Processes of preparing 3-fluoro-5-(((1s,2ar)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile

Abstract

Disclosed herein are processes for preparing 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile or a pharmaceutically acceptable salt thereof.

Description

(7) by treating compound (6): (6) with a brominating agent in the presence of a deprotonating agent in a suitable organic solvent. In an eleventh aspect, the processes of the ninth and tenth aspects, further comprise preparing compound (6): (6) by treating compound (5): (5) 10 with 4,4,5,5-tetramethyl-2-(prop-2-en-l-yl)-l,3,2-dioxaborolane in the presence of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide and a base in a suitable organic solvent. In a twelfth aspect, the process of eleventh aspect, further comprises preparing compound (5): 15 O (5) by treating compound (4): F (4) with an organolithium reagent in a suitable organic solvent. In a thirteenth aspect, the process of twelfth aspect, further comprises preparing compound (4): F 5                                                      (4) by treating compound (3): F (3) with a fluorinating agent in a suitable organic solvent. 10           In a fourteenth aspect, the process of thirteenth aspect, further comprises preparing compound (3): F (3) by treating compound (2): 15                                                      F (2) 2021364337  26 Aug 2025 with an oxidizing agent in a suitable organic solvent. In a fifteenth aspect, the process of fourteenth aspect, further comprises preparing compound (2): E F ^O^X^OH 0 F (2) by treating compound (1): (1) with ethyl 2-bromo-2,2-difluoroacetate in the presence of zinc metal, trimethylsilyl chloride, and 1,2-dibromoethane in a suitable organic solvent. Detailed Description Definitions: Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning: As used herein, the term “reacting” or “treating” when describing a certain process is used as known in the art and generally refers to the bringing together of chemical reagents in such a manner so as to allow their interaction at the molecular level to achieve a chemical or physical transformation. The reacting steps of the processes described herein can be conducted for a time and under conditions suitable for preparing the identified product. “Suitable organic solvent” refers to an organic solvent which, under the reaction conditions of the processes disclosed herein, does not enter into any appreciable reaction with either the reactants, intermediates and / or the products at the temperatures at which the reactions are carried out. A given reaction disclosed herein can be carried out in one organic solvent or a mixture of two or more organic solvents. Examples of suitable organic solvents that can be used in the reactions described herein include: halogenated solvents such as carbon tetrachloride, chloroform, dichloromethane, and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, methyl t-butyl ether, and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, n-butyl alcohol, tert-butyl alcohol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, and the like; hydrocarbons (including, for example, alkane solvent) such as benzene, toluene, xylene, cyclohexane, pentane, hexane, heptane, and the like. Additional organic solvents that can be used in the reactions described herein include polar organic solvents including, but not limited to, acetonitrile, dimethylformamide, ethyl acetate, alcohols, and the like. When polar organic solvents (e.g., alcohols, acetonitrile, DMF) contain water they are referred to herein as aqueous organic solvent. Depending on the reaction step, solvents that are suitable for the particular reaction step can be readily selected by a person skilled in the art. For example, in the preparation of compound (2), besides, THF, the reaction was also carried out in MTBE, 2-methylTHF, or toluene solvent. In the preparation of compound (3), the reaction was also carried out in THFsolvent. In the preparation of compound (4), the reaction was also carried out in CHCh solvent. In the preparation of compound (5), the reaction was also carried out in 2-methyl THF, n-heptane, or MTBE solvent. In the preparation of compound (8), the reaction was also carried out in DMF, 1,4-dioxane, THF, 2-methyl THF, toluene, oracetonitrile solvent. In the preparation of compound (9), the reaction was also carried out in a mixture of DCM / ACN / water. In the preparation of compound (10), the reaction was also carried out in DMF, ACN, 2-methyl THF, or toluene solvent. In the preparation of compound (11), the reaction was also carried out in THF, CH3OH, TFA / THF, or HOAc / THF solvent. In the preparation of compound (I), the reaction was also carried out in DCM, CH3CN, 2-methyl THF, ethyl acetate, DMF, MTBE or toluene solvent. In addition, the