Process for alkynylating 16-substituted-17-keto steroids
View Patent ↗A process ethynylates 16-methylene-17-keto steroids to the corresponding 16-methylene-17α-ethynyl-17β-hydroxy steroids by treatment with silyl-protected lithium acetylides followed by further desilylation. The resulting products are useful intermediates in the preparation of several pharmaceutically active agents, such as e.g. Nestorone® or melengestrol acetate.
1. Process for the preparation of a compound of formula (IV)
wherein
R 3 is selected from O and —OR 1 , wherein R 1 is substituted or unsubstituted C 1 -C 6 alkyl; with the proviso that when R 3 is O then there are double bonds between C 3 and R 3 and between C 4 and C 5 and single bonds between C 3 and C 4 and between C 5 and C 6 , and when R 3 is —OR 1 then there are single bonds between C 3 and R 3 and between C 4 and C 5 and double bonds between C 3 and C 4 and between C 5 and C 6 ;
R 6 is selected from H, substituted or unsubstituted C 1 -C 6 alkyl, halogen and methylene; with the proviso that when R 6 is methylene then there is a double bond between C 6 and R 6 and a single bond between C 5 and C 6 ;
R 9 is selected from H and halogen, or is absent when there is a double bond between C 9 and C 11 ;
R 11 is selected from H, OH and halogen, or is absent when there is a double bond between C 9 and C 11 ;
R 18 is selected from methyl and ethyl;
R 19 is selected from H and methyl;
is a single or double bond,
which comprises:
(a) reacting a compound of formula (II)
with a compound of formula (I)
wherein each R is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted aryl and halogen,
to afford a compound of formula (III)
and
(b) desilylating the compound of formula (III) to afford a compound of formula (IV).
2. Process according to claim 1 , wherein the compound of formula (IV) is a compound of formula (IVa) or (IVa')
wherein R 1 ,R 6 ,R 9 ,R 18 and R 19 are as defined in claim 1 .
3. Process according to claim 1 , wherein
R 3 is selected from O or —OR 1 , wherein R 1 is a C 1 -C 3 alkyl;
R 6 is selected from H, F, methyl and methylene;
R 9 is selected from H and F;
R 11 is selected from H and OH, or there is a double bond between C 9 and C 11 and R 9 and R 11 are absent;
R 18 is selected from methyl and ethyl;
R 19 is selected from H and methyl.
4. Process according to claim 1 , wherein the compound of formula (IV) is selected from
wherein R 1 is C 1 -C 3 alkyl.
5. Process according to claim 1 , wherein each R is independently selected from C 1 -C 3 alkyl and phenyl.
6. Process according to claim 1 , wherein the compound of formula (I) is lithium trimethylsilylacetylene.
7. Process according to claim 1 , wherein desilylation step (b) is performed by treatment with potassium carbonate.
8. Process according to claim 1 , wherein the ethynylated product is further converted to a compound selected from the group formed by Nestorone®, nestorone alcohol and melengestrol acetate.
9. Process for the preparation of Nestorone alcohol according to claim 8 , which comprises the following steps:
(a) treating a compound of formula (IIa-1)
with a compound of formula (I)
to afford a compound of formula (IIIa-1)
(b) desilylating the compound of formula (IIIa-1) to afford a compound of formula (IVa-1)
(c) hydrolyzing the enol ether and hydrating the ethynyl group in the compound of formula (IVa-1) to afford a compound of formula 6
(d) reacting the compound 6 with a phenylsulfenylating agent to afford a compound of formula 7
(e) reacting compound 7 with a thiophilic reagent to afford the compound of formula 8 (Nestorone® alcohol)
10. Process according to claim 9 , which further comprises acetylating the compound of formula 8 to afford Nestorone® (9)
11. Process according to claim 1 , comprising one of the following conditions (a) to (d):
(a) wherein each R is independently selected from C 1 -C 3 alkyl and phenyl;
(b) wherein the compound of formula (I) is lithium trimethylsilylacetylene;
(c) wherein desilylation step (b) is performed by treatment with potassium carbonate;
(d) wherein the ethynylated product is further converted to a compound selected from the group formed by Nestorone®, nestorone alcohol and melengestrol acetate.
12. Process according to claim 2 , comprising one of the following conditions (a) to (f):
(a) wherein R 3 is selected from O or —OR 1 , wherein R 1 is a C 1 -C 3 alkyl;
R 6 is selected from H, F, methyl and methylene;
R 9 is selected from H and F;
R 11 is selected from H and OH, or there is a double bond between C 9 and C 11 and R 9 and R 11 are absent;
R 18 is selected from methyl and ethyl; and
R 19 is selected from H and methyl;
(b) wherein the compound of formula (IV) is selected from
wherein R 1 is C 1 -C 3 alkyl;
(c) wherein each R is independently selected from C 1 -C 3 alkyl and phenyl;
(d) wherein the compound of formula (I) is lithium trimethylsilylacetylene;
(e) wherein desilylation step (b) is performed by treatment with potassium carbonate;
(f) wherein the ethynylated product is further converted to a compound selected from the group formed by Nestorone®, nestorone alcohol and melengestrol acetate.