Process for the preparation of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate
Herein is provided a novel process for the preparation of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate by a Suzuki coupling of compound (3), wherein LG represents a leaving group, with an organoboron reagent: Compound (3) is obtained by activation of compound (4) with a leaving group LG, and compound (4) is obtained by alpha-arylation of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate with 1-LG′-2,4-dichlorobenzene, wherein LG′ represents a leaving group:
1. A process for the preparation of compound (2):
in the base form or in a salt form, the process comprising a Suzuki coupling of compound (3),
wherein LG represents a leaving group chosen from a triflate group and a nonaflate group,
with an organoboron reagent OrganoB-X wherein OrganoB is a boron derivative and X is a (3S)-1-(3-fluoropropyl)-3-phenoxypyrrolidine moiety of the following formula:
2. The process according to claim 1 , wherein the organoboron reagent is chosen from (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy]pyrrolidine, the corresponding acid, and a salt thereof.
3. The process according to claim 2 , wherein the organoboron reagent is chosen from reagents (1), (2), and (3):
4. The process according to claim 1 , wherein the Suzuki coupling is carried out in the presence of a palladium complex.
5. The process according to claim 4 , wherein the palladium complex is bis(triphenylphosphine) palladium (II) dichloride.
6. The process according to claim 1 , wherein the Suzuki coupling is carried out in the presence of bis(triphenylphosphine) palladium (II) dichloride and cesium carbonate.
7. The process according to claim 1 , wherein the leaving group LG in compound (3) is a triflate group.
8. The process according to claim 1 , further comprising a salification reaction performed after the Suzuki coupling.
9. The process according to claim 8 , wherein compound (2) is prepared in the form of an oxalate salt, and wherein the oxalate salt of compound (2) is obtained using oxalic acid.
10. The process according to claim 1 , wherein compound (3) is obtained by reacting compound (4):
with a reagent bearing a leaving group chosen from a triflate group and a nonaflate group.
11. The process according to claim 10 , wherein the leaving group on the reagent bearing a leaving group is a triflate group.
12. The process according to claim 11 , wherein sodium hydride and DBU are used in the reaction of compound (4) with the reagent bearing a leaving group.
13. The process according to claim 11 , wherein the reagent bearing a leaving group is N-phenylbistriflimide.
14. The process according to claim 10 , wherein compound (4) is obtained by alpha-arylation of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate with 1-LG′-2,4-dichlorobenzene, wherein LG′ represents a leaving group.
15. The process according to claim 14 , wherein the leaving group LG′ is a halogen atom chosen from bromine and iodine.
16. The process according to claim 14 , wherein the alpha-arylation is carried out in presence of a palladium derivative, a ligand, and a mineral base.
17. The process according to claim 16 , wherein the palladium derivative is chosen from Pd(OAc) 2 and Pd 2 dba 3 .
18. The process according to claim 16 , wherein the mineral base is chosen from K 2 CO 3 , K 3 PO 4 , Cs 2 CO 3 , and tBuONa.
19. The process according to claim 16 , wherein the alpha-arylation is carried out in the presence of Pd 2 dba 3 and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
20. A process for the preparation of compound (1) or a pharmaceutically acceptable salt thereof:
by saponification of compound (2):
wherein compound (2) is prepared in the base form or in a salt form by a Suzuki coupling of compound (3),
wherein LG represents a leaving group chosen from a triflate group and a nonaflate group,
with an organoboron reagent OrganoB-X wherein OrganoB is a boron derivative and X is a (3S)-1-(3-fluoropropyl)-3-phenoxypyrrolidine moiety of the following formula:
21. The process according to claim 6 , wherein the Suzuki coupling is carried out in an organic solvent.
22. The process according to claim 9 , wherein the oxalate salt of compound (2) is obtained in isopropylacetate.
23. The process according to claim 13 , wherein the reaction of compound (4) with a reagent bearing a leaving group is carried out in Me-THF.
24. The process according to claim 16 , wherein the alpha-arylation is carried out in an organic solvent.
25. The process according to claim 19 , wherein the alpha-arylation is carried out in toluene.
26. The process according to claim 8 , wherein compound (2) is prepared in the form of a dibenzoyl tartrate salt by a salification reaction performed after the Suzuki coupling.
27. The process according to claim 26 , wherein the dibenzoyl tartrate salt of compound (2) is obtained using dibenzoyl tartaric acid.
28. The process according to claim 20 , further comprising a salification reaction performed after the Suzuki coupling.