reactions were carried out at various temperatures. Reaction temperatures that were used in the preparation of compound (2) included 20 °C, 40 °C, 60 °C, and refluxing. Reaction temperatures that were used in the preparation of compound (3) included 0 - 15 °C and 15-25 °C. Reaction temperatures that were used in the preparation of compound (4) included 0 - 10 °C, 10 - 20 °C, 20 - 30 °C, and 30 - 40 °C. Reaction temperatures that were used in the preparation of compound (5) included -30 to -40 °C, -40 to -50 °C, -50 to -60 °C, and -60 to -70 °C. Reaction temperatures that were used in the preparation of compound (6) included 35 °C, 45 °C, and 60 °C. Reaction temperatures that were used in the preparation of compound (7) 2021364337  26 Aug 2025 included -100 to -80 oC, -80 to -60 oC, and -60 to -40 oC. Reaction temperatures that were used in the preparation of compound (8) included 60 oC, 70 oC and refluxing. Reaction temperatures that were used in the preparation of compound (10) included 20 to 30 oC, and 40 oC. Reaction temperatures that were used in the preparation of compound (11) included 10 to 20 oC and -5 to 5 oC. And Reaction temperatures that were used in the preparation of compound (I) included 20 to 30 oC and -5 to 5 oC. Additionally, bases that were used in the preparation of compound (8) included NaOAc, KOAc, and K2CO3; brominating reagents that were used in the preparation of compound (7) included CBr4 and CF2BrCF2Br; catalysts that were used in the preparation of compound (8) included Pd(dppf)Cl2, Pd2(dba)3 / XPhos, Pd(OAc)2 / PPh3, and Pd(PPh3)Ch; fluorinating reagents that were used in the preparation of compound (4) included DAST, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, and HF / SF4; fluorinating reagents that were used in the preparation of compound (I) included DAST, PyFluor, AlkylFluor and SulfoxFluor; oxidizing agents that were used in the oxidation of compound (2) to (3) included 2-iodoxybenzoic acid (IBX), RuCh / NaBrO3; TEMPO / NaClO, MnO2, and TPAP / NMO; oxidizing agents that were used in the oxidation of compound (8) to (9) included RuCl3 / NaIO4, RuCl3 / Oxone® and O3; and reducing agents that were used in the reduction of compound (10) to (11) included LiBH4 and NaBH4. The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan. The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry, or mass spectrometry; or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. The compounds obtained by the reactions can be purified by any suitable method known in the art. For example, chromatography (medium pressure) on a suitable adsorbent (e.g., silica gel, alumina and the like), HPLC, or preparative thin layer chromatography; distillation; sublimation, trituration, or recrystallization. The purity of the compounds, in general, are determined by physical methods such as measuring the melting point (in case of a solid), obtaining an NMR spectrum, or performing a HPLC separation. “Cyclic ether” refers to tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane. “Alcohol” refers to an aliphatic hydrocarbon compound that carries a hydroxy group. Representative examples include, but are not limited to, methanol, ethanol, propanol, butanol, and the like. “About” as used herein means + 10%, preferably + 5% of listed value. For example, a reaction carried out at about 10 °C includes 9 °C, 11 °C, and all temperatures contained in between 9 °C and 11 °C. Embodiments: 1. In embodiment 1, provided is a process of preparing compound (11) (11) comprising reducing the keto moiety of compound (10): O (10) with: (a) sodium borohydride in an organic solvent selected from a group consisting of (i) an alcohol containing acetic acid or trifluoroacetic acid, (ii) a cyclic ether, and (iii) a mixture of a cyclic ether and an alcohol; wherein the cyclic ether of (ii) and the mixture of a cyclic ether and an alcohol of (iii) optionally contain acetic acid or trifluoroacetic acid; or (b) lithium borohydride in a suitable organic solvent optionally containing acetic acid or trifluoroacetic acid. 2. In embodiment 2, provided is a process of preparing Compound (I) as described in the first and second embodiments of the second aspect of the Summary. 2a. In embodiment 2a, provided is a process of preparing Compound (I) as described in the first embodiment of the second aspect of the Summary. 2b. In embodiment 2b, provided is a process of preparing Compound (I) as described in the second embodiment of the second aspect of the Summary. 3. In embodiment 3, the process of embodiment 2, 2a or 2b is wherein the deoxyfluorinating agent is diethylaminosulfur trifluoride, Phenofluor™, N-tosyl-4-chlorobenzene-sulfonimidoyl fluoride, pyridine-2-sulfonyl fluoride, or AlkylFluor. 