Mometasone Furoate, otherwise known as 9.alpha.,21-dichloro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-1,4-pre gnadien-3,20-dione 17-(2'-furoate), is a potent anti-inflammatory steroid having the structure: ##STR2##
It is described in U.S. Pat. No. 4,472,393, specifically in Example 12. Example 12 describes two processes for the preparation of Mometasone Furoate, Methods I and II, which use as starting materials 9.beta.,11.beta.-epoxy-17.alpha.,21-dihydroxy-16.alpha.-methyl-1,4-pregnad ien-3,20-dione and 21-chloro-17.alpha.-hydroxy-16.alpha.-methyl-1,4,9(11)-pregnatrien-3,20-di one, respectively. Only Method I therein is relevant to the present invention; it can be illustrated as follows:
METHOD I in Example 12 of U.S. Pat. No. 4,472,393: ##STR3## (where 4-DMAP is 4-dimethylaminopyridine). The process of Example 12, Method I, is carried out in three separate and distinct stages, as indicated in the above scheme.
Further study of this process has indicated that a number of steroidal by-products are formed at each stage, so that yields are reduced and elaborate purification is required. Thus, the first stage (introduction of the 21-chlorine atom) yields also a hydroxysultone (see below), a 9.alpha.,11.beta.-chlorohydrin, and a 21-pyridinium salt (this last compound amounting to some 5% of the product by NMR analysis). The second stage, esterification to introduce the 17-(2-furoyl-oxy) group, typically produces about 4-6% yield of the enol difuroate epoxide (a 21-chloro-9.alpha.,11.beta.-epoxy-20(21)-en-17.alpha.,20-diol 17,20-difuroate). We have determined that the sultone and the enol difuroate epoxide have the following structures: ##STR4##
The third stage (opening the epoxide ring) typically yields about 7-8% of two degradation products having an aromatized Ring A with the 9,10-bond broken. All these steps, therefore, introduce impurities, so that the yield of desired product is thereby reduced, and the final product needs careful purification, resulting in further losses.
It is therefore an object of the present invention to provide an improved process for the preparation of Mometasone Furoate and related 17-esters of 9.alpha.,21-dihalo-pregnane-11.beta.,17.alpha.-diol-20-ones, especially anti-inflammatory steroids.
USPTO Backgrounds
USPTO Backgrounds