| Sonstiges: |
- Nachgewiesen in: USPTO Patent Grants
- Sprachen: English
- Patent Number: 10766,921
- Publication Date: September 08, 2020
- Appl. No: 16/302057
- Application Filed: May 18, 2017
- Assignees: NZP UK Limited (Bristol, GB)
- Claim: 1. A process for preparing a compound of general formula (Ia): [chemical expression included] and salts and isotopic variants thereof wherein: R 2 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 C 1-20 alkylene, C 2-20 alkenylene or C 2-20 alkynylene linker group any of which is optionally substituted with one or more R 3 ; wherein each R 3 is independently selected from H, halo, OH, a protected OH group and NR 8 R 9 ; wherein each of R 8 and R 9 is independently selected from H, C 1-6 alkyl, C(O)Ph, benzyl, phthalimide, tert-butyloxycarbonyl and carboxybenzyl; R 4 is selected from the group consisting of 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 , OSO 3 R 10 , halo, CN, C(O)R 10 , NR 10 R 11 , BR 10 R 11 , C(O)CH 2 N 2 , —CH═CH 2 , —C≡CH, CH[C(O)OR 10 ] 2 , CH(BR 10 R 11) 2 , azide, NO 2 , NR 10 C(O)NR 10 SO 2 R 11 , NR 10 C(O)NR 10 SO 2 NR 10 R 11 , NR 10 SO 2 R 11 , C(O)NR 10 SO 2 R 11 , CH(XR 10)(XR 11), CH(R 10)(XR 11), phthalimide and a carboxylic acid mimetic group; wherein each X is independently selected from O, S and NR 8 ; wherein each R 10 and R 11 is independently selected from: a. hydrogen; and b. C 1-20 alkyl, C 3-7 cycloalkyl, C 2-20 alkenyl or C 2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from: C 1-4 alkyl, C 1-4 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , OSO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , C═O, C(O)C 1-4 alkyl, SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , N(R 19) 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 R 4 is selected from C(O)NR 10 R 11 , CH(XR 10)(XR 11), CH(R 10)(XR 11), NR 10 R 11 , BR 10 R 11 , CH[C(O)OR 10 ] 2 and CH(BR 10 R 11) 2 , an R 10 and an R 11 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 R 19 is independently selected from: H, C 1-6 alkyl, C 1-6 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, C 1-6 alkyl and C 1-6 haloalkyl; and wherein each R 13 is independently selected from: a. C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 ; wherein each R 19 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; or Y and R 4 together form a=CH 2 group; and R 5 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: [chemical expression included] wherein R 2 , R 4 , R 5 and Y are as defined for compounds of general formula (Ia).
- Claim: 2. The process according to claim 1 for preparing a compound of general formula (I): [chemical expression included] and salts and isotopic variants thereof wherein: R 2 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 C 1-20 alkylene, C 2-20 alkenylene or C 2-20 alkynylene linker group any of which is optionally substituted with one or more R 3 ; wherein each R 3 is independently selected from halo, OR 8 and NR 8 R 9 ; wherein each of R 8 and R 9 is independently selected from H or C 1-4 alkyl; R 4 is selected from the group consisting of 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 , OSO 3 R 10 , halo, CN, C(O)R 10 , CH(OR 10)(OR 11), CH(SR 10)(SR 11), NR 10 R 11 , BR 10 R 11 , C(O)CH 2 N 2 , —CH═CH 2 , —C≡CH, CH[C(O)OR 10 ] 2 , CH(BR 10 R 11) 2 , azide and a carboxylic acid mimetic group; wherein each R 10 and R 11 is independently selected from: a. hydrogen; and b. C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 ; and d. a polyethylene glycol residue; or e. when R 4 is selected from C(O)NR 10 R 11 , CH(OR 10)(OR 11), CH(SR 10)(SR 11), NR 10 R 11 , BR 10 R 11 , CH[C(O)OR 10 ] 2 and CH(BR 10 R 11) 2 , an R 10 and an R 11 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 R 19 is independently selected from: H, C 1-6 alkyl, C 1-6 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, C 1-6 alkyl and C 1-6 haloalkyl; and wherein each R 13 is independently selected from: a. C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR′, C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 ; wherein each R 19 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; or Y and R 4 together form a=CH 2 group; and R 5 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: [chemical expression included] wherein R 2 , R 4 , R 5 and Y are as defined for compounds of general formula (I).
