Patent EP-0072200-B1 (EP)
IPC: C07J5/00
Filed: 1982-08-04
Granted: 1985-11-21
Abstract: A process for the preparation of corticosteroid esters of the formulawherein--- signifies that a double bond can be present;X is hydrogen, fluorine or chlorine;R<sub>1</sub> is hydrogen, fluorine, chlorine or methyl, which may be either a or β;R<sub>2 </sub>is halogen, oxo, i.e. ketonic oxygen, or hydroxyl;R<sub>3</sub> is hydrogen, a-methyl or β-methyl;R<sub>4</sub> 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; oriii) a phenyl group;R<sub>5</sub> is hydroxyl or R<sub>6</sub>; whereR<sub>6</sub> is hydrogen, halogen, two halogen atom substituents orOR<sub>7</sub>, where R<sub>7</sub> is an acyl group of the formula R'CO in whichR', 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; oriii) a phenyl group;which comprises esterifying a compound of the formulawherein X, R<sub>1</sub>, R<sub>3</sub> and R<sub>5</sub> are as defined above, andR<sub>8</sub> is trihaloacetate, halogen or oxo;at the 17-position only, or at the 17-and 21-positions when R<sub>5</sub>, 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<sub>2</sub> is hydroxyl, Rs is R<sub>6</sub>, and X, R<sub>1</sub>, R<sub>3</sub> and R<sub>4</sub> are as defined above; or when R<sub>8</sub> is halogen or oxo and R<sub>5</sub> is R<sub>6</sub>, isolating a compound of formula I after the said esterification; or treating a compound of formula IV from the esterificationwherein R<sub>5</sub> is R<sub>6</sub>, 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<sub>2</sub> is hydroxyl, R<sub>5</sub> is R<sub>6</sub> and X, R<sub>1</sub>, R<sub>3</sub> and R<sub>4</sub> are as defined from formula I; or by so eliminating the 11-trihaloacetate group from a compound of formulawherein X, R<sub>1</sub> and R<sub>3</sub> are as defined forformula I; R<sub>9</sub> is an alkyl group of 1 to 3 carbon atoms; and R<sub>10</sub> 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; oriii) a phenyl group;to form a compound of formula 1, wherein R<sub>2</sub> and R<sub>5</sub> are both hydroxyls, and R<sub>1</sub>, R<sub>3</sub>, R<sub>4</sub> and X are as defined for formula I.