US 5,502,183 A · Steroid intermediates and processes for their preparation

A process for the preparation of steroid intermediates of the formula ##STR173## wherein Z is an acyl group;

R.sub.1 is a hydrogen, .alpha.- or .beta.-methyl, hydroxy, or a lower alkoxy group;
R.sub.2 is hydrogen, fluoro, chloro or lower alkyl;
and the dotted line represents an optional double bond;
which comprises:
a. optionally contacting a 9.alpha.-hydroxy steroid of the formula ##STR174## wherein R.sub.1 is as hereinbefore defined and ##STR175## represents i) an enol ether of the formula:
##STR176## wherein R.sub.3 is a lower alkyl or a trisubstituted silyl group wherein the silyl substituents are independently lower alkyl, phenyl or phenylalkyl;
the dashed line represents a double bond present in one or the other position;
and R.sub.2 is as hereinbefore defined;
ii) a ketal of the formula:
##STR177## wherein R.sub.10 and R.sub.11 independently are lower alkyl groups, optionally connected together to form a five or six membered ring;
the dashed lines represent an optional bond present in either the A or B ring;
and R.sub.2 is as hereinbefore defined;
or
iii) an enamine of the formula ##STR178## wherein R.sub.2, R.sub.10 and R.sub.11 are as hereinbefore defined with the proviso that the optional six membered ring may optionally contain an oxygen or nitrogen atom;
with either
1) excess base and a trisubstituted silylchloride;
2) a lower alkyl, vinyl or phenyl haloformate;
and
3) a lower alkanol;
or
1) excess base;
2) a lower alkyl, vinyl or phenyl haloformate;
and
3) an alkoxide
to afford the C-9 carbonate of the formula ##STR179## wherein R.sub.4 is a lower alkyl, vinyl or phenyl carbonate group, and R.sub.1, R.sub.2, R.sub.3, R.sub.10 and R.sub.11 are as hereinbefore defined;
b. contacting the resultant C-9 carbonate of step a or the 9.alpha.-hydroxy starting material of formula III with lithium acetylide or lithium trimethylsilyl acetylide optionally in the presence of LiX wherein X is a chloro, bromo or perchlorate ion, to afford the C-17 ethynyl compound of the formula ##STR180## wherein R.sub.5 is hydrogen, a lower alkyl carbonate, a vinyl carbonate or a phenyl carbonate group, R.sub.6 is hydrogen or a trimethylsilyl group;
R.sub.1, R.sub.2, R.sub.3, R.sub.10, R.sub.11 and the dashed and dotted lines are as hereinbefore defined;
c. esterifying the resulting C-17 hydroxyl compound of step b with
1) catalytic phenoxide formed in in situ with a metal hydride and a phenol;
and
2) a diarylcarbonate of the formula ##STR181## or an alkylaryl carbonate of the formula ##STR182## or a diarylcarboxylate of the formula ##STR183## or an arylalkylcarboxylate of the formula ##STR184## wherein R is a lower alkyl group and Ar is an aryl group;
and 3) a metal hydride;
in an aprotic solvent;
to afford the C-17 ester of the formula ##STR185## wherein R.sub.12 is a lower alkyl, aryl, lower alkoxy or aryloxy group and R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.10, R.sub.11 and the dashed and dotted lines are as hereinbefore defined;
and in the case wherein R.sub.6 is a trisubstituted silyl group, removal of that group by a conventional desilylation method;
d. contacting the resulting C-17 ester of step c with one of the following reducing agents:
1. formic acid or its salts;
2. a samarium (II) salt;
3. a transition metal;
and a palladium catalyst containing a phosphine or phosphite ligand, to afford the 17-allene of the formula ##STR186## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.10, R.sub.11 and the dashed and dotted lines are as hereinbefore defined;
e. treatment of the resulting 17-allene of step d with an aqueous strong acid to afford the 3-one of the formula ##STR187## wherein R.sub.1, R.sub.2, R.sub.5 and the dotted line are as hereinbefore defined;
f. oxidizing the resulting 3-one of step e with a dialkyl dioxirane to afford the compound of the formula ##STR188## wherein R.sub.1, R.sub.2, R.sub.5 and the dotted line are as hereinabove defined;
g. treatment of the compound of step f with an alkali metal salt of a carboxylic acid under phase-transfer conditions to afford the compound of the formula ##STR189## wherein Z is an acyl group, R.sub.1, R.sub.2, R.sub.5, and the dotted line are as hereinbefore defined;
and
h. treatment of the compound of step g with a strong acid to afford the .DELTA.9,11 steroid of formula I.

