CN100560598C - 氟替卡松丙酸酯的合成方法 - Google Patents
氟替卡松丙酸酯的合成方法 Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/24—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
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- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
本发明公开了一种合成S-氟甲基-6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰基氧基-3-酮雄甾-1，4-二烯-17β-硫代羧酸酯(氟替卡松丙酸酯)的合成方法。本发明的方法操作简便，反应条件温和，反应产品质量好，宜于规模型工业化生产。
Description
技术领域：
本发明涉及药物技术领域。具体涉及氟替卡松丙酸酯的合成方法。
发明背景：
美国专利US4335121合成了式[1]，氟替卡松丙酸酯，反应式如下：
该方法以[2]与二甲基硫代氨基甲酰氯反应得[3]，再在二乙胺中回流得[4]，然后经溴氯甲烷氯甲基反应，碘化钠、氟化银置换反应后得到[1]氟替卡松丙酸酯。该方法生产过程繁琐，路线长，包括使用昂贵的氟化银，而且收率非常低，成本高，不适于工业化生产。
WO01/62722(US2002/0133032)发明了[2]在丁酮中，碘化钠、三乙胺催化下与二甲基硫代氨基甲酰氯反应得[3]，再与硫氢化钠反应得[4]，再与氟氯甲烷反应得到[1]。在该方法中，大过量的硫氢化钠最终变成硫化氢，同时使用大量氟氯甲烷，这对环境污染，影响非常大；同时用硫氢化钠得到硫代酸[4]，在此过程所产生杂质很难去除，很难提高成品的质量，成本也高。
发明内容：
本发明提所要解决的技术问题在于研究设计简便、高效、经济的适于工业化生产制备氟替卡松丙酸酯的生产方法。
本发明提供了一种合成S-氟甲基-6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰基氧基-3-酮雄甾-1，4-二烯-17β-硫代羧酸酯(其商品名为氟替卡松丙酸酯，式[1])的合成方法。
本发明的方法包括下列步骤：
(1)通过化合物[2]，即6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰基氧基-3-酮雄甾-1，4-二烯-17β-羧酸，在酮类或醚类溶剂中，如丁酮、四氢呋喃等，4-二甲胺基吡啶催化下与N，N-二甲基硫代氨基甲酰氯反应，在温度为0～40℃反应制得[3]；
(2)17β-[(N，N-二甲基氨基甲酰)硫代]甲酰基-6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯，即[3]，在醇与磷酸盐体系中，进行碱性下脱酰胺反应得到式[4]的碱金属盐，即[4a]，再经酸中和得到[4]；
(3)在溶剂中，先使氟溴甲烷与有机碱络合，活化氟甲基后，再与6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯-17β-硫代羧酸(即[4])经氟甲基化反应制得[1]。
本发明的特点：
(a)从[2]制备[3]，不需要碘化钠或其它碘化合物为催化剂，以4-二甲胺基吡啶为酸吸收剂，在酮或醚的溶剂中，如丁酮、四氢呋喃等，与二甲基硫代氨基甲酰氯反应，温度为0～40℃，最佳温度为25～35℃，反应2～3小时，再加二甲基乙酰胺及水，冷至0～5℃得到高质量的[3]。
(b)从[3]转化为[4]，在碱金属磷酸盐与醇体系中，生成[4a]，其中M可为钾、钠或锂等；[4a]经酸化得到[4]。
在碱金属磷酸盐与醇体系中，碱金属磷酸盐包括磷酸三钾，磷酸三钠或磷酸锂等。其中最优秀的是磷酸三钾。
所使用的醇包括甲醇，乙醇或丙醇，其中好的为甲醇。其反应温度可以是0～100℃，最合适为20～40℃。其反应过程可以用TLC或HPLC跟踪。
该反应最好为磷酸钾的甲醇体系，在室温下反应3～6小时。
(c)用[4]或[4a]来制备[1]，利用氟溴甲烷与有机碱在溶剂里先络合，进一步活化氟甲基后，再与[4]反应，快速生成[1]。
在本反应中用到的有机碱包括三乙胺、二乙胺、吡啶、4-二甲胺基吡啶、a-甲基吡啶等，都能得到好的反应结果。其所用的溶剂非常广泛，可以是酮、醇、酯、酰胺、卤代烃等均可为溶剂，其反应的结果没有大的影响。反应温度在0～30℃均可。也可在制得[4a]的反应体系中直接加入氟溴甲烷，反应得到[1]。
本发明中所述式[2]，即6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯-17β-羧酸，以氟美松经高碘酸氧化，再经丙酰氯酰化而得，其路线如下所示。
为了更清楚地说明本发明，列举以下实例，但其对本发明的范围无任何限制。
本发明的方法操简便，反应条件温和，制得的产品质量好。本发明的方法宜于规模型工业化生产。
具体实施方式：
实例1
6a，9a-二氟-11β，17a-二羟基-16a-甲基-3-酮雄甾-1，4-二烯-17β-羧酸的制备
氟美松(100g)，四氢呋喃(500ml)，降温至0℃，滴加高碘酸水溶液(高碘酸85g，水250ml)，反应3小时，加水(4L)，搅拌析出固体，过滤烘干得产品，纯度99％以上。
实例2
6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯-17β-羧酸(式[2])的制备
例1所得6a，9a-二氟-11β，17a-二羟基-16a-甲基-3-酮雄甾-1，4-二烯-17β-羧酸(50g)，三乙胺(30g)，丙酮(800ml)，搅拌冷却至-5～0℃，滴加丙酰氯(28g)，搅拌1小时，再加二乙胺(40ml)，搅拌1小时，冲入到冰酸水中，析出产品，过滤烘干得产品，纯度98％以上。
