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US 10,766,921 B2Granted
Process and intermediates for the 6,7-alpha-epoxidation of steroid 4,6-dienes
AssigneeNZP UK Limited
InventorsAlexander Weymouth-Wilson, Zofia Komsta, Laura Wallis, Timothy Evans
Life of this patent
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Abstract
The invention relates to a process for preparing a compound of general formula (Ia): wherein R2, Y, R4 and R5 are as defined herein, wherein the epoxidation is conducted using an oxidant and methyltrioxorhenium as a catalyst (MeReO3). The invention also relates to certain compounds per se. The compounds are intermediates in the synthesis of synthetic bile acids.
Claims25
A process for preparing a compound of general formula (Ia):
- and salts and isotopic variants thereof
- wherein:
- R2 is selected from the group consisting of H, halo, OH and a protected OH group;
- Y is selected from the group consisting of a bond, and a C1-20 alkylene, C2-20 alkenylene or C2-20 alkynylene linker group any of which is optionally substituted with one or more R3;
- wherein each R3 is independently selected from H, halo, OH, a protected OH group and NR8R9;
- wherein each of R8 and R9 is independently selected from H, C1-6 alkyl, C(O)Ph, benzyl, phthalimide, tert-butyloxycarbonyl and carboxybenzyl;
- R4 is selected from the group consisting of C(O)OR10, OC(O)R10, C(O)NR10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, OSO3R10, halo, CN, C(O)R10, NR10R11, BR10R11, C(O)CH2N2, —CH═CH2, —C≡CH, CH[C(O)OR10]2, CH(BR10R11)2, azide, NO2, NR10C(O)NR10SO2R11, NR10C(O)NR10SO2NR10R11, NR10SO2R11, C(O)NR10SO2R11, CH(XR10)(XR11), CH(R10)(XR11), phthalimide and a carboxylic acid mimetic group;
- wherein each X is independently selected from O, S and NR8;
- wherein each R10 and R11 is independently selected from:
- a. hydrogen;
- and
- b. C1-20 alkyl, C3-7 cycloalkyl, C2-20 alkenyl or C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from:
- C1-4 alkyl, C1-4 haloalkyl, halo, NO2, CN, OR19, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, OSO2R19, SO3R19, OSO3R19, N(R19)2 and 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, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2;
- and
- c. a 6- to 14-membered aryl, 5- to 14-membered heteroaryl group or 3- to 10-membered heterocyclic ring, any of which is optionally substituted with one or more substituents selected from:
- C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, C═O, C(O)C1-4alkyl, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19, N(R19)2, phenyl, 5- to 14-membered heteroaryl, 3- to 10-membered heterocyclic ring, methylenedioxy and ethylenedioxy;
- and
- d. a polyethylene glycol residue;
- or
- e. when R4 is selected from C(O)NR10R11, CH(XR10)(XR11), CH(R10)(XR11), NR10R11, BR10R11, CH[C(O)OR10]2 and CH(BR10R11)2, an R10 and an R11 group, together with the atom or atoms to which they are attached, may combine to form a 3- to 10-membered heterocyclic ring;
- wherein each R19 is independently selected from:
- H, C1-6 alkyl, C1-6 haloalkyl, and 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 halo, C1-6 alkyl and C1-6 haloalkyl;
- and wherein each R13 is independently selected from:
- a. C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from:
- halo, NO2, CN, OR19, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19, OSO3R19, N(R19)2 and 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, SO2R19, SO3R19 and N(R19)2;
- and
- 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, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2;
- wherein each R19 is independently selected from:
- H, C1-6 alkyl and C1-6 haloalkyl;
- or
- Y and R4 together form a=CH2 group;
- and
- R5 is selected from H, OH or a protected OH group;
- comprising:
- oxidation of a compound of general formula (IIa) or a salt or isotopic variant thereof
- using an oxidant and methyltrioxorhenium as catalyst:
- wherein R2, R4, R5 and Y are as defined for compounds of general formula (Ia).
