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1. 发明申请

WO2007000121A1 A METHOD FOR THE PRODUCTION OF THE HEMI-CALCIUM SALT OF (E)-7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-[METHYL(METHYLSULFONYL)AMINO]PYRIMIDIN-5-YL](3R,5S)-3,5-DIHYDROXYHEPT-6-ENOIC ACID 审中-公开
标题翻译：（E）-7- [4-（4-氟苯基）-6-异丙基-2- [甲基（甲基磺酰基）氨基]嘧啶-5-基]（3R，5S）的硫酸钙的生产方法）-3,5-二羟基庚-6-烯酸
公开(公告)号：WO2007000121A1
公开(公告)日：2007-01-04
申请号：PCT/CZ2006/000039
申请日：2006-06-08
申请人： ZENTIVA, a.s. , RADL, Stanislav , STACH, Jan , KLVANA, Robert , JIRMAN, Josef
发明人： RADL, Stanislav , STACH, Jan , KLVANA, Robert , JIRMAN, Josef
IPC分类号： C07D239/42 , A61K31/505
CPC分类号： C07D239/42 , Y02P20/55
摘要： A method of producing the hemi-calcium salt of rosuvastatin, i.e. of ( E )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3 R ,5 S )-3,5-dihydroxyhept-6-enoic acid of formula (I), in the crystalline or amorphous solid state, wherein a) the lactone of formula (IV), or ester or amid of general formulae (V) or (XIII), wherein X is either oxygen or amino group, R 1 CR 2 is a protecting group, wherein R 1 and R 2 are preferably selected from C 1 to C 3 alkyls, and R is an alkyl selected from C 1 to C 10 alkyls, preferably methyl, ethyl or tert-butyl, after removing the protecting group in the case of the compound of formula (V), ia converted, by alkaline hydrolysis with an alkali metal or Ca 2+ base, into a salt of rosuvastatin, b) in the case that an alkali metal base was used in step (a), the resulting alkali salt of rosuvastatin is converted into the calcium salt of rosuvastatin by reaction with a calcium salt in aqueous environment, c) crude calcium salt of rosuvastatin of formula (I) is extracted into a solvent partially miscible with water selected from the group including R 1 COOR 2 , R 1 COR 2 , or R 1 OH, wherein R 1 and R 2 independently mean hydrogen or a residue of a C 1 to C 10 aliphatic hydrocarbon, C 6 aromatic hydrocarbon, C 5 or C 6 cyclic hydrocarbon, or a combination of an aliphatic and aromatic or cyclic hydrocarbon, d) the solution of the calcium salt of rosuvastatin prepared according to step (c) is further washed with water, and e) the product of formula (I) is isolated by cooling the solution and filtration, or by adding an anti-solvent and filtration, or by spraying into the stream of an inert gas.
摘要翻译：（E）-7- [4-（4-氟苯基）-6-异丙基-2- [甲基（甲基磺酰基）氨基]嘧啶-5-基]（3R）的半舒康的半钙盐的制备方法，式（I）的5S）-3,5-二羟基庚-6-烯酸，其结构或无定形固态，其中a）式（Ⅳ）的内酯，或通式（Ⅴ）或（XIII），其中X为氧或氨基，R 1为CR 2为保护基，其中R 1和R 2为 > 2优选选自C 1至C 3烷基，R是选自C 1至C 3烷基的烷基，在式（V）化合物的情况下除去保护基后，通过碱金属或碱金属碱性水解转化，优选甲基，乙基或叔丁基，优选甲基，乙基或叔丁基， 2 +底物转化为罗苏伐他汀的盐，b）在步骤（a）中使用碱金属碱的情况下，将所得的瑞舒伐他汀碱盐转化为罗苏伐他汀的钙盐他汀类药物通过在水性环境中与钙盐反应，c）式（I）的瑞舒伐他汀的粗钙盐被萃取到与选自以下的水部分混溶的溶剂中：R＆lt; 2，R 1，R 2，或R 1 OH，其中R 1和R 2， SUP> 2独立地表示氢或C 1至C 10脂族烃，C 6芳烃，C 5或C 6环状烃，或脂族和芳族或环状烃的组合，d）根据步骤（c）制备的瑞舒伐他汀钙盐溶液，进一步用水洗涤，e）通过冷却溶液和过滤，或通过加入反溶剂和过滤，或通过喷雾入惰性气体流来分离式（I）的产物。

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