4. In embodiment 4, the process of embodiment 2, 2a (in step (ii)), 2b, or 3 is wherein the organic solvent is halogenated hydrocarbon, cyclic ethers, ethers, aromatic hydrocarbon, or a polar solvent. Preferably, the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethylacetate, dimethylformamide, methyl tert-butyl ether, or toluene. 5. In embodiment 5, the process of embodiment 2, 2a, or 2b is wherein the deoxyfluorinating agent is pyridine-2-sulfonyl fluoride and the base is 1,8-diazabicyclo-[5.4.0]undec-7-ene or 7-methyl-l,5,7-triaza-bicyclo[4.4.0]dec-l-ene. 6. In embodiment 6, the process of embodiment 1, 2a, 2b or 2b is wherein the reduction of the keto group of compound (10) is carried out with sodium borohydride in tetrahydrofuran, 2-methyltetrahydrofuran, a mixture of tetrahydrofuran or 2-methyltetrahydrofuran and methanol, tetrahydrofuran containing acetic acid or trifluoroacetic acid, 2-methyltetrahydrofuran containing acetic acid or trifluoroacetic acid, or methanol containing acetic acid or trifluoroacetic acid. 7. In embodiment 7, the process of embodiment 6 is wherein the organic solvent is a mixture of tetrahydrofuran and methanol and the reaction is carried out at about -5 °C to about 30°C. 8. In embodiment 8, the process of embodiment 6 is wherein the organic solvent is a mixture of tetrahydrofuran and methanol and the reaction is carried out at about -5 °C to about 5 °C. 9. In embodiment 9, the process of embodiment 5 is wherein the molar ratio of 1,8-diazabicyclo[5.4.0]-undec-7-ene to compound (11) is at least about 2 to about 1 and the organic solvent is tetrahydrofuran. 10. In embodiment 10, the process of embodiment 5 or 9 is wherein the reaction is carried out at 20 °C to about 30 °C. 11. In embodiment 11, provided is process of preparing compound (10): (10) comprising reacting compound (9): O (9) with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent other than dimethylformamide. 12. In embodiment 12, the process of any one of embodiments 1 to 10 further comprises preparing compound (10): (10) by reacting compound (9): (9) with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent. 13. In embodiment 13, the process of embodiment 11 or 12 is wherein the base is an inorganic base. 14. In embodiment 14, the process of embodiment 13 is wherein the inorganic base is cesium carbonate or potassium carbonate. 15. In embodiment 15, the process of any one of embodiments 11 to 14 is wherein the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, acetonitrile, or toluene. 16. In embodiment 16, the process of embodiment 15 is wherein the organic solvent is tetrahydrofuran. 17. In embodiment 17, the process of any one of embodiments 11 to 16 is wherein the reaction is carried out at about 20 °C to about 40 °C. 18. In embodiment 17, the process of any one of embodiments 11 to 17 further comprises crystallizing compound (10) from a mixture of an ether and an alkane solvent. 19. In embodiment 19, the process of embodiment 18 is wherein compound (10) is crystallized from a mixture of methyl tert-butyl ether and n-heptane. 20. In embodiment 20, provided is a process for preparing compound (9): (9) comprising carrying out oxidative cleavage of the vinylidene moiety of compound (8): (8) with (i) sodium periodate in the presence of ruthenium chloride in aqueous acetonitrile, (ii) Oxone® in the presence of ruthenium chloride in a suitable organic or aqueous organic solvent, or (iii) Ozone in a suitable organic or aqueous organic solvent. 21. In embodiment 21, the process of any one of embodiments 11 to 19 further comprises preparing compound (9): (9) 2021364337  26 Aug 2025 by carrying out oxidative cleavage of the vinylidene moiety of compound (8): (8) with a suitable oxidizing agent in a suitable organic or aqueous organic solvent. 22. In embodiment 22, the process of embodiment 21 is wherein the oxidative cleavage of the vinylidene is carried out with (i) sodium periodate or Oxone® in the presence of ruthenium chloride or (ii) Ozone. 23. In embodiment 23, the process of embodiment 21, is wherein the solvent is a mixture of dichloromethane, acetonitrile and water or the solvent is aqueous acetonitrile. 24. In embodiment 24, the process of any one of embodiments 20 to 23 is wherein the oxidative cleavage of the vinylidene is carried out with sodium periodate in the presence of catalytic amount of ruthenium chloride in aqueous acetonitrile. 24a. In embodiment 24a, the process of any one of embodiments 20 to 24 further comprises purification of compound (9) from a mixture of an ether and an alkane solvent. 24b. In embodiment 24b, the process of embodiment 24a is wherein purification of compound (9) is from a mixture of methyl tert-butyl ether and n-heptane. 25. In embodiment 25, provided is a process for preparing compound (8): (8) comprising performing intramolecular cyclization between the alkene and bromo groups in compound (7): (7) by treating compound (7) with a palladium catalyst in the presence of a base in a suitable organic solvent other than dimethylformamide. 