THF), acetone.
5. a kind of high purity fluticasone propionate preparation method according to claim 1, in step (3) operation, with reagent c, dissolve, wherein reagent c comprises ethyl acetate, methyl acetate, propyl acetate, ethyl formate, propyl formate, methyl propionate, propyl propionate, methylene dichloride, ethylene dichloride, trichloromethane.
6. a kind of high purity fluticasone propionate preparation method according to claim 1, dissolves with reagent d in step (5) operation, adds discoloring agent, use alcohol recrystallization, wherein reagent d comprises methyl alcohol, tetrahydrofuran (THF), acetone, acetonitrile, DMF, N, N N,N-DIMETHYLACETAMIDE; Discoloring agent comprises gac, Periodic acid, sodium periodate, hydrogen peroxide, hypochlorous acid, clorox; Alcohol comprises methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol.
7. a kind of high purity fluticasone propionate preparation method according to claim 1, in step (1), (2), (4) operation, drip acid, wherein acid comprise hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid with and different concns or multiple mixing acid wherein.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016054280A1 (en) * | 2014-10-03 | 2016-04-07 | Amphastar Pharmaceuticals, Inc. | Methods of preparing intermediate of fluticasone propionate |
| CN106279341A (en) * | 2015-05-11 | 2017-01-04 | 正大天晴药业集团股份有限公司 | A kind of preparation method of fluticasone furoate |
| CN110759960A (en) * | 2019-10-30 | 2020-02-07 | 山东赛托生物科技股份有限公司 | Refining method of fluticasone propionate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998017676A1 (en) * | 1996-10-24 | 1998-04-30 | Glaxo Group Limited | A novel polymorphic crystalline form of fluticasone propionate, a method for its production and pharmaceutical compositions thereof |
| CN1903871A (en) * | 2005-07-26 | 2007-01-31 | 上海奥锐特国际贸易有限公司 | Synthesis method of fluoticarson propionate |
-
2013
- 2013-02-25 CN CN201310058297.2A patent/CN104004044A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998017676A1 (en) * | 1996-10-24 | 1998-04-30 | Glaxo Group Limited | A novel polymorphic crystalline form of fluticasone propionate, a method for its production and pharmaceutical compositions thereof |
| CN1903871A (en) * | 2005-07-26 | 2007-01-31 | 上海奥锐特国际贸易有限公司 | Synthesis method of fluoticarson propionate |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016054280A1 (en) * | 2014-10-03 | 2016-04-07 | Amphastar Pharmaceuticals, Inc. | Methods of preparing intermediate of fluticasone propionate |
| CN107108690A (en) * | 2014-10-03 | 2017-08-29 | 美药星制药有限公司 | The preparation method of fluticasone propionate thio-acid intermediate |
| CN106279341A (en) * | 2015-05-11 | 2017-01-04 | 正大天晴药业集团股份有限公司 | A kind of preparation method of fluticasone furoate |
| CN110759960A (en) * | 2019-10-30 | 2020-02-07 | 山东赛托生物科技股份有限公司 | Refining method of fluticasone propionate |
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