Process and new intermediates for the preparation of 11-methylene steroids
A process for the preparation of 11-methylene steroids from di-keto steroids involves selective olefination of the ketone at position 11 of the di-keto steroids. The resulting 11-methylene steroid products can be used as intermediates in the preparation of the synthetic steroids, Etonogestrel and Desogestrel, as well as other pharmaceutically active agents.
1. A process for the preparation of a compound of formula (I), or a solvate thereof
wherein
X represents H or it forms together with the carbon atom to which it is bonded a ketone protecting group;
Y together with the carbon atom to which it is bonded represents C═CH 2 or C(OH)CH 2 Z, wherein Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl;
R 6 is selected from H, C 1 -C 6 alkyl and halogen;
R 10 is selected from H, C 1 -C 6 alkyl and halogen, or is absent when there is a double bond between C 1 and C 10 ; R 13 is selected from H and C 1 -C 6 alkyl; R 16 is selected from H, C 1 -C 6 alkyl and halogen;
- - - is a single or double bond;
which comprises reacting a compound of formula (II) or a solvate thereof
wherein X, R 6 , R 10 , R 13 , R 16 , and - - - have the meanings defined above;
with a compound of formula (III)
wherein Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl and M is selected from Li, MgBr, MgCl and Mgl.
2. The process according to claim 1 , wherein R 6 , R 10 , R 16 are H; and R 13 is selected from C 1 -C 6 alkyl.
3. The process according to claim 1 , wherein Z represents a SiR′ 3 group wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl.
4. The process according to claim 1 , wherein Y together with the carbon atom to which it is bonded represents C═CH 2 .
5. The process according to claim 4 , which comprises:
(a) reacting a compound of formula (II), or a solvate thereof, with a compound of formula (III) to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 , wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl; and
(b) treating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 , wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl, with an acid or a base to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH 2 .
6. The process according to claim 1 , which further comprises ethynylating the compound of formula (I), or a solvate thereof, to obtain a compound of formula (IV), or a solvate thereof
wherein
Y, R 6 , R 10 , R 13 , R 16 and - - - are as defined in claim 1 ;
X represents H or it forms together with the carbon atom to which it is bonded a ketone group or a ketone protecting group; and
R 1 is selected from H and SiR″ 3 , wherein each R″ is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl and halogen.
7. The process according to claim 6 , which comprises:
(a) reacting a compound of formula (II), or a solvate thereof, with a compound of formula (III) to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl;
(b) treating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 , wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl, with an acid or a base to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH 2 ; and
(c) ethynylating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH 2 , to obtain a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH 2 .
8. The process according to claim 7 , which comprises:
(a) reacting a compound of formula (II), or a solvate thereof, with a compound of formula (III) to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 , wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl;
(b) ethynylating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl, to obtain a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl; and
(c) treating a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH 2 Z group, wherein Z is selected from H and SiR′ 3 , wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl, with an acid or a base to obtain a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH 2 .
9. A process for the preparation of Desogestrel, Etonogestrel, or a solvate thereof, the process comprising:
preparing a compound of formula (I) or a solvate thereof
wherein
X represents H or it forms together with the carbon atom to which it is bonded a ketone protecting group;
Y together with the carbon atom to which it is bonded represents C═CH 2 or C(OH)CH 2Z , wherein Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl;
R 6 is selected from H, C 1 -C 6 alkyl and halogen;
R 10 is selected from H, C 1 -C 6 alkyl and halogen, or is absent when there is a double bond between C 1 and C 10 ;R 13 is selected from H and C 1 -C 6 alkyl; R 16 is selected from H, C 1 -C 6 alkyl and halogen;
- - - is a single or double bond;
by reacting a compound of formula (II) or a solvate thereof
wherein X, R 6 , R 10 , R 13 , R 16 , and - - - have the meanings defined above;
with a compound of formula (III)
wherein Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl and M is selected from Li, MgBr, MgCI and MgI; and
converting the compound of formula (I), or a solvate thereof to Desogestrel, Etonogestrel, or a solvate thereof.
