阅读说明：本技术 用于制备6-(2,4-二氯苯基)-5-[4-[(3s)-1-(3-氟丙基)吡咯烷-3-基]氧基苯基]-8,9-二氢-7h-苯并[7]轮烯-2-甲酸甲酯的方法 (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 ) 是由 A·拉比恩 M·塔巴特 C·韦里 于 2019-09-06 设计创作，主要内容包括：本文提供了一种用于通过以下方式制备6-(2,4-二氯苯基)-5-[4-[(3S)-1-(3-氟丙基)吡咯烷-3-基]氧基苯基]-8,9-二氢-7H-苯并[7]轮烯-2-甲酸甲酯的新颖方法：将化合物(3),其中LG表示离去基团,与有机硼试剂的铃木偶联：(3)。化合物(3)通过用离去基团LG活化化合物(4)而获得,并且化合物(4)通过用1-LG’-2,4-二氯苯对5-氧代-6,7,8,9-四氢-5H-苯并[7]轮烯-2-甲酸甲酯进行α-芳基化而获得,其中LG’表示离去基团：(4)。(Provided herein is a process for the preparation of 6- (2, 4-dichlorophenyl) -5- [4- [ (3S) -1- (3-fluoropropyl) pyrrolidin-3-yl]Oxy-phenyl]-8, 9-dihydro-7H-benzo [7]]Novel process for the preparation of cyclene-2-carboxylic acid methyl ester: coupling a compound (3), wherein LG represents a leaving group, to Suzuki of an organoboron reagent: (3). The compound (3) is obtained by activating the compound (4) with a leaving group LG, and the compound (4) is obtained by p-5-oxo-6, 7,8, 9-tetrahydro-5H-benzo [7] with 1-LG' -2, 4-dichlorobenzene]Rotacene-2-carboxylic acid methyl ester, wherein LG' represents a leaving group: (4).)

1. A process for the preparation of compound (2) in base form or in salt form:

characterized in that compound (2) is obtained by: a compound (3)

Wherein LG represents a leaving 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 formula:

suzuki coupling is carried out, optionally followed by salt formation.

2. The method of claim 1, wherein the organoboron reagent is (3S) -1- (3-fluoropropyl) -3- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy ] pyrrolidine, the corresponding acid, or a salt thereof.

3. The process of claim 2 wherein the organoboron reagent is selected from the group consisting of reagents (1), (2) and (3):

4. the method of any one of claims 1 to 3, wherein the Suzuki coupling is carried out in the presence of a palladium complex.

5. The method of claim 4, wherein the palladium complex is bis (triphenylphosphine) palladium (II) dichloride.

6. The method of any one of claims 1 to 5, wherein the Suzuki coupling is carried out in the presence of bis (triphenylphosphine) palladium (II) dichloride and cesium carbonate in an organic solvent.

7. The process according to any one of claims 1 to 6, wherein the leaving group LG in compound (3) represents a triflate group.

8. The process according to any one of claims 1 to 7, wherein compound (2) is prepared in the form of an oxalate salt by performing a salt formation reaction after the Suzuki coupling.

9. The method according to claim 8, wherein the oxalate salt of compound (2) is obtained in isopropyl acetate using oxalic acid.

10. The process according to any one of claims 1 to 9, wherein compound (3) is obtained by activating compound (4) with a leaving group LG:

11. the process according to claim 10, wherein compound (4) is activated to compound (3') with a triflating reagent:

12. the process according to claim 11, wherein sodium hydride is used as strong base and DBU is used as catalyst.

13. The process according to claim 11 or 12, wherein N-phenyl bis trifluoromethanesulfonimide is used as trifluoromethanesulfonylating reagent in Me-THF as organic solvent.

14. The method according to any one of claims 10 to 13, wherein compound (4) is obtained by α -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 method according to claim 14, wherein the leaving group LG' is a halogen atom selected from bromine or iodine.

16. The process according to claim 14 or 15, wherein the α -arylation is carried out in an organic solvent in the presence of a palladium derivative as catalyst, a ligand and a mineral base.

17. The method of claim 16, wherein the palladium derivative is Pd (OAc)₂Or Pd₂dba₃。

18. The method of claim 16 or 17, wherein the mineral base is K₂CO₃、K₃PO₄、Cs₂CO₃Or tBuONa.

19. The process according to any one of claims 16 to 18, wherein the a-arylation is in toluene over Pd as catalyst₂dba₃And 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene as ligand。

20. A process for preparing compound (1) or a pharmaceutically acceptable salt thereof:

the process is carried out by saponification of compound (2):

characterized in that compound (2) is obtained by the process according to any one of claims 1 to 19.

21. Compounds (4), (3) and (3'), wherein LG represents a leaving group: