Process for the preparation of 17-(3-hydroxypropyl)-17-hydroxysteroids
View Patent ↗The present invention relates to a process for the preparation of 17α-(3-hydroxypropyl)-17β-hydroxysteroids of the formula I starting from 17-ketosteroids of the formula III via the intermediates of the formula V wherein the radicals R 3 , R 5 , R 6 , R 7 , R 10 , R 13 , R 15 , R 16 , R 40 , R 41 and R 42 have the meaning indicated in the description.
1. A compound of formula V
wherein
R 3 is hydrogen or
R 30 , R 31 , R 32 are, independently of one another, hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy;
R 5 is hydrogen, or hydroxyl or together with R 6 can be a double bond;
R 6 is hydrogen, or together with R 5 or R 7 is a double bond; or together with R 7 is an α or β-CH 2 group;
R 7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl; or together with R 6 is a double bond or an α or β-CH 2 group;
R 10 is hydrogen, methyl or ethyl;
R 13 is methyl, or ethyl;
R 15 is hydrogen, or C 1 -C 4 -alkyl, or together with R 16 is a —CH 2 group or a double bond;
R 16 is hydrogen or together with R 15 is a —CH 2 group or a double bond, and
R 40 , R 41 , R 42 independently of one another is hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy.
2. A compound according to claim 1 , which is a compound of formula Va
3. A compound according to claim 1 , which is a compound of formula Vb
4. A compound according to claim 1 , which is 6β,7β;15β,16β-dimethylene-17α-(3-benzyloxypropynyl)androstane-3β,5β,17β-triol.
5. 1 A process in which a reaction of a compound of formula V according to claim 1 leads to the preparation of a 17α-(3-hydroxypropyl)-17β-hydroxysteroid of formula I
comprising
a) reacting a 17-ketosteroid of formula III
wherein
R 3 is hydrogen or the group
R 30 , R 31 , R 32 are, independently of one another, hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy;
R 5 is hydrogen, or hydroxyl or together with R 6 is a double bond;
R 6 is hydrogen, or together with R 5 or R 7 is a double bond; or together with R 7 is an α or β-CH 2 group;
R 7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl; or together with R 6 is a double bond or an α or β-CH 2 group;
R 10 is hydrogen, methyl or ethyl;
R 13 is methyl, or ethyl;
R 15 is hydrogen, or C 1 -C 4 -alkyl, or together with R 16 is a —CH 2 group or a double bond; and
R 16 is hydrogen or together with R 15 is a —CH 2 group or a double bond,
in the presence of a base,
with a prop-1-yn-3-ol ether of formula IV
wherein
R 40 , R 41 , R 42 are, independently of one another, hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy,
to give a compound of formula V
b) completely catalytic hydrogenating the alkyne function of the compound of formula V,
and
c) removing the benzylic protective group.
6. A process according to claim 5 , wherein in the compound of formula III
R 5 is hydrogen or hydroxyl;
R 6 is hydrogen or together with R 7 is an α or β-CH 2 group;
R 7 is hydrogen or an α or β-CH 2 group;
R 10 is hydrogen, methyl or ethyl;
R 13 is methyl, or ethyl;
R 15 is hydrogen, or C 1 -C 4 -alkyl, or together with R 16 is a —CH 2 group; and
R 16 is hydrogen or together with R 15 is a —CH 2 group.
7. A process according to claim 5 , wherein the compound of formula I is a compound of formula Ia
wherein the compound of formula III is a compound of formula IIIa
and wherein the compound of formula V is a compound of formula Va
8. A process according to claim 5 , wherein the prop-1-yn-3-ol ether is a compound of formula IVa
9. A process according to claim 5 , wherein the compound of formula I is a compound of formula Ia
wherein the compound of formula III is a compound of formula IIIa
wherein the compound of formula IV is a compound of formula IVa
and wherein the compound of formula V is a compound of formula Vb
10. A process for preparing a compound of formula V
comprising
reacting a 17-ketosteroid of formula III
wherein
R 3 is hydrogen or the group
R 30 , R 31 , R 32 are, independently of one another, hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy;
R 5 is hydrogen, or hydroxyl or together with R 6 is a double bond;
R 6 is hydrogen, or together with R 5 or R 7 is a double bond; or together with R 7 is an α or β-CH 2 group;
R 7 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -thioacyl; or together with R 6 is a double bond or an α or β-CH 2 group;
R 10 is hydrogen, methyl or ethyl;
R 13 is methyl, or ethyl;
R 15 is hydrogen, or C 1 -C 4 -alkyl, or together with R 16 is a —CH 2 group or a double bond; and
R 16 is hydrogen or together with R 15 is a —CH 2 group or a double bond,
in the presence of a base,
with a prop-1-yn-3-ol ether of formula IV
wherein
R 40 , R 41 , R 42 are, independently of one another, hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy.
11. A process according to claim 10 , wherein the prop-1-yn-3-ol ether is a compound of formula IVa