实例3
17β-[(N，N-二甲基氨基甲酰)硫代]甲酰基-6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯(式[3])的制备
6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯-17β-羧酸(45.5g)，丁酮(1L)，二甲胺基吡啶(30.5g)，N，N-二甲基硫代氨基甲酰氯(24.7g)，室温下搅拌3小时，降温至10～15℃，加入DMA(300ML)，水(2L)，混合物被冷却至0～5℃，过滤水洗，烘干得产品，纯度98.5％以上。
实例4
6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯-17β-硫代羧酸([4])的制备
17β-[(N，N-二甲基氨基甲酰)硫代]甲酰基-6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯(20g)，磷酸三钾(12.7g)，甲醇(200ml)，氮气保护下，室温搅拌3小时，加水(200ml)，控温在20℃下，用2N盐酸调PH1～2，过滤水洗至中性，烘干得产品，纯度98.6％。
实例5
S-氟甲基-6a，9a-二氟-11beta-羟基-16a-甲基-17a-丙酰基氧基-3-酮雄甾-1，4-二烯-17beta-硫代羧酸酯(式[1]即氟替卡松丙酸酯)的制备
丙酮100ml，二甲胺基吡啶(12.2g)，降温至0～5℃，加入氟溴甲烷(5.65g)，搅拌1小时，加入6a，9a-二氟-11β-羟基-16a-甲基-17a-丙酰氧基-3-酮雄甾-1，4-二烯-17β-硫代羧酸(20g)，搅拌2小时，冲入到酸水中，过滤，水洗至中性，烘干得到氟替卡松丙酸酯，经乙酸乙酯精制得到高纯度的产品，HPLC检测纯度为99.6％。
Claims (5)
1、一种合成氟替卡松丙酸酯的方法，该方法包括下列步骤：
(1)化合物[2]制备化合物[3]：在酮或醚溶剂中，在4-二甲胺基吡啶的存在下，不需要碘化钠或其它碘化物为催化剂，使用N，N-二甲基硫代氨基甲酰氯制得[3]；
(2)在碱金属磷酸盐的醇体系中，[3]经脱酰胺制得[4a]，其中M为钾、钠或锂，[4a]经酸化得到[4]；
(3)在溶剂中，用有机碱与氟溴甲烷先进行络合，再与[4]或[4a]反应制得[1]
2、根据权利要求1所述的一种合成氟替卡松丙酸酯的方法，其特征在于其中所述从化合物[2]制备化合物[3]，溶剂为丁酮或四氢呋喃，其温度为0～40℃。
3、根据权利要求1所述的一种合成氟替卡松丙酸酯的方法，其特征在于其中所述，从化合物[3]制备化合物[4]，其中M为钾、钠或锂；[4a]经酸化得到[4]；在碱金属磷酸盐与醇体系中，碱金属磷酸盐为磷酸三钾，磷酸三钠或磷酸三锂；所使用的醇为甲醇，乙醇或丙醇；其反应温度为0～100℃。
4、根据权利要求1所述的一种合成氟替卡松丙酸酯的方法，其特征在于，用有机碱先与氟溴甲烷络合，再与[4]或[4a]反应制备[1]，所用的有机碱为三乙胺、二乙胺、吡啶、4-二甲胺基吡啶或α-甲基吡啶；所用的溶剂为酮、醇、酯或酰胺；反应温度在0～30℃。
5、根据权利要求4所述的方法，其特征在于所用的溶剂为丙酮、DMF或DMA。
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100281472A CN100560598C (zh) | 2005-07-26 | 2005-07-26 | 氟替卡松丙酸酯的合成方法 |
| PCT/CN2005/001339 WO2007012228A1 (fr) | 2005-07-26 | 2005-08-29 | Procédé de préparation du propionate de fluticasone |
| EP05781841A EP1911741A4 (en) | 2005-07-26 | 2005-08-29 | PROCESS FOR PREPARING FLUTICASON PROPIONATE |
| US12/020,519 US20080125407A1 (en) | 2005-07-26 | 2008-01-26 | Method for preparation of fluticasone propionate |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100281472A CN100560598C (zh) | 2005-07-26 | 2005-07-26 | 氟替卡松丙酸酯的合成方法 |
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| Publication Number | Publication Date |
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| CN1903871A CN1903871A (zh) | 2007-01-31 |
| CN100560598C true CN100560598C (zh) | 2009-11-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2005100281472A Expired - Fee Related CN100560598C (zh) | 2005-07-26 | 2005-07-26 | 氟替卡松丙酸酯的合成方法 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20080125407A1 (zh) |
| EP (1) | EP1911741A4 (zh) |
| CN (1) | CN100560598C (zh) |
