公开(公告)号：EP0072200B1

公开(公告)日：1985-11-21

申请号：EP82304116.5

申请日：1982-08-04

申请人： PLURICHEMIE ANSTALT

发明人： Page, Philip Ronald Rua dos Girassois, Lote 38A ,  Heggie, William

IPC分类号： C07J5/00 ,  C07J7/00 ,  A61K31/57

CPC分类号： C07J5/0053 ,  C07J5/0076 ,  C07J7/0055 ,  C07J7/0085

公开(公告)号：EP0072200A2

公开(公告)日：1983-02-16

申请号：EP82304116.5

申请日：1982-08-04

申请人： PLURICHEMIE ANSTALT

发明人： Page, Philip Ronald Rua dos Girassois, Lote 38A ,  Heggie, William

IPC分类号： C07J5/00 ,  C07J7/00 ,  A61K31/57

CPC分类号： C07J5/0053 ,  C07J5/0076 ,  C07J7/0055 ,  C07J7/0085

摘要： A process for the preparation of corticosteroid esters of the formula
wherein

--- signifies that a double bond can be present;
X is hydrogen, fluorine or chlorine;
R 1 is hydrogen, fluorine, chlorine or methyl, which may be either a or β;
R 2 is halogen, oxo, i.e. ketonic oxygen, or hydroxyl;
R 3 is hydrogen, a-methyl or β-methyl;
R 4 is an acyl group of the formula RCO, in which R is one of the following:

i) an alkyl group containing 1 to 16 carbon atoms, whether straight-chained, branched or cyclic;
ii) an aralkyl group of 7 to 8 carbon atoms; or
iii) a phenyl group;

R 5 is hydroxyl or R 6 ; where
R 6 is hydrogen, halogen, two halogen atom substituents or
OR 7 , where R 7 is an acyl group of the formula R'CO in which
R', which can be identical or different to R in the same molecule, is one of the following:

i) an alkyl group containing 1 to 16 carbon atoms, whether straight-chained, branched or cyclic;
ii) an aralkyl group of 7 to 8 carbon atoms; or
iii) a phenyl group;

which comprises esterifying a compound of the formula
wherein X, R 1 , R 3 and R 5 are as defined above, and
R 8 is trihaloacetate, halogen or oxo;
at the 17-position only, or at the 17-and 21-positions when R 5 , in formula III, is hydroxyl, the said esterification being carried out with the anhydride of the acid containing the group it is desired to enter at the 17- position, or at the 17- and 21- positions, together with a pair of strong acids; and if desired eliminating immediately thereafter any 11-trihaloacetate substituent, to form a compound of formula I, wherein R 2 is hydroxyl, Rs is R 6 , and X, R 1 , R 3 and R 4 are as defined above; or when R 8 is halogen or oxo and R 5 is R 6 , isolating a compound of formula I after the said esterification; or treating a compound of formula IV from the esterification
wherein R 5 is R 6 , by eliminating the 11-trihaloacetate group therefrom by reaction, in the presence of a lower alcohol, with an organic amine (other than one in which the nitrogen forms part of an aromatic ring), or ammonia gas dissolved in a suitable anhydrous solvent, or ammonium hydroxide or hydrazine, to produce a compound of formula I wherein R 2 is hydroxyl, R 5 is R 6 and X, R 1 , R 3 and R 4 are as defined from formula I; or by so eliminating the 11-trihaloacetate group from a compound of formula
wherein X, R 1 and R 3 are as defined forformula I; R 9 is an alkyl group of 1 to 3 carbon atoms; and R 10 is a hydrocarbon group comprising one of the following:

i) an alkyl group of 1 to 16 carbon atoms, whether straight-chained, branched or cyclic;
ii) an aralkyl group of7 to 8 carbon atoms; or
iii) a phenyl group;


to form a compound of formula 1, wherein R 2 and R 5 are both hydroxyls, and R 1 , R 3 , R 4 and X are as defined for formula I.