# US 10,766,921 B2 · Process and intermediates for the 6,7-alpha-epoxidation of steroid 4,6-dienes

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,766,921 B2
- Document ID: US10766921B2
- Status: Granted
- Kind: B2
- Application number: 16/302,057
- Filed: 2017-05-18
- Published: 2019-10-10
- Granted: 2020-09-08
- Earliest claimed: 2016-05-18
- Assignees: NZP UK Limited
- Applicants: NZP UK Limited
- Inventors: Alexander Weymouth-Wilson; Zofia Komsta; Laura Wallis; Timothy Evans
- Web page: https://patentgrep.com/patent/US10766921B2

## CPC

- C07J 71/001: {Oxiranes}
- C07J 9/005: {containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton}
- C07J 41/0088: {containing unsubstituted amino radicals}
- C07J 41/0094: {containing nitrile radicals, including thiocyanide radicals}
- C07J 43/003: {not condensed}
- C07J 9/00: Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J 13/007: {with double bond in position 17 (20)}
- C07J 17/00: Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton (cardanolide, bufanolide C07J19/00)
- C07J 31/006: {not covered by C07J31/003}
- C07J 41/0055: {the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives}
- C07J 41/0061: {one of the carbon atoms being part of an amide group}
- C07J 51/00: Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
- C07J: STEROIDS (seco-steroids C07C)

## 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.

## Claims

### Claim 1

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).

### Claim 2 (depends on 1)

The process according to claim 1 for preparing a compound of general formula (I):
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 halo, OR8 and NR8R9;
wherein each of R8 and R9 is independently selected from H or C1-4 alkyl;
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, CH(OR10)(OR11), CH(SR10)(SR11), NR10R11, BR10R11, C(O)CH2N2, —CH═CH2, —C≡CH, CH[C(O)OR10]2, CH(BR10R11)2, azide and a carboxylic acid mimetic group;
wherein each R10 and R11 is independently selected from:
a. hydrogen;
and
b. 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, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2;
and
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, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2;
and
d. a polyethylene glycol residue;
or
e. when R4 is selected from C(O)NR10R11, CH(OR10)(OR11), CH(SR10)(SR11), 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, SR′, 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 H, OH or a protected OH group;
comprising:
oxidation of a compound of general formula (II) 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 (I).

### Claim 3 (depends on 1)

The process according to claim 1, wherein the methyltrioxorhenium is present in the reaction at 0.1-10 mol %.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the oxidant is selected from the group consisting of hydrogen peroxide, urea-hydrogen peroxide, and sodium percarbonate.

### Claim 5 (depends on 1)

The process according to claim 1, wherein up to 3 equivalents of oxidant are used per mole of compound of general formula (II).

### Claim 6 (depends on 1)

The process according to claim 1, wherein the reaction is carried out in the presence of a ligand.

### Claim 7 (depends on 6)

The process according to claim 6, wherein the ligand is a Lewis base.

### Claim 8 (depends on 6)

The process according to claim 6, wherein the ligand is a moiety which is bound to the rhenium via 1 to 3 atoms of at least one element selected from oxygen and nitrogen, such that the 5- to 7-valency of rhenium is fulfilled.

### Claim 9 (depends on 6)

The process according to claim 6, wherein the ligand is selected from the group consisting of 3-cyanopyridine, 4-cyanopyridine, 2-hydroxypyridine, 3-methyl pyridine, and 3-methyl pyrazole.

### Claim 10 (depends on 1)

The process according to claim 1, wherein the reaction solvent is selected from the group consisting of CH2Cl2, CHCl3, toluene, CH3CN, EtOAc, IPA, MIBK, nBuOAc, fluorinated solvents, and mixtures thereof.

### Claim 11 (depends on 10)

The process according to claim 10, wherein the reaction solvent comprises fluorinated solvent.

### Claim 12 (depends on 10)

The process according to claim 10, wherein the fluorinated solvent is selected from the group consisting of HFIP (hexafluoroisoproanol), TFE (2,2,2-trifluoroethanol), hexafluorobutanol, trifluorotoluene, and hexafluorobenzene.

### Claim 13 (depends on 10)

The process according to claim 10, wherein the reaction solvent is a mixture of a fluorinated solvent and a non-fluorinated solvent.

### Claim 14 (depends on 1)

The process according to claim 1, wherein the reaction is carried out in the temperature range of about −10° C. to about 50° C.

### Claim 15 (depends on 1)

The process according to claim 1, wherein R2 is H.

### Claim 16 (depends on 1, 2)

The process according to claim 1, wherein Y is selected from a bond or a C1-3 alkylene or C2-3 alkenylene linker group, either of which is optionally substituted with one or two R3 groups, wherein R3 is as defined in claim 1 or claim 2.

### Claim 17 (depends on 16)

The process according to claim 16, wherein Y is selected from —CH2CH2— and —CH═CH—.

### Claim 18 (depends on 1)

The process according to claim 1, wherein R3 is selected from the group consisting of H, halo, OH, OC(O)R14, OSi(R16)3, and NR8R9; wherein RH is selected from C1-6 alkyl and phenyl; each R16 is independently selected from C1-6 alkyl and phenyl; and each R8 and R9 is independently selected from H, methyl, ethyl and tert-butoxycarbonyl.