- Claim: 3. The process according to claim 1 , wherein the methyltrioxorhenium is present in the reaction at 0.1-10 mol %.
- Claim: 4. 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. 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. The process according to claim 1 , wherein the reaction is carried out in the presence of a ligand.
- Claim: 7. The process according to claim 6 , wherein the ligand is a Lewis base.
- Claim: 8. 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. 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. The process according to claim 1 , wherein the reaction solvent is selected from the group consisting of CH 2 Cl 2 , CHCl 3 , toluene, CH 3 CN, EtOAc, IPA, MIBK, nBuOAc, fluorinated solvents, and mixtures thereof.
- Claim: 11. The process according to claim 10 , wherein the reaction solvent comprises fluorinated solvent.
- Claim: 12. 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. The process according to claim 10 , wherein the reaction solvent is a mixture of a fluorinated solvent and a non-fluorinated solvent.
- Claim: 14. 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. The process according to claim 1 , wherein R 2 is H.
- Claim: 16. The process according to claim 1 , wherein Y is selected from a bond or a C 1-3 alkylene or C 2-3 alkenylene linker group, either of which is optionally substituted with one or two R 3 groups, wherein R 3 is as defined in claim 1 or claim 2 .
- Claim: 17. The process according to claim 16 , wherein Y is selected from —CH 2 CH 2 — and —CH═CH—.
- Claim: 18. The process according to claim 1 , wherein R 3 is selected from the group consisting of H, halo, OH, OC(O)R 14 , OSi(R 16) 3 , and NR 8 R 9 ; wherein R H is selected from C 1-6 alkyl and phenyl; each R 16 is independently selected from C 1-6 alkyl and phenyl; and each R 8 and R 9 is independently selected from H, methyl, ethyl and tert-butoxycarbonyl.
- Claim: 19. The process according to claim 1 , wherein R 4 is selected from the group consisting of C(O)OR 10 , OC(O)R 10 , OR 10 , C(O)NR 10 R 11 , OSi(R 13) 3 , OSO 2 R 10 , SO 3 R 10 , OSO 3 R 10 , halo, CN, C(O)R 10 , NR 10 R 11 , CH(XR 10)(XR 11), CH═CH 2 , CH[C(O)OR 10 ] 2 , azide, C(O)NR 10 SO 2 R 11 , phthalimide, tetrazole, substituted tetrazole and BR 10 R 11 or wherein Y and R 4 together form a ═CH 2 group.
- Claim: 20. The process according to claim 1 , wherein each R 10 and R 11 is independently selected from: a. hydrogen; and b. C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl, any of which is optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , OSO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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 C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , C═O, C(O)C 1-4 alkyl, SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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 R 4 is C(O)NR 10 R 11 , CH(XR 10)(XR 11), CH(R 10)(XR 11), NR 10 R 11 or BR 10 R 11 , an R 10 and an R 11 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. The process according to claim 1 , wherein R 10 is selected from hydrogen; and C 1-6 alkyl or C 2-6 alkenyl, either of which is optionally substituted with 6- to 14-membered aryl.
- Claim: 22. The process according to claim 1 , wherein R 5 is H.