10. The process according to claim 9 , wherein converting to Etonogestrel, or a solvate thereof, comprises the following steps:
(a) reacting a compound of formula (IIa), or a solvate thereof,
wherein
X forms together with the carbon atom to which it is bonded a ketone protecting group; and
- - - is a single or double bond;
with a compound of formula (III)
wherein
M is selected from Li, MgBr, MgCl and MgI; and
Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl;
to afford a compound of formula (Ia-1) or a solvate thereof
(b) treating a compound of formula (Ia-1), or a solvate thereof, with an acid or a base to afford a compound of formula (Ia-2), or a solvate thereof,
(c) ethynylating a compound of formula (Ia-2), or a solvate thereof, to afford a compound of formula (IVa-1), or a solvate thereof
wherein
X forms together with the carbon atom to which it is bonded a ketone group or a ketone protecting group
R 1 is selected from H and SiR″ 3 , wherein each R″ is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl and halogen; and
(d) if necessary, carrying out one or both of the following steps in any order:
(i) if X forms together with the carbon atom to which it is bonded a ketone protecting group, cleavage of the ketone protecting group to afford a compound of formula (IVa-1), or a solvate thereof, wherein X forms together with the carbon atom to which it is bonded a ketone group,
(ii) if R 1 is a SiR″ 3 group, removal of the SiR″ 3 group to afford a compound of formula (IVa-1), or a solvate thereof, wherein R 1 is H.
11. The process according to claim 9 , wherein converting to Etonogestrel, or a solvate thereof, comprises the following steps:
(a) reacting a compound of formula (IIa), or a solvate thereof,
wherein
X forms together with the carbon atom to which it is bonded a ketone protecting group; and
- - - is a single or double bond;
with a compound of formula (III)
wherein
M is selected from Li, MgBr, MgCl and MgI; and
Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl;
to afford a compound of formula (Ia-1), or a solvate thereof,
(b) ethynylating a compound of formula (Ia-1), or a solvate thereof, to afford a compound of formula (IVa-2), or a solvate thereof
wherein R 1 is selected from H and SiR″ 3 , wherein each R″ is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl and halogen;
(c) treating a compound of formula (IVa-2), or a solvate thereof, with an acid or a base to afford a compound of formula (IVa-1), or a solvate thereof
wherein
X forms together with the carbon atom to which it is bonded a ketone group or a ketone protecting group
R 1 is selected from H and SiR″ 3 , wherein each R″ is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl and halogen; and
(d) if necessary, carrying out one or both of the following steps in any order:
(i) if X forms together with the carbon atom to which it is bonded a ketone protecting group, cleavage of the ketone protecting group to afford a compound of formula (IVa-1), or a solvate thereof, wherein X forms together with the carbon atom to which it is bonded a ketone group,
(ii) if R 1 is a SiR″ 3 group, removal of the SiR″ 3 group to afford a compound of formula (IVa-1), or a solvate thereof, wherein R 1 is H.
12. The process according to claim 9 , wherein converting to Desogestrel, or a solvate thereof, comprises the following steps:
(a) reacting compound (12), or a solvate thereof,
with a compound of formula (III)
wherein
M is selected from Li, MgBr, MgCl and MgI; and
Z is selected from H and SiR′ 3 wherein each R′ is independently selected from C 1 -C 6 alkyl and C 6 -C 10 aryl;
to afford a compound of formula (Ib-1) or a solvate thereof
(b) treating a compound of formula (Ib-1), or a solvate thereof, with an acid or a base to afford a compound of formula (Ib-2), or a solvate thereof,
(c) ethynylating a compound of formula (Ib-2), or a solvate thereof, to afford a compound of formula (IVb-1), or a solvate thereof
wherein R 1 is selected from H and SiR″ 3 , wherein each R″ is independently selected from C 1 -C 6 alkyl, C 6 -C 10 aryl and halogen; and
(d) if R 1 is a SiR″ 3 group, removing SiR″ 3 group to afford Desogestrel, or a solvate thereof.