Process for the preparation of steroid derivatives

Details Process for the preparation of steroid derivatives Process for the preparation of steroid derivatives

1997-05-23

1998-05-12

Shah, Mukund J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07J 7100

Patent

active

057507341

DESCRIPTION:

BRIEF SUMMARY
This is a 371 application of PCT/GB95/02568, filed Nov. 2, 1995.
The present invention relates an improved process for the preparation of 16,17-acetals of pregnane derivatives by the transacetalisation of the corresponding 16,17-acetonides. The process of the invention is conveniently applicable to the synthesis of intermediates useful for the preparation of pharmacologically active steroids, such as compounds described, for example, in WO 94/14834. The present process also directly provides known pharmacologically active steroids such as budesonide.
Methods for the preparation of 16,17-acetals of pregnane derivatives, which are based upon the transacetalisation of 16,17-acetonides with an aldehyde, are described in EP-B-355859, EP-B-262108, EP-A2-164636 and ES527509A1. Each of the methods therein describes the transacetalisation either in a heterogeneous system comprising an organic solvent and a catalytic amount of perchloric acid or a hydrohalogen or organic sulphonic acid, or in a homogeneous system where the aqueous hydrohalogen (e.g. hydrofluoric or hydrochloric) acid is also the solvent for the reaction. However, none of the aforementioned methods are ideal for various reasons. The use of hydrofluoric or hydrochloric acid on a large scale requires specialised equipment, and reaction with hydrofluoric acid at low temperatures (as described in EP-A2-164636) is especially difficult to apply industrially. Heterogeneous systems involve the use of high dilution and/or abrasive distribution modifiers with an oxidising acid to achieve a good epimeric distribution at C22.
The present invention overcomes the drawbacks in the art methodology by utilising sulphuric acid or phosphoric acid as a reactive solvent. Thus, according to a first aspect, the invention provides a process for the preparation of a compound of formula (I) ##STR2## or a stereoisomeric compound thereof, wherein: the 1,2-position is saturated or is a double bond; X.sup.1 and X.sup.2 are each independently hydrogen or halogen; ##STR3## (wherein the 1,2-position is saturated or is a double bond and X.sup.1, X.sup.2, R.sup.1 and R.sup.2 are as defined hereinabove) with an aldehyde R.sup.3 CHO (wherein R.sup.3 is as defined hereinabove) in either phosphoric acid or about 60% to about 75% w/w sulphuric acid. The reaction may conveniently be effected at a temperature within the range of about 0.degree. C. to about 50.degree. C., and preferably at about 20.degree. C.
As herein described, the term "halogen" means fluorine, chlorine, bromine or iodine and is preferably fluorine. The term "acyl" as a group or part of an "acyloxy" group includes, for example, a group with 1-10 carbon atoms arranged in a straight or branched chain and is preferably a C.sub.2-6 alkanoyl group (e.g. acetyl). The term "alkyl" within R.sup.3 includes a straight or branched hydrocarbon chain having 1-10 carbon atoms and is preferably a C.sub.1-4 alkyl group, especially n-propyl.
The process of the present invention has a number of advantages over the methods in the art. Thus, for example, sulphuric acid and phosphoric acid are inexpensive reagents which are non-oxidising and can be used on an industrial scale without specialised equipment. The use of sulphuric acid or phosphoric acid as the solvent for the reaction means that the reaction is homogeneous and is consequently facile and scalable. The reaction also proceeds in high epimeric distribution, i.e. with a high propensity for (R) stereochemistry at C.sub.22.
The process of the present invention may preferably be used to prepare compounds of formula (I) in which R.sup.1 is hydrogen and R.sup.2 is hydroxyl.
The process of the present invention may also preferably be used to prepare compounds of formula (I) in which X.sup.1 and X.sup.2 are both fluorine atoms.
The present process is particularly suitable for the preparation of a compound of formula (III) ##STR4## or a stereoisomeric compound thereof, especially the 22R-isomer thereof (i.e. the compound (22R)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11.

REFERENCES:
patent: 4221786 (1980-09-01), Kalvoda

Affiliated with

Also associated with

Rating

Process for the preparation of steroid derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of steroid derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of steroid derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-980684