5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal FXR modulators
The invention relates to compounds of formula (I): wherein R 1 , R 2 , Y, R 4 and R 5 are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acids.
1. A compound of formula (I):
wherein:
R 1 is C 1-4 alkyl optionally substituted with one or more substituents selected from halo, OR 6 or NR 6 R 7 ;
where each of R 6 and R 7 is independently selected from H or C 1-4 alkyl;
R 2 is H, halo or OH or a protected OH;
Y 1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R 3 ;
each R 3 is independently halo, OR 8 or NR 8 R 9 ;
where each of R 8 and R 9 is independently selected from H or C 1-4 alkyl;
and
R 4 is C(O)OR 10 , OC(O)R 10 , C(O)NR 10 R 11 , OR 10 , OSi(R 13 ) 3 , S(O)R 10 , SO 2 R 10 , OSO 2 R 10 , SO 3 R 10 , or OSO 3 R 10 ;
where each R 10 and R 11 is independently:
a) hydrogen or
b) C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, —O—C 1-20 alkyl, —O—C 2-20 alkenyl or —O—C 2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 , or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
c) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
d) a polyethylene glycol residue;
each R 19 of R 10 and R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C 1-6 alkyl or C 1-6 haloalkyl;
each R 13 is independently
a) C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 , a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
b) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ;
each R 19 of R 13 is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 5 is H or OH or a protected OH;
or a salt or an isotopic variant thereof.
2. A compound according to claim 1 wherein, independently or in any combination:
Y 1 is an alkylene linker group having from 1 to 8 carbon atoms and optionally substituted with one or more groups R 3 , wherein R 3 is as defined in claim 1 ;
R 5 is H or OH.
3. A compound according to claim 1 wherein, independently or in any combination:
R 1 is ethyl; and/or
R 2 is H; and/or
Y 1 is a bond, —CH 2 — or —CH 2 CH 2 —, and/or
R 4 is C(O)OR 10 , where R 10 is H, C 1-6 alkyl or benzyl; and/or
R 5 is H.
4. A compound according to claim 1 which is (6β,5β,7α)-6-ethyl-7-hydroxy-3-oxo-cholan-24-oic acid or the C 1-6 alkyl and benzyl esters thereof and salts thereof.
5. A process for the preparation of a compound of formula (I)
wherein:
R 1 is C 1-4 alkyl optionally substituted with one or more substituents selected from halo, OR 6 or NR 6 R 7 ;
where each of R 6 and R 7 is independently selected from H or C 1-4 alkyl;
R 2 is H, halo or OH or a protected OH;
Y 1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R 3 ;
each R 3 is independently halo, OR 8 or NR 8 R 9 ;
where each of R 8 and R 9 is independently selected from H or C 1-4 alkyl;
and
R 4 is C(O)OR 10 , OC(O)R 10 , C(O)NR 10 R 11 , OR 10 , OSi(R 13 ) 3 , S(O)R 10 , SO 2 R 10 , OSO 2 R 10 , SO 3 R 10 , or OSO 3 R 10 ;
where each R 10 and R 11 is independently:
a) hydrogen or
b) C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, —O—C 1-20 alkyl, —O—C 2-20 alkenyl or —O—C 2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 , or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
c) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
d) a polyethylene glycol residue;
each R 19 of R 10 and R 11 independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C 1-6 alkyl or C 1-6 haloalkyl;
each R 13 is independently
a) C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 , a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
b) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ;
each R 19 of R 13 is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 5 is H or OH or a protected OH;
said process comprising either:
A) reducing a compound of formula (II):
wherein Y is a bond or an alkylene, alkenylene or alkynylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R 3 ; or
B) converting a compound of general formula (I) to another compound of formula (I).
6. A process according to claim 5 wherein the reduction is carried out by catalytic hydrogenation.
7. A process according to claim 6 wherein the catalytic hydrogenation is carried out using a catalyst selected from a palladium/carbon, palladium/calcium carbonate, palladium/aluminium oxide, platinum/palladium or Raney nickel catalyst.
8. A process according to claim 6 wherein the catalyst is a palladium/carbon or palladium/calcium carbonate catalyst.
9. A process according to claim 8 wherein, in the catalyst the palladium is present in an amount of 5-10% by weight with respect to the weight of the matrix, where the matrix is the carbon or calcium carbonate.
10. A process according to claim 6 wherein the hydrogenation is carried out in a solvent selected from alcoholic solvents; ethyl acetate; pyridine; acetic acid; cyclopentyl methyl ether (CPME) or N,N-dimethylformamide (DMF), any of which may optionally be mixed with a co-solvent and/or a base.