- Claim: 23. 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): [chemical expression included] wherein R 1 is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl optionally substituted with one or more substituents selected from halo, OR 6 and NR 6 R 7 ; wherein each of R 6 and R 7 is independently selected from H and C 1-4 alkyl; R 2 is selected from the group consisting of H, halo and OH; R 5a is selected from the group consisting of H and OH; and Y 1 is selected from the group consisting of a bond, and a C 1-20 alkylene linker group which is optionally substituted with one or more R 3 ; wherein each R 3 is independently selected from H, halo, OH, a protected OH group and NR 8 R 9 ; wherein each of R 8 and R 9 is independently selected from H, C 1-6 alkyl, C(O)Ph, benzyl, phthalimide, tert-butyloxycarbonyl and carboxybenzyl; R 4 is selected from the group consisting of 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 , OSO 3 R 10 , halo, CN, C(O)R 10 , NR 10 R 11 , BR 10 R 11 , C(O)CH 2 N 2 , —CH═CH 2 , —C≡CH, CH[C(O)OR 10 ] 2 , CH(BR 10 R 11) 2 , azide, NO 2 , NR 10 C(O)NR 10 SO 2 R 11 , NR 10 C(O)NR 10 SO 2 N R 10 R 11 , NR 10 SO 2 R 11 , C(O)NR 10 SO 2 R 11 , CH(XR 10)(XR 11), CH(R 10)(XR 11), phthalimide and a carboxylic acid mimetic group; wherein each X is independently selected from 0, S and NR 8 ; wherein each R 19 and R 11 is independently selected from: a hydrogen; and b. C 1-20 alkyl, C 3-7 cycloalkyl, C 2-20 alkenyl or C 2-20 alkynyl, any of which is optionally substituted with one or more substituents selected from: C 1-4 alkyl, C 1-4 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , OSO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , C═O, C(O)C 1-4 alkyl, SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , N(R 19) 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 R 4 is selected from C(O)NR 10 R 11 , CH(XR 10)(XR 11), CH(R 10)(XR 11), NR 10 R 11 , BR 10 R 11 , CH[C(O)OR 10 ] 2 and CH(BR 10 R 11) 2 , an R 10 and an R 11 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 R 19 is independently selected from: H, C 1-6 alkyl, C 1-6 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, C 1-6 alkyl and C 1-6 haloalkyl; and wherein each R 13 is independently selected from: a C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 , wherein each R 19 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; or Y 1 and R 4 together form a=CH 2 group; comprising: i. preparing a compound of general formula (Ia): [chemical expression included] wherein: R 2 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 C 1-20 alkylene, C 2-20 alkenylene or C 2-20 alkynylene linker group any of which is optionally substituted with one or more R 3 ; wherein each R 3 is independently as defined for general formula (XVIIIa); R 4 is as defined for general formula (XVIIIa); or Y and R 4 together form a=CH 2 group; and R 5 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: [chemical expression included] 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 Y 1 —R 4 ; ii. selective alkylation of a compound of general formula (Ia) with an organometallic reagent to give a compound of general formula (XIXa): [chemical expression included] wherein R 1 is as defined for compounds of general formula (XVIIIa) and Y, R 2 , R 4 and R 5 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 Y 1 —R 4 ; iii. reducing a compound of formula (XIXa) using a suitable reducing agent to give a compound of general formula (XXa): [chemical expression included] wherein R 1 and Y 1 are as defined for compounds of general formula (XVIIIa) and R 2 , R 4 and R 5 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 Y 1 —R 4 ; iv. oxidising a compound of general formula (XXa) using a suitable oxidizing agent to give a compound of general formula (XXIa): [chemical expression included] wherein R 1 and Y 1 are as defined for compounds of general formula (XVIIIa) and R 2 , R 4 and R 5 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 Y 1 —R 4 ; v. epimerisation of a compound of general formula (XXIa) to give a compound of general formula (XXIIa): [chemical expression included] wherein R 1 and Y 1 are as defined for compounds of general formula (XVIIIa) and R 4 is as defined for compounds of general formula (Ia); R 2 is selected from H, OH and a protected OH group which is stable under basic conditions; and R 5b 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 Y 1 —R 4 ; and vi. reduction of the compound of general formula (XXIIa) 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 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 Y 1 —R 4 .
- Claim: 25. The process according to claim 24 for the preparation of a compound of general formula (XVIII): [chemical expression included] wherein R 1 is C 1-4 alkyl optionally substituted with one or more substituents selected from halo, OR 6 and NR 6 R 7 ; wherein each of R 6 and R 7 is independently selected from H and C 1-4 alkyl; R 2 is selected from the group consisting of H, halo and OH; R 5a is selected from the group consisting of H and OH; and Y 1 is selected from the group consisting of a bond, and a C 1-20 alkylene linker group which is optionally substituted with one or more R 3 ; wherein each R 3 is independently selected from halo, OR 8 and NR 8 R 9 ; wherein each of R 8 and R 9 is independently selected from H or C 1-4 alkyl; R 4 is selected from the group consisting of 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 , OSO 3 R 10 , halo, CN, C(O)R 10 , CH(OR 10)(OR 11), CH(SR 10)(SR 11), NR 1 OR 11 , BR 10 R 11 , C(O)CH 2 N 2 , —CH═CH 2 , —C≡CH, CH[C(O)OR 10 ] 2 , CH(BR 10 R 11) 2 , azide and a carboxylic acid mimetic group; wherein each R 10 and R 11 is independently selected from: a. hydrogen; and b. C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 ; and d. a polyethylene glycol residue; or e. when R 4 is selected from C(O)NR 10 R 11 , CH(OR 10)(OR 11), CH(SR 10)(SR 11), NR 10 R 11 , BR 10 R 11 , CH[C(O)OR 10 ] 2 and CH(BR 10 R 11) 2 , an R 10 and an R 11 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 R 19 is independently selected from: H, C 1-6 alkyl, C 1-6 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, C 1-6 alkyl and C 1-6 haloalkyl; and wherein each R 13 is independently selected from: a. C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 ; wherein each R 19 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; or Y 1 and R 4 together form a=CH 2 group; comprising: i. preparing a compound of general formula (I): [chemical expression included] wherein: R 2 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 C 1-20 alkylene, C 2-20 alkenylene or C 2 -20 alkynylene linker group any of which is optionally substituted with one or more R 3 ; wherein each R 3 is independently selected from halo, OR 8 and NR 8 R 9 ; wherein each of R 8 and R 9 is independently selected from H or C 1-4 alkyl; R 4 is selected from the group consisting of 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 , OSO 3 R 10 , halo, CN, C(O)R 10 , CH(OR 10 (OR 11), CH(SR 10)(SR 11), NR 10 R 11 , BR 10 R 11 , C(O)CH 2 N 2 , —CH═CH 2 , —C≡CH, CH[C(O)OR 10 ] 2 , CH(BR 10 R 11) 2 , azide and a carboxylic acid mimetic group; wherein each R 10 and R 11 is independently selected from: a. hydrogen; and b. C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 , and d. a polyethylene glycol residue; or e. when R 4 is selected from C(O)NR 10 R 11 , CH(OR 10)(OR 11), CH(SR 10)(SR 11), NR 10 R 11 , BR 10 R 11 , CH[C(O)OR 10 ] 2 and CH(BR 10 R 11) 2 , an R 10 and an R 11 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 R 19 is independently selected from: H, C 1-6 alkyl, C 1-6 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, C 1-6 alkyl and C 1-6 haloalkyl; and wherein each R 13 is independently selected from: a. C 1-20 alkyl, C 2-20 alkenyl or 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 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 , OSO 3 R 19 , N(R 19) 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 C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SO 2 R 19 , SO 3 R 19 and N(R 19) 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: C 1-6 alkyl, C 1-6 haloalkyl, halo, NO 2 , CN, OR 19 , SR 19 , C(O)OR 19 , C(O)N(R 19) 2 , SO 2 R 19 , SO 3 R 19 and N(R 19) 2 ; wherein each R 19 is independently selected from: H, C 1-6 alkyl and C 1-6 haloalkyl; or Y and R 4 together form a=CH 2 group; and R 5 is H, OH or a protected OH group; by oxidation of a compound of general formula (II) using an oxidant and methyltrioxorhenium as catalyst: [chemical expression included] wherein Y, R 2 , R 4 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 Y 1 —R 4 ; ii. selective alkylation of a compound of general formula (I) with an organometallic reagent to give a compound of general formula (XIX): [chemical expression included] wherein R 1 is as defined for compounds of general formula (XVIII) and Y, R 2 , R 4 and R 5 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 Y 1 —R 4 ; iii. reducing a compound of formula (XIX) using a suitable reducing agent to give a compound of general formula (XX): [chemical expression included] wherein R 1 and Y 1 are as defined for compounds of general formula (XVIII) and R 2 , R 4 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 Y 1 —R 4 ; iv. oxidising a compound of general formula (XX) using a suitable oxidizing agent to give a compound of general formula (XXI): [chemical expression included] wherein R 1 and Y 1 are as defined for compounds of general formula (XVIII) and R 2 , R 4 and R 5 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 Y 1 —R 4 ; v. epimerisation of a compound of general formula (XXI) to give a compound of general formula (XXII): [chemical expression included] wherein R 1 and Y 1 are as defined for compounds of general formula (XVIII) and R 4 is as defined for compounds of general formula (I); R 2 is H 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 optionally converting the compound of general formula (XXII) to a second compound of general formula (XXII) by modifying the side chain Y 1 —R 4 ; and vi. reduction of a compound of general formula (XXII) 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 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 Y 1 —R 4 .
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- Primary Examiner: Solola, Taofiq A
- Attorney, Agent or Firm: Morgan, Lewis & Bockius LLP
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