US 2017/0320907 A1Published application

5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal fxr modulators

AssigneeNZP UK Limited

InventorsAlexander WEYMOUTH-WILSON, Zofia KOMSTA, James BOYDELL, Laura WALLIS, Nathan BARTLETT, Montserrat SHELBOURNE

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Abstract

The invention relates to compounds of formula (I): wherein R1, R2, Y, R4 and R5 are as defined herein. The compounds are intermediates in the synthesis of synthetic bile acids.

Claims21

Dependent claims

A compound of general formula (I):

wherein:
R1 is C1-4 alkyl optionally substituted with one or more substituents selected from halo, OR6 or NR6R7;
where each of R6 and R7 is independently selected from H or C1-4 alkyl;
R2 is H, halo or OH or a protected OH;
Y1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R3;
each R3 is independently halo, OR8 or NR8R9;
where each of R8 and R9 is independently selected from H or C1-4 alkyl;
and
R4 is C(O)OR10, OC(O)R10, C(O)NR10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, or OSO3R10;
where each R10 and R11 is independently:
a. hydrogen or
b. C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, —O—C1-20 alkyl, —O—C2-20 alkenyl or —O—C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)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 C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
or
d. a polyethylene glycol residue;
each R19 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C1-6 alkyl or C1-6 haloalkyl;
each R13 is independently
a. C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SO2R19, SO3R19 or N(R19)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 C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
each R19 is independently selected from H, C1-6 alkyl or C1-6 haloalkyl;
R5 is H or OH or a protected OH;
or a salt or an isotopic variant thereof.

21 more elements

A process for the preparation of a compound of general formula (I)

wherein:
R1 is C1-4 alkyl optionally substituted with one or more substituents selected from halo, OR6 or NR6R7;
where each of R6 and R7 is independently selected from H or C1-4 alkyl;
R2 is H, halo or OH or a protected OH;
Y1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R3;
each R3 is independently halo, OR8 or NR8R9;
where each of R8 and R9 is independently selected from H or C1-4 alkyl;
and
R4 is C(O)OR10, OC(O)R10, C(O)NR10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, or OSO3R10;
where each R10 and R11 is independently:
a) hydrogen or
b) C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, —O—C1-20 alkyl, —O—C2-20 alkenyl or —O—C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)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 C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
or
d) a polyethylene glycol residue;
each R19 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C1-6 alkyl or C1-6 haloalkyl;
each R13 is independently
a) C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SO2R19, SO3R19 or N(R19)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 C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
each R19 is independently selected from H, C1-6 alkyl or C1-6 haloalkyl;
R5 is H or OH or a protected OH;
said process comprising either:
A) reducing a compound of general 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 R3;
or
B) converting a compound of general formula (I) to another compound of general formula (I).

25 more elements

A process for the preparation of a compound of general formula (XIX):

wherein
R1 is C1-4 alkyl optionally substituted with one or more substituents selected from halo, OR6 or NR6R7;
where each of R6 and R7 is independently selected from H or C1-4 alkyl;
Y1 is a bond or an alkylene linker group having from 1 to 20 carbon atoms and optionally substituted with one or more groups R3;
each R3 is independently halo, OR8 or NR8R9;
where each of R8 and R9 is independently selected from H or C1-4 alkyl;
and
R4 is C(O)OR10, OC(O)R10, C(O)NR10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, or OSO3R10;
where each R10 and R11 is independently:
a) hydrogen or
b) C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, —O—C1-20 alkyl, —O—C2-20 alkenyl or —O—C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)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 C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
or
d) a polyethylene glycol residue;
each R19 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, or a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group either of which is optionally substituted with halo, C1-6 alkyl or C1-6 haloalkyl;
each R13 is independently
a) C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl optionally substituted with one or more substituents selected from halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2, a 6- to 14-membered aryl or 5 to 14-membered heteroaryl group, either of which is optionally substituted with C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SO2R19, SO3R19 or N(R19)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 C1-6 alkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, SR19, SO2R19, SO3R19 or N(R19)2;
each R19 is independently selected from H, C1-6 alkyl or C1-6 haloalkyl;
R2 is H, halo or OH;
R5a is H or OH;
the process comprising:
(i) oxidation of the compound of general formula (I)
wherein:
R2 is H, halo or OH or a protected OH;
and
R5 is H or OH or a protected OH;
using a suitable oxidizing agent to give a compound of general formula (XX):
wherein
R2 is H, halo or OH or a protected OH;
and
R5 is H or OH or a protected OH;
and
(ii) epimerisation of the compound of general formula (XX) to give a compound of general formula (XXI):
wherein
R2 is H, halo or OH or a protected OH group which is stable under basic conditions;
and
R5b is H or OH or a protected OH group which is stable under basic conditions;
and
(iii) reduction of the compound of general formula (XXI) using a suitable reducing agent and, where R2 and/or R5b is a protected OH, removal of the protecting group(s), to give a compound of general formula (XIX), wherein removal of the protecting group can take place before or after the reduction;
and optionally
(iv) conversion of a compound of general formula (XIX) to another compound of general formula (XIX).

41 more elements

Dependencies are inferred from the claim text.

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