26. In embodiment 26, the process of any one of embodiments 20 to 24 further comprises preparing compound (8): (8) by performing intramolecular cyclization between the alkene and bromo groups in compound (7): FVF F I / OH Br \ (7) with a palladium catalyst in the presence of a base in a suitable organic solvent. 27. In embodiment 27, the process of embodiment 25 or 26 is wherein the palladium catalyst is Pd(PPhs)4, Pd(dppf)C12, Pd(PPh3)2C12, Pd(PPh3)2(OAc)2, Pd2(dba)3 / XPhos, or Pd(l,2-bis(diphenylphosphino)ethane)(OAc)2, and the organic solvent is acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, 1,4-di oxane, or dimethylformamide. 28. In embodiment 28, the process of embodiment 27 is wherein the base is sodium acetate, potassium acetate, sodium carbonate, potassium carbonate or cesium carbonate. 29. In embodiment 29, the process of any one of embodiments 25, 26, or 28 is wherein the palladium catalyst is Pd(PPh3)2C12, the base is potassium acetate, and the solvent is acetonitrile. 30. In embodiment 30, the process of embodimen 29 is wherein the reaction is carried out between about 60 °C to about 80 °C. 31. In embodiment 31, provided is a process for preparing compound (7): (7) comprising brominating compound (6): (6) with 1,2-dibromo-l. 1.2.2-tetrafluoroethane in the presence of a deprotonating agent in a suitable organic solvent. 32. In embodiment 32, the process of any one of embodiments 25 to 30 further comprises preparing compound (7): (7) by treating compound (6): (6) with a brominating agent in the presence of a deprotonating agent in a suitable organic solvent. 33. In embodiment 33, the process of embodiment 32 is wherein the brominating agent is carbon tetrabromide or l,2-dibromo-l,l,2,2-tetrafluoroethane. 33a. In embodiment 33a, the process of embodiment 32 is wherein the brominating agent is bromotrichloromethane, l,2-dibromo-l,l,2,2-tetrachioroethane, 1,2-dibromo-l, 1,2,2-tetrafluoroethane, carbon tetrabromide, iV-bromosuccinimide, A-bromophthalimide, / V-bromosaccharin,#-bromoacetamide, l,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, monosodium bromoisocyanurate, bromodimethylsulfonium bromide, 5,5-dibromomeldrum's acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate; and bromine and its equivalents, such as bromine -1,4-dioxane complex, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, and I-butyl-3-methylimidazolium tribromide. 2021364337  26 Aug 2025 34. In embodiment 34, the process of embodiment 31 or 32 is wherein the brominating agent is 1,2-dibromo-1,1,2,2-tetrafluoroethane, the deprotonating agent is lithium diisopropylamide and the solvent is tetrahydrofuran. 35. In embodiment 35, the process of embodiment 34 is wherein the reaction is carried out at about -100 °C to about -20 °C. 36. In embodiment 36, the process of any one of embodiments 31 to 35 further comprises preparing compound (6): (6) by treating compound (5): (5) with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane in the presence of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide and a base in a suitable organic solvent. 37. In embodiment 37, the process of embodiment 36 is wherein the base is sodium tert-butoxide and the organic solvent is a mixture of methanol and toluene. 38. In embodiment 38, the process of embodiment 36 or 37 further comprises preparing compound (5): (5) by treating compound (4): 2021364337  26 Aug 2025 (4) with an organolithium reagent in a suitable organic solvent. 39. In embodiment 39, the process of embodiment 38 is wherein the organolithium reagent is n-butyllithium and the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane and methyl tert-butylether. 40. In embodiment 40, the process of embodiment 38 or 39 is wherein the solvent is tetrahydrofuran. 41. In embodiment 41, the process of any one of embodiments 38 to 40 further comprises preparing compound (4): xOVf YpF o F (4) by treating compound (3): F F ^O.X.0 O M F (3) with a fluorinating agent in a suitable organic solvent. 42. In embodiment 42, the process of embodiment 41 is wherein the fluorinating agent is diethylaminosulfur trifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, or sulfur tetrafluoride and hydrofluoric acid. 43. In embodiment 43, the process of embodiment 42 is wherein the fluorinating agent is sulfur tetrafluoride and hydrofluoric acid and the solvent is dichloromethane. 44. In embodiment 44, the process of any one of embodiments 41 to 43 further comprises preparing compound (3): 2021364337  26 Aug 2025 (3) by treating compound (2): F (2) with an oxidizing agent in a suitable organic solvent. 