Method of manufacturing an amorphous form of the hemi-calcium salt of (3r, 5r) 7-3-phenly-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl!-3, 5-dihydroxyheptanoic acid (actorvastatin)
申请人:Radl Stanislav
公开号:US20050131055A1
公开(公告)日:2005-06-16
A method of manufacturing an amorphous form of the hemi-calcium salt of (3R, 5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid of formula (I), in which (3R, 5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid or its salt with a cation M
+
wherein M
30
is either a cation of an alkali metal or an ammonium cation of formula R
n
N
(+)
H
(4−n)
wherein R is lower C
1
-C
5
alkyl, n may reach values ranging between 0 and 3, is, without isolating the intermediate in the form of the hemi-calcium salt or of another salt, acid or lactone, converted, in a solution, by the treatment with the calcium salt or calcium hydroxide, or a calcium C
1
-C
5
alcoholate, to the hemi-calcium salt, and the latter is precipitated with a C
1
-C
5
hydrocarbon or dialkylether of formula R
1
OR
2
, wherein each of R
1
and R
2
is a C
1
-C
5
alkyl group. The starting acid or its salt is prepared starting from (3R, 5R) tert-butyl (6-2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl)acetate of formula II.
一种制备(3R,5R)7-[3-苯基-4-苯基氨甲酰基-2-(4-氟苯基)-5-异丙基吡咯-1-基]-3,5-二羟基庚酸的半钙盐非晶态的方法,其中(3R,5R)7-[3-苯基-4-苯基氨甲酰基-2-(4-氟苯基)-5-异丙基吡咯-1-基]-3,5-二羟基庚酸或其与M+阳离子形成的盐,其中M30为碱金属阳离子或公式RnN(+)H(4−n)的铵阳离子,其中R为较低的C1-C5烷基,n的值在0到3之间,不需要将中间体以半钙盐或其他盐、酸或内酯的形式分离,通过处理钙盐或氢氧化钙或C1-C5醇钙盐的溶液,将其转化为半钙盐,并用公式R1OR2的C1-C5烃或双烷基醚沉淀。起始酸或其盐是从公式II的(3R,5R)叔丁基(6-2-[3-苯基-4-苯基氨甲酰基-2-(4-氟苯基)-5-异丙基吡咯-1-基]-乙基}-2,2-二甲基-[1,3]二氧杂环戊烷-4-基)醋酸酯开始制备的。