WO2022082329A1 - Procédés de préparation de 3-fluoro-5-(((1s, 2ar)-1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tétrahydro-1 h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile - Google Patents

Procédés de préparation de 3-fluoro-5-(((1s, 2ar)-1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tétrahydro-1 h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile Download PDF

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WO2022082329A1
WO2022082329A1 PCT/CN2020/121745 CN2020121745W WO2022082329A1 WO 2022082329 A1 WO2022082329 A1 WO 2022082329A1 CN 2020121745 W CN2020121745 W CN 2020121745W WO 2022082329 A1 WO2022082329 A1 WO 2022082329A1
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WIPO (PCT)
Prior art keywords
compound
organic solvent
suitable organic
agent
tetrahydrofuran
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PCT/CN2020/121745
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English (en)
Inventor
Yuetao SHI
Jiping Fu
Yan Lou
Yigang He
Peng Zhou
Xingxing Li
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Nikang Therapeutics, Inc.
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Priority to PCT/CN2020/121745 priority Critical patent/WO2022082329A1/fr
Priority to CN202180070640.8A priority patent/CN116507601A/zh
Priority to KR1020237015120A priority patent/KR20230092936A/ko
Priority to JP2023522392A priority patent/JP2023548666A/ja
Priority to CA3197932A priority patent/CA3197932A1/fr
Priority to EP21805779.2A priority patent/EP4229033A1/fr
Priority to PCT/US2021/055295 priority patent/WO2022086822A1/fr
Priority to AU2021364337A priority patent/AU2021364337A1/en
Priority to IL301897A priority patent/IL301897A/en
Priority to TW110138778A priority patent/TW202233569A/zh
Publication of WO2022082329A1 publication Critical patent/WO2022082329A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/58—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by elimination of halogen, e.g. by hydrogenolysis, splitting-off
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
    • C07C35/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings
    • C07C35/32—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with hydroxy on a condensed ring system having two rings the condensed ring system being a (4.3.0) system, e.g. indenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/48—Halogenated derivatives
    • C07C35/52—Alcohols with a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/40—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with ozone; by ozonolysis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
    • C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
    • C07C49/737—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system having three rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings

Definitions

  • Compound (I) is a hypoxia inducible factor-2 ⁇ (HIF-2 ⁇ ) inhibitor and is being developed for treating diseases mediated by aberrant activity of HIF-2 ⁇ including cancer, such as renal cancer, glioblastoma, neuroblastoma, pheochromocytomas and paragangliomas, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors (GIST) , pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, and retinal tumors and non-cancer diseases such as pulmonary artery hypertension (PAH) , reflux esophagitis, hepatic steatosis, NASH, inflammatory disease such as inflammatory bowel disease, autoimmune disease such as Graft-versus-Host-Disease, and iron overload.
  • cancer such as renal cancer, glioblastoma, neuroblastoma, pheochromocytomas and paragangliomas,
  • the process of the first aspect further comprises converting compound (11) :
  • the processes of the first and second aspects further comprise preparing compound (10) :
  • the processes of the third and fourth aspects further comprise preparing compound (9) :
  • the processes of the fifth and sixth aspects further comprise preparing compound (8) :
  • the processes of the seventh and eighth aspects further comprise preparing compound (7) :
  • the processes of the ninth and tenth aspects further comprise preparing compound (6) :
  • the process of eleventh aspect further comprises preparing compound (5) :
  • the process of twelfth aspect further comprises preparing compound (4) :
  • the process of thirteenth aspect further comprises preparing compound (3) :
  • the process of fourteenth aspect further comprises preparing compound (2) :
  • 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 an/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.
  • Suitable organic solvents include: halogenated solvents such as carbon tetrachloride, chloroform, dichloromethane, and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, l, 3-dioxane, l, 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 such as benzene, toluene, xylene, cyclohexane, pentane, hexane, heptane, and the like.
  • halogenated solvents such as carbon tetrachloride,
  • 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.
  • polar organic solvents e.g., alcohols, acetonitrile, DMF
  • solvents that are suitable for the particular reaction step can be readily selected by a person skilled in the art.
  • the reaction was also carried out in MTBE, 2-methylTHF, or toluene solvent.
  • the reaction was also carried out in THFsolvent.
  • the reaction was also carried out in CHCl 3 solvent.
  • the reaction was also carried out in 2-methyl THF, n-heptane, or MTBE solvent.
  • the reaction was also carried out in DMF, 1, 4-dioxane, THF, 2-methyl THF, toluene, oracetonitrile solvent.
  • reaction was also carried out in a mixture of DCM/ACN/water.
  • reaction was also carried out in DMF, ACN, 2-methyl THF, or toluene solvent.
  • preparation of compound (11) the reaction was also carried out in THF, CH 3 OH, TFA/THF, or HOAc/THF solvent.
  • preparation of compound (I) the reaction was also carried out in DCM, CH 3 CN, 2-methyl THF, ethyl acetate, DMF, MTBE or toluene solvent.
  • 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) included-100 to-80 °C, -80 to-60 °C, and-60 to-40 °C.
  • Reaction temperatures that were used in the preparation of compound (8) included 60 °C, 70 °C and refluxing.
  • Reaction temperatures that were used in the preparation of compound (10) included 20 to 30 °C, and 40 °C.
  • Reaction temperatures that were used in the preparation of compound (11) included 10 to 20 °C and-5 to 5 °C.
  • Reaction temperatures that were used in the preparation of compound (I) included 20 to 30 °C and-5 to 5 °C.
  • bases that were used in the preparation of compound (8) included NaOAc, KOAc, and K 2 CO 3 ;
  • brominating reagents that were used in the preparation of compound (7) included CBr 4 and CF 2 BrCF 2 Br;
  • catalysts that were used in the preparation of compound (8) included Pd (dppf) Cl 2 , Pd 2 (dba) 3 /XPhos, Pd (OAc) 2 /PPh 3 , and Pd (PPh 3 ) Cl 2 ;
  • fluorinating reagents that were used in the preparation of compound (4) included DAST, 4-tert-butyl-2, 6-dimethylphenylsulfur trifluoride, and HF/SF 4 ;
  • 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) , RuCl 3 /NaBrO 3 ; TEMPO/NaClO, MnO 2 , and TPAP/NMO.
  • oxidizing agents that were used in the oxidation of compound (8) to (9) included RuCl 3 /NaIO 4 , and O 3 ;
  • reducing agents that were used in the reduction of compound (10) to (11) included LiBH 4 and NaBH 4 .
  • reactions of the processes described herein can be carried out in air or under an inert atmosphere.
  • 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.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) , infrared spectroscopy, spectrophotometry, or mass spectrometry; or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high performance liquid 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.
  • a reaction carried out at about 10°C includes 9°C, 11°C, and all temperatures contained in between 9°C and 11°C.
  • the process of embodiment 2 is wherein the deoxyfluorinating agent is diethylaminosulfur trifluoride, Phenofluor TM , N-tosyl-4-chlorobenzene-sulfonimidoyl fluoride, pyridine-2-sulfonyl fluoride, or AlkylFluor.
  • the deoxyfluorinating agent is diethylaminosulfur trifluoride, Phenofluor TM , N-tosyl-4-chlorobenzene-sulfonimidoyl fluoride, pyridine-2-sulfonyl fluoride, or AlkylFluor.
  • the process of embodiment 2 or 3 is wherein the organic solvent is halogenated hydrocarbon, cyclic ethers, ethers, aromatic hydrocarbon, or a polar solvent.
  • the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethylacetate, dimethylformamide, methyl tert-butylether, or toluene.
