公开(公告)号：EP0072200A3

公开(公告)日：1983-06-01

申请号：EP82304116

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： C07J05/00 ,  C07J07/00 ,  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.

摘要翻译： 一种制备下式的皮质类固醇酯的方法，其中---表示可以存在双键; X是氢，氟或氯; R1是氢，氟，氯或甲基，其可以是α或β; R2是卤素，氧代即酮氧或羟基; R3是氢，α-甲基或β-甲基; R4是式RCO的酰基，其中R是以下之一：i）含有1-16个碳原子的烷基，无论是直链的，支链还是环状的; ii）7至8个碳原子的芳烷基; 或iii）苯基; R5是羟基或R6; 其中R 6是氢，卤素，两个卤素原子取代基或OR 7，其中R 7是式R'CO的酰基，其中R'可以与同一分子中的R相同或不同，为以下之一： i）含有1至16个碳原子的烷基，无论是直链，支链还是环状的; ii）7至8个碳原子的芳烷基; 或iii）苯基; 该方法包括将下式化合物酯化：其中X，R1，R3和R5如上所定义，且R8为三卤代乙酸酯，卤素或氧代; 在式III中R5是羟基时，所述酯化反应是在含有该基团的酸的酸酐的情况下进行的，所述酯的酸酐需要在17-位置处或在17-位置和21-位置处， 位置，或在17位和21位，连同一对强酸; 如果需要，立即除去任何11-三卤代乙酸酯取代基，形成式I化合物，其中R2是羟基，R5是R6，且X，R1，R3和R4如上所定义; 或者当R8是卤素或氧代并且R5是R6时，在所述酯化后分离式I化合物; 或通过在低级醇存在下，用有机胺（除了其中氮形成一部分的一个有机胺的反应）除去11-三卤代乙酸酯基团，从其中R5是R6的酯化反应中处理式IV化合物 芳香环）或氨气溶解于合适的无水溶剂或氢氧化铵或肼中，生成式I化合物，其中R 2为羟基，R 5为R 6且X，R 1，R 3和R 4如式I所定义; 或者通过如此从式III化合物中除去11-三卤代乙酸酯基团，其中X，R1和R3如式I所定义; R9是1至3个碳原子的烷基; 并且R 10是包含以下之一的烃基：i）具有1至16个碳原子的烷基，无论是直链的，支链的还是环状的; ii）7至8个碳原子的芳烷基; 或iii）苯基; 以形成式1的化合物，其中R 2和R 5都是羟基，且R 1，R 3，R 4和X如对式I所定义。