45. In embodiment 45, the process of embodiment 44 is wherein the oxidizing agent is dimethyl sulfoxide / oxalyl chloride, 2-iodoxybenzoic acid, RuCh NaBrO;, MnO2, NaBrOs / NaHSOs, or TPAP / NMO. 46. In embodiment 46, the process of embodiment 45 is wherein the oxidizing agent is TPAP / NMO and reaction is carried in dichloromethane, acetonitrile or tetrahydrofuran, preferably dichloromethane. 47. In embodiment 47, the process of any one of embodiments 44 to 46 further comprises preparing compound (2): F (2) by treating compound (1): F (1) with ethyl 2-bromo-2,2-difluoroacetate in the presence of zinc metal, trimethylsilyl chloride, and 1,2-dibromoethane in a suitable organic solvent. 48. In embodiment 48, the process of embodiment 47 is wherein the organic solvent is tetrahydrofuran or 2-methyl tetrahydrofuran. 2021364337  26 Aug 2025 EXAMPLES Abbreviations: ACN: acetonitrile AcOH or HOAc: acetic acid AlkylFluor: CAS Registry No. 2043361-32-4 Cs2CO3: cesium carbonate DAST: diethylaminosulfur trifluoride DCM: dichloromethane HF: hydrofluoric acid HCl: hydrochloric acid KOAc: potassium acetate LDA: Lithium diisopropylamide MTBE: methyl tert-butyl ether NMO: N-Methylmorpholine N-oxide MeOH: methanol NaBH4: sodium borohydride NaIO4: sodium periodiate n-BuLi: n-butyllithium Pd(PPh3)2(OAc)2: bis(acetato)bis(triphenylphosphine)palladium(II) Pd(PPh3)2Cl2: bis(triphenylphosphine)palladium(II) dichloride Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) PyFluor: 2-pyridinesulfonyl Fluoride RuCl3^3H2O: ruthenium (III) chloride hydrate SF4: sulfur tetrafluoride SulfoxFluor: [methyl(oxo){1-[6-(trifluoromethyl)-3-pyridyl]ethyl}-X6-sulfanylidene]cyanamide TEMPO:  (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1- yl)oxidanyl TFA: trifluoroacetic acid THF: tetrahydronfuran TPAP: tetrapropylammonium perruthenate t-BuONa: sodium tert-butoxide XPhos: 2-dicyclohexylphosphino-2‘,4‘,6‘-triisopropylbiphenyl Example 1 Synthesis of 2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-one Step 1: ethyl 3-(2-bromo-4-fluorophenyl) -2,2-difluoro-3-hydroxypropanoate To a mixture of zinc (211.36 g, 3.23 mol, 1.31 eq.) in THF (1.50 L) was added 1,2-dibromoethane (13.88 g, 73.89 mmol, 0.030 eq.) and TMSC1 (53.52 g, 492.59 mmol, 0.20 eq.) in one portion. The mixture was stirred at 25 °C for 0.5 h, then a solution of 2-bromo-4-fluoro-benzaldehyde (500 g, 2.46 mol, 1.00 eq.) and ethyl 2-bromo-2,2-difluoro-acetate (549.93 g, 2.71 mol, 1.10 eq.) in THF (1.50 L) was added to the mixture dropwise over 1 h under refluxing, and the reaction mixture was stirred continually under refluxing for 1 h. The reaction mixture was cooled, then filtered, and the cake was washed with ethyl acetate. The filtrate was quenched with 1.0 M aqueous HC1 (800 mL), then adjusted to pH = 5 - 6 and the mixture was extracted with ethyl acetate. The combined organic phase was washed with 10% brine, dried with Na2SO4, concentrated in vacuum to give the title compound (857.0 g,, 88.8% assay purity, 94.5% assay yield) as a yellow oil, which was used for next step without further purification. Step 2: ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate F                                         F A mixture of NMO (297.86 g, 2.54 mol, 1.40 eq.), TPAP (15.96 g, 45.41 mmol, 0.025 eq.) and 4A MS (94.0 g) in DCM (1000 mL) was degassed and purged with N2 and a solution of ethyl 3-(2-bromo-4-fluorophenyl)- 2,2-difluoro-3-hydroxypropanoate (669.00 g, 1.82 mol, 88.8% assay, 1.00 eq.) in DCM (1000 mL) was added dropwise at 0-5 °C over 1.5 h. The resulting mixture was further stirred at 25 °C for 2 h under N2 atmosphere, then was filtered through silica gel pad and the pad cake was washed with MTBE. The combined filtrate was washed with 1.0 M aqueous HC1. The combined aqueous phase was extracted with MTBE. The combined MTBE organic phase was washed with H2O, filtered through a silica gel pad and the pad cake was washed with MTBE. The combined filtrate was concentrated to give the title compound (561.0 g, 95.1% yield) as a yellow oil, which was used for next step without further purification. Alternative Method: To a stirred mixture of ethyl 3-(2-bromo-4-fluorophenyl)- 2,2-difluoro-3-hydroxy-propanoate (285.9 g, after assay adjustment, 0.874 mol, 1.00 eq.) in acetonitrile (900 mL) and water (900 mL) were added NaH2PO4 (63.0 g, 0.525 mol, 0.60 eq.) and RuCh (1.81 g, 8.726 mmol, 0.010 eq.) sequentially at 20-30 °C. NaBrOs (158.27 g, 1.049 mol, 1.20 eq.) was then added in portions at 20-30°C. After further stirring at 20-30°C for 2 h, the reaction mixture was diluted with EtOAc, followed by washing with water, aqueous Na2SO3, water and then brine. The organic layer was concentrated to obtain the title compound (272.8 g, 95.2% purity, 91.4% yield) as a yellow oil, which was used for next step without further purification. Step 3: ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate F                                            F To an