11. A process according to claim 10 wherein the solvent is methanol, ethanol or DMF.
12. A process according to claim 11 wherein the solvent is methanol optionally comprising a substoichiometric amount of a base.
13. A process according to claim 12 , wherein the reaction is conducted at a temperature of about −30 to 25° C.
14. A process according to claim 11 wherein the solvent is DMF optionally mixed with a co-solvent selected from acetone, TBME, THF, acetonitrile or acetone/water and optionally comprising a substoichiometric amount, of a base.
15. A process according to claim 12 wherein the reaction is conducted at a temperature of −30 to 0° C.
16. A process for the preparation of a compound of formula (XIX):
wherein
R 1 is C 1-4 alkyl optionally substituted with one or more substituents selected from halo, OR 6 or NR 6 R 7 ;
where each of R 6 and R 7 is independently selected from H or C 1-4 alkyl;
Y 1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R 3 ;
each R 3 is independently halo, OR 8 or NR 8 R 9 ;
where each of R 8 and R 9 is independently selected from H or C 1-4 alkyl;
and
R 4 is C(O)OR 10 , OC(O)R 10 , C(O)NR 10 R 11 , OR 10 , OSi(R 13 ) 3 , S(O)R 10 , SO 2 R 10 , OSO 2 R 10 , SO 3 R 10 , or OSO 3 R 10 ;
where each R 10 and R 11 is independently:
a) hydrogen or
b) C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, —O—C 1-20 alkyl, —O—C 2-20 alkenyl or —O—C 2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 , or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
c) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
d) a polyethylene glycol residue;
each R 19 of R 10 and R 11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C 1-6 alkyl or C 1-6 haloalkyl;
each R 13 is independently
a) C 1-20 alkyl, C 2-20 alkenyl or C 2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 , a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C 1-6 alkyl, C 1-6 haloalkyl, halo, NO2, CN, OR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ; or
b) a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , SO 2 R 19 , SO 3 R 19 or N(R 19 ) 2 ;
each R 19 of R 13 is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is H, halo or OH;
R 5a is H or OH;
the process comprising:
(i) oxidation of the compound of formula (I)
wherein:
R 2 is H, halo or OH or a protected OH; and
R 5 is H or OH or a protected OH;
using a suitable oxidizing agent to give a compound of formula (XX):
wherein
R 2 is H, halo or OH or a protected OH; and
R 5 is H or OH or a protected OH; and
(ii) epimerisation of the compound of formula (XX) to give a compound of formula (XXI):
wherein
R 2 is H, halo or OH or a protected OH group which is stable under basic conditions; and
R 5b is H or OH or a protected OH group which is stable under basic conditions; and
(iii) reduction of the compound of formula (XXI) using a suitable reducing agent and, where R 2 and/or R 5b is a protected OH, removal of the protecting group(s), to give a compound of formula (XIX), wherein removal of the protecting group can take place before or after the reduction; and optionally
(iv) conversion of a compound of formula (XIX) to another compound of formula (XIX).
17. A process according to claim 16 wherein, in step (i) the oxidation reaction is carried out using a Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol); a hypochlorite under acidic conditions; a Jones reaction using sodium dichromate or chromic trioxide in dilute sulfuric acid; or TEMPO ((2,2,6,6-Tetramethyl-piperidin-1-yl)oxy) or a derivative thereof.
18. A process according to claim 16 wherein, in the epimerization reaction of step (ii), the compound of formula (XX) is dissolved in an alcoholic solvent, optionally mixed with water and contacted with a base selected from sodium or potassium hydroxide or a sodium or potassium alkoxide.
19. A process according to claim 18 wherein,
in the compound of formula (XX), R 4 is C(O)OR 10 , and in step (ii) the base is sodium or potassium hydroxide and the epimerization is accompanied by hydrolysis to give a compound of formula (XXI) in which R 4 is C(O)OH; and/or
in the compound of formula (XX), R 2 and/or R 5 is a group OC(O)OR 14 , where R 14 is C 1-6 alkyl or benzyl; and wherein the epimerisation step yields a compound of formula (XXI) in which R 2 and/or R 5b is OH; or
in the compound of formula (XX), R 2 and/or R 5 is a protected OH which is stable under basic conditions and the process further comprises the step of removing the protecting group before or after step (iii).
20. A process according to claim 16 wherein, in step (iii), the reducing agent is a hydride.
21. A process according to claim 16 for the preparation of a compound of formula (XIX) wherein R 1 is ethyl, R 2 and Rya are both H, Y 1 is —CH 2 CH 2 —, and R 4 is C(O)OH.