  • the process of embodiment 2 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-1, 5, 7-triaza-bicyclo [4.4.0] dec-1-ene.
  • the process of embodiment 1, 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.
  • 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°Cto about 30°C.
  • 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°Cto about 5°C.
  • 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.
  • the process of embodiment 11 or 12, is wherein the base is an inorganic base.
  • the process of embodiment 13, is wherein the inorganic base is cesium carbonate or potassium carbonate.
  • the process of any one of embodiments 11 to 14, is wherein the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, acetonitrile, or toluene.
  • the process of embodiment 15, is wherein the organic solvent is tetrahydrofuran.
  • 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.
  • the process of embodiment 18 is wherein compound (10) is crystallized from a mixture of methyl tert-butyl ether and n-heptane.
  • the process of embodiment 21, is wherein the oxidative cleavage of the vinylidene is carried out with (i) sodium periodate or in the presence of ruthenium chloride or (ii) Ozone.
  • the process of embodiment 21, is wherein the solvent is a mixture of dichloromethane, acetonitrile and water or aqueous acetonitrile.
  • 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.
  • embodiment 24b the process of embodiment 24a, is wherein purification of compound (10) is from a mixture of methyl tert-butyl ether and n-heptane.
  • the process of embodiment 25 or 26, is wherein the palladium catalyst is Pd (PPh 3 ) 4, Pd (dppf) Cl 2, Pd (PPh 3 ) 2 Cl 2, Pd (PPh 3 ) 2 (OAc) 2 , Pd 2 (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 .
  • the palladium catalyst is Pd (PPh 3 ) 4, Pd (dppf) Cl 2, Pd (PPh 3 ) 2 Cl 2, Pd (PPh 3 ) 2 (OAc) 2 , Pd 2 (dba) 3 /XPhos, or Pd (1, 2-bis (diphenylphosphino) ethane) (OAc) 2 and the organic
  • the process of embodiment 27, is wherein the base is sodium acetate, potassium acetate, sodium carbonate, potassium carbonate or cesium carbonate.
  • the process of any one of embodiments 25, 26, or 28, is wherein the palladium catalyst is Pd (PPh 3 ) 2 Cl 2 , the base is potassium acetate and the solvent is acetonitrile.
  • the process of embodimen 29 is wherein the reaction is carried out between about 60°C to about 80°C.
  • 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.
  • the process of embodiment 36 is wherein the base is sodium tert-butoxide and the organic solvent is a mixture of methanol and toluene.
  • the process of claim 38 is wherein the organolithium reagent is n-butyllithium and the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane and methyl ter-butylether.
  • embodiment 40 the process of embodiment 38 or 39, is wherein the solvent is tetrahydrofuran.
  • the process of claim 41 is wherein the fluorinating agent is diethylaminosulfur trifluoride, 4-tert-butyl-2, 6-dimethylphenylsulfur trifluoride, or sulfur tetrafluoride and hydrofluoric acid.
  • the fluorinating agent is diethylaminosulfur trifluoride, 4-tert-butyl-2, 6-dimethylphenylsulfur trifluoride, or sulfur tetrafluoride and hydrofluoric acid.
  • the process of embodiment 42 is wherein the fluorinating agent is sulfur tetrafluoride and hydrofluoric acid and the solvent is dichloromethane.
  • the process of embodiment 44 is wherein the oxidizing agent is dimethyl sulfoxide/oxalyl chloride, 2-iodoxybenzoic acid, RuCl 3 /NaBrO 3 , MnO 2 , NaBrO 3 /NaHSO 3, or TPAP/NMO.
  • the oxidizing agent is dimethyl sulfoxide/oxalyl chloride, 2-iodoxybenzoic acid, RuCl 3 /NaBrO 3 , MnO 2 , NaBrO 3 /NaHSO 3, or TPAP/NMO.
  • the process of embodiment 45 is wherein the oxidizing agent is is TPAP/NMO and reaction is carried in dichloromethane, acetonitrile or tetrahydrofuran, preferably dichloromethane.
  • the process of embodiment 47 is wherein the organic solvent is tetrahydrofuran or 2-methyl tetrahydrofuran.
  • NMO N-Methylmorpholine N-oxide
  • Pd (PPh 3 ) 2 Cl 2 bis (triphenylphosphine) palladium (II) dichloride
  • TEMPO (2, 2, 6, 6-Tetramethylpiperidin-1-yl) oxyl or (2, 2, 6, 6-tetramethylpiperidin-1-yl) oxidanyl
  • TPAP tetrapropylammonium perruthenate
  • Step 1 ethyl 3- (2-bromo-4-fluorophenyl) -2, 2-difluoro-3-hydroxypropanoate
  • Step 2 ethyl 3- (2-bromo-4-fluorophenyl) -2, 2-difluoro-3-oxopropanoate
  • the resulting mixture was further stirred at 25°C for 2 h under N 2 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 HCl.
  • the combined aqueous phase was extracted with MTBE.
  • the combined MTBE organic phase was washed with H 2 O, 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.
  • Step 3 ethyl 3- (2-bromo-4-fluorophenyl) -2, 2, 3, 3-tetrafluoropropanoate
  • Step 4 2, 2, 3, 3, 6-pentafluoro-2, 3-dihydro-1H-inden-1-one
  • Step 1 (R) -1-allyl-2, 2, 3, 3, 6-pentafluoro-2, 3-dihydro-1H-inden-1-ol
  • the organic layer was cooled to 0°C andwashed with 1.0 M aqueous HCl, 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) -1-allyl-7-bromo-2, 2, 3, 3, 6-pentafluoro-2, 3-dihydro-1H-inden-1-ol
  • Step 3 (R) -3, 3, 4, 4, 7-pentafluoro-1-methylene-1, 2, 3, 4-tetrahydro-2aH-cyclopenta [cd] inden-2a-ol
  • the organic layer was diluted with n-heptane and passed through a silica gel pad (200 g) .
  • 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-1H-cyclopenta [cd] inden-1-one
  • Step 1 (R) -3-fluoro-5- ( (3, 3, 4, 4-tetrafluoro-2a-hydroxy-1-oxo-2, 2a, 3, 4-tetrahydro-1H-cyclopenta [cd] inden-7-yl) oxy) benzonitrile
  • Step 2 3-fluoro-5- ( ( (1R, 2aR) -3, 3, 4, 4-tetrafluoro-1, 2a-dihydroxy-2, 2a, 3, 4-tetrahydro-1H-cyclopenta [cd] inden-7-yl) oxy) benzonitrile
  • 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. ) .