| WO (1) | WO2007012228A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
| TWI695723B (zh) | 2009-05-29 | 2020-06-11 | 美商沛爾醫療股份有限公司 | 用於經由呼吸道輸送活性劑的組成物以及相關方法與系統 |
| CN104004044A (zh) * | 2013-02-25 | 2014-08-27 | 武汉诺安药业有限公司 | 高纯度丙酸氟替卡松制备方法 |
| US20140275517A1 (en) | 2013-03-15 | 2014-09-18 | Pearl Therapeutics, Inc. | Methods and systems for conditioning of particulate crystalline materials |
| US9303060B1 (en) | 2014-10-03 | 2016-04-05 | Amphaster Pharmaceuticals, Inc. | Methods of preparing intermediate of fluticasone propionate |
| CN111751455A (zh) * | 2019-03-29 | 2020-10-09 | 天津药业研究院有限公司 | 原料药中氟溴甲烷残留的检测方法 |
| CN110698530A (zh) * | 2019-10-30 | 2020-01-17 | 山东赛托生物科技股份有限公司 | 一种丙酸氟替卡松的合成方法 |
| KR20240042438A (ko) | 2021-07-09 | 2024-04-02 | 아스트라제네카 파마수티컬스 엘피 | 에어로졸 약물 전달을 위한 조성물, 방법 및 시스템 |
| WO2023119093A1 (en) | 2021-12-20 | 2023-06-29 | Astrazeneca Ab | Compositions, methods and systems for aerosol drug delivery |
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| US5079369A (en) * | 1976-04-12 | 1992-01-07 | Fujisawa Pharmaceutical Company, Ltd. | Syn-isomer of 3,7-disubstituted-3-cephem-4-carboxylic acid compounds and processes for the preparation thereof |
| CA1205464A (en) * | 1980-02-15 | 1986-06-03 | Gordon H. Phillipps | Androstane carbothioates |
| JPS56138200A (en) | 1980-02-15 | 1981-10-28 | Glaxo Group Ltd | Androstane carbothioate compound |
| US20020133032A1 (en) | 2000-02-25 | 2002-09-19 | Jufang Barkalow | Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods |
| TW200300676A (en) * | 2001-12-04 | 2003-06-16 | Tanabe Seiyaku Co | Biotin intermediate and its production |
| GB0202563D0 (en) * | 2002-02-04 | 2002-03-20 | Glaxo Group Ltd | Process |
| WO2004001369A2 (en) * | 2002-06-20 | 2003-12-31 | Sun Pharmaceutical Industries Limited | 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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- 2005-07-26 CN CNB2005100281472A patent/CN100560598C/zh not_active Expired - Fee Related
- 2005-08-29 WO PCT/CN2005/001339 patent/WO2007012228A1/zh active Application Filing
- 2005-08-29 EP EP05781841A patent/EP1911741A4/en not_active Withdrawn
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- 2008-01-26 US US12/020,519 patent/US20080125407A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CN1903871A (zh) | 2007-01-31 |
| WO2007012228A1 (fr) | 2007-02-01 |
| EP1911741A4 (en) | 2009-06-03 |
| EP1911741A1 (en) | 2008-04-16 |
| US20080125407A1 (en) | 2008-05-29 |
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