autoclave was charged ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate (550.00 g, 1.69 mol, 1.00 eq.) and DCM (55.5 mL). The mixture was cooled to -78 °C and HF (33.85 g, 1.69 mol, 1.00 eq.) was charged, followed by SF4 (202.00 g, 1.87 mol, 1.11 eq.). The reaction mixture was warmed to room temperature and stirred at this temperature for 16 h. The reaction mixture was quenched by added slowly into saturated aqueous Na2CCL (2.5 L) and then extracted with petroleum ether. The combined organic layer was washed with 10% brine, dried over Na2SO4, filtered and concentrated. The residue was further purified by vacuum distillation to afford the title compound (474.0 g, 81.1% yield) as yellow oil. Step 4: 2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-one A stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate (100.0. g, 288.11 mol, 1.00 eq.) inTHF (1.0 L) was cooled to -65 °C, andn-BuLi (2.5 M, 138.0 mL, 345.0 mol, 1.20 eq.) was added dropwise at -60 to -70 °C over 1 h under nitrogen atmosphere. The resulting mixture was stirred further at -65 °C for 1 h, then was quenched with saturated aqueous NH4CI at -30 to -40 °C, followed by dilution with ethyl acetate and H2O. After phase separation, the aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with 10% brine, dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by vacuum distillation, and the distillate was triturated with petroleum ether at low temperature to give the title compound (41.0 g, 64.1% yield) as a white solid. Example 2 Synthesis of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-l-one Step 1: (R)-l-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-ol To a dry 3-neck flask were added 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (94.57 g, 562.78 mmol, 1.21 eq.), (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethyl-butanamide (36.51 g, 119.14 mmol, 0.26 eq.), t-BuONa (4.33 g, 45.06 mmol, 0.097 eq.), toluene (900 mL) and MeOH (28.8 g, 898.88 mmol, 1.94 eq.). The mixture was stirred at 20 °C under nitrogen atmosphere until a clear solution formed. The reaction mixture was heated to 60 °C, and a solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-one (103.09 g, 464.14 mmol, 1.00 eq.) in toluene (100 mL) was added slowly over 2 h at 60 °C. The resulting mixture was stirred continually for 16 h at 60 °C, then cooled to room temperature, quenched with water, and extracted with MTBE. The organic layer was cooled to 0 °C andwashed with 1.0 M aqueous HC1, 0.5 M aqueous NaOH, water and 10% brine. The organic layer was concentrated to give the title compound (146.71g, 73.5% assay purity, 87.9% assay yield, 90.7% e.e.). Step 2: (R)-l-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-ol To a dry 3-neck flask were added THF (500 mL) and LDA (356.82g, 25%, 832.76 mmol, 2.21 eq.) and then the solution was cooled to -50 °C under nitrogen atmosphere. A solution of (R)-l-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-ol (100.00 g, 378.50 mmol, 1.00 eq.) in THF (200 mL) was added slowly at -50 °C. The resulting mixture was stirred at -50 °C for Ih, then cooled to -80 °C to form solution A. To another dry 3-neck flask were added dibromotetrafluoroethane (196.66 g, 756.91 mmol, 2.00 eq.) and THF (100 mL), and the solution was cooled to -80 °C. Solution A was slowly added with stirring and while maintaining the reaction temperature at about -80 °C. The mixture was stirred at -80 °C for additional 30 min and then slowly quenched by slowly adding a solution of AcOH (75.00 g, 1248.96 mmol, 3.30 eq.) in THF (75 mL) at temperature below -60 °C. The mixture was warmed slowly to room temperature anddiluted with water. The mixture was extracted with MTBE, and the combined organic layer was washed with water and 10% brine. The organic layer was concentrated to give the title compound as a solution in THF (204.40g, 50.4% assay purity, 79.3% assay yield). Step 3: (R)-3,3,4,4,7-pentafluoro-l-methylene-l,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol Into a solution of (R)-l-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-lH-inden-l-ol (100.00 g, 291.47 mmol, 1.00 eq.) in acetonitrile (1.50 L) were added KOAc (86.50g, 881.39 mmol, 3.03 eq.) and Pd(PPh3)2C12 (10.30 g, 14.67 mmol, 0.050 eq.) under N2 atmosphere. The mixture was stirred for 4 h at 80 °C and then concentrated under vacuum to about 1 / 3 volume. The residue was diluted with MTBE and washed with water. The organic layer was diluted with n-heptane and passed through a silica gel pad (200 g). The pad was rinsed with MTBE / n-heptane=l / 3 to wash out the product. The eluent was concentrated and exchange the solvent into acetonitrile to give the title compound as a solution in acetonitrile (120.15g, 51.7% assay purity, 81.3% assay yield, 90.6% e.e.). Step 4: (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-l -one To a stirred mixture of (R)-3,3,4,4,7-pentafluoro-l-methylene-l,2,3,4-tetrahydro-2aH-cyclopenta[cd]inden-2a-ol (80.00 g, 305.13 mmol, 1.00 eq.) in ACN (1200 mL) and H2O (3200 mL) was added RuCk^ELO (4.00 g, 15.30 mmol, 0.050 eq.), followed by NaIO4 (456.87 g, 2.14 mol, 7.01 eq.) in portions while maintaining the reaction temperature at 10 to20 °C. After stirring further at 10 to 20 °C for 1 h, MTBE (800 mL) was added to the mixture and the mixture was filtered through a Celite layer. The Celite solid cake was washed with MTBE. The organic layer was separated from the combined filtrate, and the aqueous layer was extracted with MTBE. The combined organic layer was washed with 5% aqueous Na2SO3 and 10% aqueous Na2SO4. The organic layer was concentrated, and the residue was dissolved in MTBE and n-heptane. The solution was filtered through a silica gel pad (200 g) and the pad solid cake was rinsed with MTBE / n-heptane=l / 3. The combined eluent was concentrated to about 3V to precipitate out the product which was filtered and dried to give the title compound as a white solid (70.62 g, 88.4% assay purity, 77.5% assay yield, ~ 91.7% e.e.). Example 3 Synthesis of 3-fluoro-5-(((lR,2aR)-3,3,4,4-tetrafluoro-l,2a-dihydroxy- 2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-7-yl)oxy)benzonitrile N HO Step 1: (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-l-oxo-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-7-yl)oxy)benzonitrile To a stirred mixture of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden -1-one (100.00 g, after assay adjustment, 378.57 mmol, 1.00 eq.) in THF (500 mL) were added 3-fluoro-5-hydroxybenzonitrile (57.10 g, 416.45 mmol, 1.10 eq.) and CS2CO3 (74.01 g, 227.15 mmol, 0.60 eq.) at room temperature. The resulting mixture was stirred at 40 °C for 20 h. The mixture was cooled to room temperature and MTBE was added, followed by water. After layer separation, the aqueous layer was extracted with MTBE and the combined organic layer was washed with 5% aqueous Na2COs and then 10% brine. The organic layer was concentrated and the residue was recrystallized from MTBE / n-heptane = 3 / 20 to give the title compound as a yellow solid (145.78 g, 84.4% assay purity, 85.2% assay yield, 98.4% e.e.). Step 2: 3-fluoro-5-(((lR,2aR)-3,3,4,4-tetrafluoro-l,2a-dihydroxy- 2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-7-yl)oxy)benzonitrile N                                         N To a stirred solution of (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-l-oxo-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-7-yl)oxy)benzonitrile (50.00 g, after assay adjustment, 131.14 mmol, 1.00 eq.) in MeOH (53.0 mL, 1.31 mol, 10.00 eq.) and THF (500 mL) was added NaBH4 (1.84 g, 48.64 mmol, 0.37 eq.) in portions at -5 to 0 °C. The reaction mixture was stirred at -5 to 0 °C for an additional hour, then quenched with 2.0 M aqueous HC1 (about 30.0 g) below 5 °C to pH = 5 - 7 and diluted with water. The mixture was extracted with MTBE, and the combined organic layer was washed with water and 10% brine. The organic layer is concentrated and the solvent was exchanged to THF to obtain a THF solution of the title compound (286.66 g, 16.6% assay purity, 94.7% assay yield, 97.7% e.e.). 'HNMR (400MHz, CDCh) 8 = 7.55 (d, 1H), 7.18 - 7.16 (m, 2H), 7.13 (d, 1H), 7.08 (d, 1H), 5.89 - 5.84 (m, 1H), 3.06 (s, 1H), 2.83 -2.78 (m, 1H), 2.47 - 2.42 (m, 1H), 2.35 (d, 1H). Example 4 Synthesis of 3-fluoro-5-(((lS,2aR)-l,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-lH- cyclopenta[cd]inden-7-yl)oxy)benzonitrile To a stirred solution of 3-fluoro-5-(((lR,2aR)-3,3,4,4-tetrafluoro-l,2a-dihydroxy-2,2a,3,4-tetrahydro-lH-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (54.30 g, 141.68 mmol, 1.00 eq.) and DBU (43.14 g, 283.37 mmol, 2.00 eq.) in THF (1200 mL) was added a solution of pyridine-2-sulfonyl fluoride (32.00 g, 198.57 mmol, 1.40 eq.) in THF (200 mL) dropwise at 20-30 °C over 2 h under nitrogen atmosphere. The resulting mixture was stirred further for 20 h at 20-30 °C, quenched with 0.5N aqueous NaOH (600 mL). After stirring at 20-30 °C for 30 min, the layers were separated. The aqueous layer was extracted with MTBE. The combined organic layers were concentrated, and the residue was dissolved in MTBE. The organic layer was washed with water, 0.5 N aqueous HC1, water and 10% brine. The organic layer was concentrated and the residue was purified with a silica gel column, eluted with n-heptane / ethyl acetate=4 / l, to obtain crude product (49.0g), which was further recrystallized from MTBE / n-heptane=l / 9 to give the title product (42.0g, 76.9% yield). The HPLC purity of the title compound was 95.4%. ’H NMR (400MHz, CDCh) 8 = 7.71 - 7.67 (m, 1H), 7.29 - 7.26 (m, 2H), 7.25 - 7.09 (m, 2H), 6.60 - 5.80 (ddd, 1H), 2.87 (s, 1H), 2.91 - 2.57 (m, 2H).