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Abstract

Sont divulgués ici des procédés de préparation de 3-fluoro-5-(((1S, 2aR)-1, 3, 3, 4, 4-pentafluoro-2 a-hydroxy -2, 2a, 3, 4-tétrahydro-1H-cyclopenta[cd]inden-7-yl)oxy)benzonitrile (ci-après désigné en tant que composé (I) ayant la structure présentée ci-après).
PCT/CN2020/121745 2020-10-19 2020-10-19 Procédés de préparation de 3-fluoro-5-(((1s, 2ar)-1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tétrahydro-1 h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile WO2022082329A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
PCT/CN2020/121745 WO2022082329A1 (fr) 2020-10-19 2020-10-19 Procédés de préparation de 3-fluoro-5-(((1s, 2ar)-1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tétrahydro-1 h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile
CN202180070640.8A CN116507601A (zh) 2020-10-19 2021-10-15 制备3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的方法
KR1020237015120A KR20230092936A (ko) 2020-10-19 2021-10-15 3-플루오로-5-(((1S,2aR)-1,3,3,4,4-펜타플루오로-2a-하이드록시-2,2a,3,4-테트라하이드로-1H-사이클로펜타[cd]인덴-7-일)옥시)-벤조니트릴의 제조 방법
JP2023522392A JP2023548666A (ja) 2020-10-19 2021-10-15 ３－フルオロ－５－（（（１Ｓ，２ａＲ）－１，３，３，４，４－ペンタフルオロ－２ａ－ヒドロキシ－２，２ａ，３，４－テトラヒドロ－１Ｈ－シクロペンタ［ｃｄ］インデン－７－イル）オキシ）－ベンゾニトリルを調製する方法
CA3197932A CA3197932A1 (fr) 2020-10-19 2021-10-15 Procedes de preparation de 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
EP21805779.2A EP4229033A1 (fr) 2020-10-19 2021-10-15 Procédés de préparation de 3-fluoro-5-(((1s,2ar)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile
PCT/US2021/055295 WO2022086822A1 (fr) 2020-10-19 2021-10-15 Procédés de préparation de 3-fluoro-5-(((1s,2ar)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile
AU2021364337A AU2021364337A1 (en) 2020-10-19 2021-10-15 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
IL301897A IL301897A (en) 2020-10-19 2021-10-15 Preparation processes of 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
TW110138778A TW202233569A (zh) 2020-10-19 2021-10-19 製備３—氟—５—（（（１Ｓ，２ａＲ）—１，３，３，４，４—五氟—２ａ—羥基—２，２ａ，３，４—四氫—１Ｈ—環戊［ｃｄ］茚—７—基）氧基）苯甲腈之方法

Applications Claiming Priority (1)

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PCT/CN2020/121745 WO2022082329A1 (fr) 2020-10-19 2020-10-19 Procédés de préparation de 3-fluoro-5-(((1s, 2ar)-1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tétrahydro-1 h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile

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PCT/CN2020/121745 WO2022082329A1 (fr) 2020-10-19 2020-10-19 Procédés de préparation de 3-fluoro-5-(((1s, 2ar)-1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tétrahydro-1 h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile
PCT/US2021/055295 WO2022086822A1 (fr) 2020-10-19 2021-10-15 Procédés de préparation de 3-fluoro-5-(((1s,2ar)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile

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PCT/US2021/055295 WO2022086822A1 (fr) 2020-10-19 2021-10-15 Procédés de préparation de 3-fluoro-5-(((1s,2ar)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tétrahydro-1h-cyclopenta[cd]inden-7-yl)oxy)-benzonitrile

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KR (1) KR20230092936A (fr)
CN (1) CN116507601A (fr)
AU (1) AU2021364337A1 (fr)
CA (1) CA3197932A1 (fr)
IL (1) IL301897A (fr)
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WO2022082337A1 (fr) 2020-10-19 2022-04-28 Nikang Therapeutics, Inc. Procédé de préparation de 3-fluoro-5(((1r, 2 ar))-3,3,4, 4-tétrafluoro-1, 2a-dihydroxy-2, 2a, 3, 4-tétrahydro-1h-cyclopenta[cd]indén-7-yl)oxy)benzonitrile

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CA3197932A1 (fr) 2022-04-28
TW202233569A (zh) 2022-09-01
IL301897A (en) 2023-06-01
AU2021364337A1 (en) 2023-06-01
KR20230092936A (ko) 2023-06-26
CN116507601A (zh) 2023-07-28
WO2022086822A1 (fr) 2022-04-28
EP4229033A1 (fr) 2023-08-23

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