35 more elements
A process for the preparation of a compound of general formula (XVIIIa):
- wherein R1 is selected from the group consisting of C1-4 alkyl, C2-4 alkenyl and C2-4 alkynyl optionally substituted with one or more substituents selected from halo, OR6 and NR6R7;
- wherein each of R6 and R7 is independently selected from H and C1-4 alkyl;
- R2 is selected from the group consisting of H, halo and OH;
- R5a is selected from the group consisting of H and OH;
- and
- Y1 is selected from the group consisting of a bond, and a C1-20 alkylene linker group which is optionally substituted with one or more R3;
- wherein each R3 is independently selected from H, halo, OH, a protected OH group and NR8R9;
- wherein each of R8 and R9 is independently selected from H, C1-6 alkyl, C(O)Ph, benzyl, phthalimide, tert-butyloxycarbonyl and carboxybenzyl;
- R4 is selected from the group consisting of C(O)OR10, OC(O)R10, C(O)NR10R11, OR10, OSi(R13)3, S(O)R10, SO2R10, OSO2R10, SO3R10, OSO3R10, halo, CN, C(O)R10, NR10R11, BR10R11, C(O)CH2N2, —CH═CH2, —C≡CH, CH[C(O)OR10]2, CH(BR10R11)2, azide, NO2, NR10C(O)NR10SO2R11, NR10C(O)NR10SO2N R10R11, NR10SO2R11, C(O)NR10SO2R11, CH(XR10)(XR11), CH(R10)(XR11), phthalimide and a carboxylic acid mimetic group;
- wherein each X is independently selected from 0, S and NR8;
- wherein each R19 and R11 is independently selected from:
- a hydrogen;
- and
- b. C1-20 alkyl, C3-7 cycloalkyl, C2-20 alkenyl or C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from:
- C1-4 alkyl, C1-4 haloalkyl, halo, NO2, CN, OR19, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, OSO2R19, SO3R19, OSO3R19, N(R19)2 and 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, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2;
- and
- c. a 6- to 14-membered aryl, 5- to 14-membered heteroaryl group or 3- to 10-membered heterocyclic ring, any of which is optionally substituted with one or more substituents selected from:
- C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, halo, NO2, CN, OR19, C═O, C(O)C1-4alkyl, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19, N(R19)2, phenyl, 5- to 14-membered heteroaryl, 3- to 10-membered heterocyclic ring, methylenedioxy and ethylenedioxy;
- and
- d. a polyethylene glycol residue;
- or
- e. when R4 is selected from C(O)NR10R11, CH(XR10)(XR11), CH(R10)(XR11), NR10R11, BR10R11, CH[C(O)OR10]2 and CH(BR10R11)2, an R10 and an R11 group, together with the atom or atoms to which they are attached, may combine to form a 3- to 10-membered heterocyclic ring;
- wherein each R19 is independently selected from:
- H, C1-6 alkyl, C1-6 haloalkyl, and 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 halo, C1-6 alkyl and C1-6 haloalkyl;
- and wherein each R13 is independently selected from:
- a C1-20 alkyl, C2-20 alkenyl or C2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from:
- halo, NO2, CN, OR19, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19, OSO3R19, N(R19)2 and 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, SO2R19, SO3R19 and N(R19)2,
- and
- 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, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2,
- wherein each R19 is independently selected from:
- H, C1-6 alkyl and C1-6 haloalkyl;
- or
- Y1 and R4 together form a=CH2 group;
- comprising:
- i. preparing a compound of general formula (Ia):
- wherein:
- R2 is selected from the group consisting of H, halo, OH and a protected OH group;
- Y is selected from the group consisting of a bond, and a C1-20 alkylene, C2-20 alkenylene or C2-20 alkynylene linker group any of which is optionally substituted with one or more R3;
- wherein each R3 is independently as defined for general formula (XVIIIa);
- R4 is as defined for general formula (XVIIIa);
- or
- Y and R4 together form a=CH2 group;
- and
- R5 is selected from H, OH or a protected OH group;
- by oxidation of a compound of general formula (IIa) using an oxidant and methyltrioxorhenium as catalyst:
- wherein Y, R2, R4 and R5 are as defined for compounds of general formula (Ia) and optionally converting the compound of general formula (Ia) to a second compound of general formula (Ia) by modifying the side chain Y1—R4;
- ii. selective alkylation of a compound of general formula (Ia) with an organometallic reagent to give a compound of general formula (XIXa):
- wherein R1 is as defined for compounds of general formula (XVIIIa) and Y, R2, R4 and R5 are as defined for compounds of general formula (Ia);
- and optionally converting the compound of general formula (XIXa) to a second compound of general formula (XIXa) by modifying the side chain Y1—R4;
- iii. reducing a compound of formula (XIXa) using a suitable reducing agent to give a compound of general formula (XXa):
- wherein R1 and Y1 are as defined for compounds of general formula (XVIIIa) and R2, R4 and R5 are as defined for compounds of general formula (Ia) and optionally converting the compound of general formula (XXa) to a second compound of general formula (XXa) by modifying the side chain Y1—R4;
- iv. oxidising a compound of general formula (XXa) using a suitable oxidizing agent to give a compound of general formula (XXIa):
- wherein R1 and Y1 are as defined for compounds of general formula (XVIIIa) and R2, R4 and R5 are as defined for compounds of general formula (Ia) and optionally converting the compound of general formula (XXIa) to a second compound of general formula (XXIa) by modifying the side chain Y1—R4;
- v. epimerisation of a compound of general formula (XXIa) to give a compound of general formula (XXIIa):
- wherein R1 and Y1 are as defined for compounds of general formula (XVIIIa) and R4 is as defined for compounds of general formula (Ia);
- R2 is selected from H, OH and a protected OH group which is stable under basic conditions;
- and
- R5b is selected from H, OH and a protected OH group which is stable under basic conditions and optionally converting the compound of general formula (XXIIa) to a second compound of general formula (XXIIa) by modifying the side chain Y1—R4;
- and
- vi. reduction of the compound of general formula (XXIIa) 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 (XVIIIa), wherein removal of the protecting group can take place before or after the reduction;
- and optionally converting the compound of general formula (XVIIIa) to a second compound of general formula (XVIIIa) by modifying the side chain Y1—R4.
59 more elements
Dependencies are inferred from the claim text.