Claims

1. A process of preparing compound (11)HO(11)comprising reducing the keto moiety of compound (10):with:(a) sodium borohydride in an organic solvent selected from a group consisting of (i) an alcohol containing acetic acid or trifluoroacetic acid, (ii) a cyclic ether, and (iii) a mixture of a cyclic ether and an alcohol; wherein the cyclic ether of (ii) and the mixture of a cyclic ether and an alcohol of (iii) optionally contain acetic acid or trifluoroacetic acid; or(b) lithium borohydride in a suitable organic solvent optionally containing acetic acid or trifluoroacetic acid.

2. The process of claim 1, further comprising converting compound (11):HO(11)to Compound (I):F2021364337   02 Oct 2026by reacting compound (11) with a deoxyfluorinating agent in the presence of an organic base in a suitable organic solvent.

3. The process of claim 2, wherein the deoxyfluorinating agent is pyridine-2-sulfonylfluoride and the base is 1,8-diazabicyclo-[5.4.0]undec-7-ene or 7-methyl-1,5,7-triaza-bicyclo-[4.4.0]dec-1-ene.

4. The process of claim 1 or 2, wherein the reduction of the keto moiety of compound(10) is carried out with sodium borohydride in:(i) tetrahydrofuran, 2-methyltetrahydrofuran, a mixture of tetrahydrofuran or 2-methyltetrahydrofuran and methanol, tetrahydrofuran containing acetic acid or trifluoroacetic acid, 2-methyltetrahydrofuran containing acetic acid or trifluoroacetic acid, or methanol containing acetic acid or trifluoroacetic acid; or(ii) a mixture of tetrahydrofuran and methanol and the reaction is carried out at about -5 °C to about 30 °C.

5. The process of claim 3, wherein the molar ratio of 1,8-diazabicyclo[5.4.0]-undec-7-ene to compound (11) is at least about 2 to about 1 and the organic solvent is tetrahydrofuran.

6. A process of preparing compound (10):(10)comprising reacting compound (9):F 'OH(9)with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent other than dimethylformamide.2021364337   02 Oct 20267.The process of any one of claims 1 to 5, further comprising preparingcompound (10):(10)by reacting compound (9):(9)with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent.

8. The process of claim 6 or 7, wherein the base is:(i) an inorganic base; or(ii) an inorganic base which is cesium carbonate or potassium carbonate.

9. The process of any one of claims 6 to 8, wherein the organic solvent istetrahydrofuran.

10. The process of any one of claims 6 to 9, further comprising crystallizing compound(10) from:(i)     a mixture of an ether and an alkane solvent; or(ii)    a mixture of methyl tert-butyl ether and n-heptane.

11. The process of any one of claims 6 to 10, further comprising preparingcompound (9):2021364337   02 Oct 2026by carrying out oxidative cleavage of the vinylidene moiety of compound (8):(8)with a suitable oxidizing agent in a suitable organic or aqueous organic solvent.

12. The process of claim 11, wherein the oxidative cleavage of the vinylidene moiety is carried out with sodium periodate in the presence of catalytic amount of ruthenium chloride in aqueous acetonitrile.

13. The process of claim 11 or 12, further comprising preparing compound (8):(8)by performing intramolecular cyclization between the alkene and bromo groups in compound (7):(7)with a palladium catalyst in the presence of a base in a suitable organic solvent.

14. The process of claim 13, wherein:(i)     the palladium catalyst is Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2,Pd(PPh3)2(OAc)2, Pd2(dba)3 / Xphos, or Pd(1,2-bis(diphenylphosphino)-ethane)(OAc)2, and the organic solvent is acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, 1,4-dioxane, or dimethylformamide; or(ii) the palladium catalyst is Pd(PPh3)2Cl2, the base is potassium acetate, and the organic solvent is acetonitrile.

15. The process of claim 14, further comprising preparing compound (7):2021364337   02 Oct 2026by treating compound (6):(7)(6)with a brominating agent in the presence of a deprotonating agent in a suitable organic solvent.

16. The process of claim 15, wherein the deprotonating agent is lithium diisopropylamide17. The process of claim 15, wherein the brominating agent is 1,2-dibromo-1,1,2,2-tetrafluoroethane, the deprotonating agent is lithium diisopropylamide and the organic solvent is tetrahydrofuran.

18. The process of any one of claims 15 to 17, further comprising preparing compound (6):(6)by treating compound (5):O2021364337   02 Oct 2026with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane in the presence of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide and a base in a suitable organic solvent.

19. The process of claim 18, wherein the base is sodium tert-butoxide and the organic solvent is a mixture of methanol and toluene.Nikang Therapeutics, Inc.Patent Attorneys for the Applicant / Nominated Person SPRUSON & FERGUSON