Preparation of corticoids from 17-keto steroids

Abstract

The present invention is a process for the transformation of a 17-keto steroid (II) to a corticoid (XI) which has pharmaceutical utility.

Description

Claims

1. A process for the preparation of a corticoid of the formula ##STR1## which comprises (1) contacting a protected 17-keto steroid selected from the group consisting of compounds of the formula ##STR2## with a metallated 1,2-dihalogenated ethene of the formula ##STR3## to form the corresponding protected C.sub.21 -steroid selected from the group consisting of compounds of the formula ##STR4## respectively; (2) hydrolyzing the protected C.sub.21 -steroid (IVa-IVe) with acid to remove the protecting group and give a C.sub.21 -steroid of the formula ##STR5## (3) contacting the C.sub.21 -steroid (V) with a sulfenylating agent of the formula

R.sub.22 --S--X (VI)

to give a 20,21-dihalo steroid of the formula ##STR6## (4) contacting the 20,21-dihalo steroid (VII) with a base selected from the group consisting of an alkoxide or mercaptide of the formula OR.sub.20.sup.-, or SR.sub.20.sup.-, respectively, to give a sulfoxide of the formula ##STR7## (5) contacting the sulfoxide (VIII) with a thiophile to give a 20-unsaturated steroid of the formula ##STR8## (6) hydrolyzing the 20-unsaturated steroid (IX) with acid to give a 21-halo steroid of the formula ##STR9## and (7) contacting the 21-halo steroid (X) with an anion of the formula R.sub.21 CO.sup..crclbar. where A is a fluorine, chlorine or bromine atom; M is a fluorine, chlorine or bromine atom; R.sub.3 is alkyl of 1 thru 5 carbon atoms with the proviso that with the ketal (IIIc and IIIe), the R.sub.3 groups can be connected to form the ethylene ketal; R.sub.3 ' is alkyl of 1 thru 5 carbon atoms; R.sub.3 " is alkyl of 1 thru 5 carbon atoms; R.sub.6 is a hydrogen or fluorine atom or methyl group; R.sub.9 is a hydrogen or fluorine atom, hydroxyl group, --OSi(R).sub.3 or nothing; R.sub.11 is H, H,H, H, .beta.-OH, H, .beta.-OSi(R).sub.3, or O; R.sub.16 is hydrogen atom or methyl group; R.sub.20 is alkyl of 1 thru 4 carbon atoms or phenyl; R.sub.21 is alkyl of 1 thru 4 carbon atoms or phenyl; R.sub.22 is alkyl of 1 thru 5 carbon atoms, trichloromethyl, phenyl, phenyl substituted with 1-4 carbon atoms or substituted with 1 thru 3 nitro or trifluoromethyl groups, aralkyl of 7 thru 12 carbon atoms or --N--(R.sub.122).sub.2 or phthalimide; X is a chlorine or bromine atom, phenylsulfone, phthalimide or imidazole group; Z is --OR.sub.20 or --SR.sub.20 ; metal is lithium, sodium or potassium; .infin. indicates the attached group can be in either the .alpha. or .beta. configuration; is a single or double bond.

2. A process according to claim 1 where for the corticoid (XI), R.sub.6 and R.sub.16 are hydrogen atoms, where R.sub.9 is nothing and R.sub.11 is [H] which gives a .DELTA..sup.9,11 functionality in the C ring.

3. A process according to claim 1, where the temperature for the coupling reaction is from about -120.degree. to about -20.degree..

4. A process according to claim 1, where the coupling reaction is performed in a dry solvent.

5. A process according to claim 1, where the metallated 1,2-dihalogenated ethene (III) is selected from the group consisting of lithiated trans-1,2-dichloroethene, lithiated trans-1,2-chlorofluoroethene, lithiated trans-1,2-dibromoethene, lithiated trans1,2-difluoroethene and lithiated trans-1,2-bromofluoroethene.

6. A process according to claim 5 where the metallated 1,2-dihalogenated ethene (III) is lithiated trans-1,2-dichloroethene.

7. A process according to claim 1, where the acid to remove the C.sub.3 protecting group is present in a catalytic amount.

8. A process according to claim 1, where the acid to remove the C.sub.3 protecting group is selected from the group consisting of p-TSA, hydrochloric acid, sulfuric acid, and phosphoric acid.

9. A process according to claim 1 where for the sulfenylating agent. R.sub.22 -S-X, X is a chlorine or bromine atom, and R.sub.22 is a phenyl group.

10. A process according to claim 1 where the temperature range for the sulfenylating reaction is from about -80.degree. to about 25.degree..

11. A process according to claim 1, where the base is an alkoxide.

12. A process according to claim 11 where the alkoxide is methoxide or phenoxide.

13. A process according to claim 1, where the reaction with base is performed in a polar solvent.

14. A process according to claim 1, where 1.5-2.0 equivalents of base are used.

15. A process according to claim 1 where the thiophile is selected from the group consisting of acetone, 3-pentanone, cyclohexanone, 1-(phenylthio)acetone, 2,4-pentanedione, trimethylphosphite, mesityl oxide, dimethyl malonate, 2,6-di-t-butylphenol, ethylvinyl ether, and dihydropyran.

16. A process according to claim 1 where the thiophile is a ketone.

17. A process according to claim 16 where the ketone is acetone.

18. A process according to claim 1 where the acid for hydrolyzing the 20-unsaturated steroid (IX) is p-TSA, hydrochloric acid, sulfuric acid, or phosphoric acid.