### Claim 19 (depends on 1)

The process according to claim 1, wherein R4 is selected from the group consisting of C(O)OR10, OC(O)R10, OR10, C(O)NR10R11, OSi(R13)3, OSO2R10, SO3R10, OSO3R10, halo, CN, C(O)R10, NR10R11, CH(XR10)(XR11), CH═CH2, CH[C(O)OR10]2, azide, C(O)NR10SO2R11, phthalimide, tetrazole, substituted tetrazole and BR10R11 or wherein Y and R4 together form a ═CH2 group.

### Claim 20 (depends on 1)

The process according to claim 1, wherein each R10 and R11 is independently selected from:
a. hydrogen; and
b. C1-10 alkyl, C2-10 alkenyl or C2-10 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 10-membered aryl, 5- to 10-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)C1-4 alkyl, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and 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 C(O)NR10R11, CH(XR10)(XR11), CH(R10)(XR11), NR10R11 or BR10R11, 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 heterocylic ring.

### Claim 21 (depends on 1)

The process according to claim 1, wherein R10 is selected from hydrogen; and C1-6 alkyl or C2-6 alkenyl, either of which is optionally substituted with 6- to 14-membered aryl.

### Claim 22 (depends on 1)

The process according to claim 1, wherein R5 is H.

### Claim 23 (depends on 1)

The process according to claim 1, wherein:
the compound of general formula (I) is compound (IA): (6α, 7α, 22E)-6,7-epoxy-3-oxo-4,22-choladien-24-oic acid ethyl ester and the compound of general formula (II) is compound (IIA): (22E)-3-oxo-4,6,22-cholatrien-24-oic acid ethyl ester; or the compound of general formula (I) is compound (IB): (6α, 7α)-6,7-epoxy-3-oxo-4-cholen-24-oic acid ethyl ester and the compound of general formula (II) is compound (IIB): 3-oxo-4,6-choladien-24-oic acid ethyl ester.

### Claim 24

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.

### Claim 25 (depends on 24)

The process according to claim 24 for the preparation of a compound of general formula (XVIII):
wherein R1 is C1-4 alkyl 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 halo, OR8 and NR8R9; wherein each of R8 and R9 is independently selected from H or C1-4 alkyl;
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, CH(OR10)(OR11), CH(SR10)(SR11), NR1OR11, BR10R11, C(O)CH2N2, —CH═CH2, —C≡CH, CH[C(O)OR10]2, CH(BR10R11)2, azide and a carboxylic acid mimetic group;
wherein each R10 and R11 is independently selected from:
a. hydrogen;
and
b. 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, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2;
and
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, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2;
and
d. a polyethylene glycol residue;
or
e. when R4 is selected from C(O)NR10R11, CH(OR10)(OR11), CH(SR10)(SR11), 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 (I):
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 halo, OR8 and NR8R9;
wherein each of R8 and R9 is independently selected from H or C1-4 alkyl;
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, CH(OR10 (OR11), CH(SR10)(SR11), NR10R11, BR10R11, C(O)CH2N2, —CH═CH2, —C≡CH, CH[C(O)OR10]2, CH(BR10R11)2, azide and a carboxylic acid mimetic group;
wherein each R10 and R11 is independently selected from:
a. hydrogen;
and
b. 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, SR19, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2; and
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, C(O)OR19, C(O)N(R19)2, SO2R19, SO3R19 and N(R19)2,
and
d. a polyethylene glycol residue;
or
e. when R4 is selected from C(O)NR10R11, CH(OR10)(OR11), CH(SR10)(SR11), 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 H, OH or a protected OH group;
by oxidation of a compound of general formula (II) using an oxidant and methyltrioxorhenium as catalyst:
wherein Y, R2, R4 and IV are as defined for compounds of general formula (I) and optionally converting the compound of general formula (II) to a second compound of general formula (II) by modifying the side chain Y1—R4;
ii. selective alkylation of a compound of general formula (I) with an organometallic reagent to give a compound of general formula (XIX):
wherein R1 is as defined for compounds of general formula (XVIII) and Y, R2, R4 and R5 are as defined for compounds of general formula (I) and optionally converting the compound of general formula (XIX) to a second compound of general formula (XIX) by modifying the side chain Y1—R4;
iii. reducing a compound of formula (XIX) using a suitable reducing agent to give a compound of general formula (XX):
wherein R1 and Y1 are as defined for compounds of general formula (XVIII) and R2, R4 and IV are as defined for compounds of general formula (I) and optionally converting the compound of general formula (XX) to a second compound of general formula (XX) by modifying the side chain Y1—R4;
iv. oxidising a compound of general formula (XX) using a suitable oxidizing agent to give a compound of general formula (XXI):
wherein R1 and Y1 are as defined for compounds of general formula (XVIII) and R2, R4 and R5 are as defined for compounds of general formula (I) and optionally converting the compound of general formula (XXI) to a second compound of general formula (XXI) by modifying the side chain Y1—R4;
v. epimerisation of a compound of general formula (XXI) to give a compound of general formula (XXII):
wherein R1 and Y1 are as defined for compounds of general formula (XVIII) and R4 is as defined for compounds of general formula (I);
R2 is H 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 optionally converting the compound of general formula (XXII) to a second compound of general formula (XXII) by modifying the side chain Y1—R4; and
vi. reduction of a compound of general formula (XXII) 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 (XVIII), wherein removal of the protecting group can take place before or after the reduction; and optionally converting the compound of general formula (XVIII) to a second compound of general formula (XVIII) by modifying the side chain Y1—R4.