42 more elements

A process for the preparation of steroid intermediates of the formula ##STR193## wherein Z is an acyl group;

R.sub.1 is a hydrogen, .alpha.- or .beta.-methyl, hydroxy, or a lower alkoxy group;
which comprises:
a) contacting a 9.alpha.-hydroxy steroid of the formula ##STR194## wherein R.sub.3 is lower alkyl and R.sub.1 is as hereinbefore defined;
with
1) excess base and a trialkylsilyl chloride
2) a lower alkyl chloroformate;
and
3) a lower alkanol;
or
1) excess base;
2) a lower alkyl chloroformate;
and
3) an alkoxide
to afford the C-9 carbonate of the formula ##STR195## wherein R.sub.4 is lower alkyl, and R.sub.1 and R.sub.3 are as hereinbefore defined,
b. contacting the resultant C-9 carbonate of step a with about 2 equivalents of lithium acetylide in the presence of LiX wherein X is a chloro, bromo or perchlorate ion to afford the C-17 ethynyl compound of the formula ##STR196## wherein R.sub.1, R.sub.3 and R.sub.4 are as hereinbefore defined;
c. esterifying the resulting C-17 hydroxyl compound of step b with
1. catalytic phenoxide formed in situ with a metal hydride and a phenol;
and
2. a diarylcarbonate of the formula ##STR197## or an alkylaryl carbonate of the formula ##STR198## or a diarylcarboxylate of the formula ##STR199## or an arylalkylcarboxylate of the formula ##STR200##
wherein R is a lower alkyl group and Ar is an aryl group;
and 3. a metal hydride;
in an aprotic solvent;
to afford the C-17 ester of the formula ##STR201## wherein R.sub.12 is a lower alkyl, aryl, lower alkoxy or aryl oxy group and R.sub.1, R.sub.3 and R.sub.4 are as hereinbefore defined;
d. contacting the resulting C-17 ester of step c with one of the following reducing agents:
1. formic acid or its salts;
2. a samarium (II) salt;
3. a transition metal;
and a palladium catalyst containing a phosphine or phospite ligand, to afford the 17-allene of the formula ##STR202## wherein R.sub.1, R.sub.3 and R.sub.4 are as hereinbefore defined;
e. treatment of the resulting 17-allene of step d with an aqueous strong acid to afford the 3-one of the formula ##STR203## f) oxidizing the resulting 3-one of step e with a dialkyl dioxirane to afford the compound of the formula ##STR204## wherein R.sub.1 and R.sub.4 are as hereinabove defined;
g) treatment of the compound of step f with an alkali metal salt of a carboxylic acid under phase-transfer conditions to afford the compound of the formula ##STR205## wherein R.sub.1, R.sub.4 and Z are as hereinbefore defined;
and h) treatment of the compound of step g with a mineral or strong organic acid to afford the .DELTA.9,11 steroid of formula II.

28 more elements

A process for the preparation of .DELTA.9(11) enes of the formula ##STR219## wherein A and B together are keto, ketal, allene;

##STR220## or .dbd.CHCH.sub.2 OR.sub.13, or A is hydrogen, lower alkyl, lower alkenyl, lower alkynyl aryl or alkylaryl;
--CN, ##STR221## or --COCH.sub.2 W;
B is hydrogen, OH, OR.sub.13, or together with carbon 16 forms a 16,17-double bond or a 16,17-epoxide;
R.sub.1 is hydrogen, .alpha.- or .beta.-methyl, hydroxy or lower alkoxy;
R.sub.2 is hydrogen, fluoro, chloro or lower alkyl;
R.sub.13 is a conventional hydroxyl protecting group;
W is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl or alkylaryl;
--OR, --SR, ##STR222## halogen, --N.sub.3, ##STR223## --NRR, --SCN, --CN, --SO.sub.2 R, --N(R)NRR, --N(R)OR or --ONRR;
R is independently hydrogen, lower alkyl, cycloalkyl, alkenyl, aryl, optionally substituted by lower alkyl, halogen or nitro groups;
which comprises treatment of a compound of formulae XXVIIa or XXVIIb ##STR224## wherein R.sub.4 is a lower alkyl, vinyl or phenyl carbonate group;
##STR225## represents i) an enol ether of the formula:
##STR226## wherein R.sub.3 is a lower alkyl or a trisubstituted silyl group wherein the silyl substituents are independently lower alkyl, phenyl or phenylalkyl;
the dashed line represents a double bond present in one or the other position;
and R.sub.2 and R.sub.4 are as hereinbefore defined;
ii) a ketal of the formula:
##STR227## wherein R.sub.10 and R.sub.11 independently are lower alkyl groups, optionally connected together to form a ring which optionally may contain an oxygen or nitrogen atom;
the dashed lines represent an optional bond present in either the A or B ring;
R.sub.4 is as hereinbefore defined;
and
iii) an enamine of the formula ##STR228## wherein R.sub.2, R.sub.4, R.sub.10 and R.sub.11 are as hereinbefore defined;
A, B and R.sub.1 are as hereinbefore defined, with a strong acid in the case of compounds XXVIIA or an aqueous strong acid for compounds XXVIIa or XXVIIb to generate the 9(11) enes of formula XXVIII.

18 more elements

Steroid intermediates and processes for their preparation

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Steroid intermediates and processes for their preparation

Life of this patent

Abstract

Claims35