Process for the preparation of hypoxia inducible factor-2 alpha (HIF-2 alpha) inhibitors

Abstract

Disclosed herein are methods 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, or a pharmaceutically acceptable salt thereof.

Description

[0001] Cross-references to related applications

[0002] This application is a PCT international application claiming the benefit of PCT / CN2020 / 121745, filed on October 19, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This article discloses a method for preparing 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-7-yl)oxy)benzonitrile (hereinafter referred to as compound (I)) or a pharmaceutically acceptable salt thereof, said compound having the structure:

[0004] Background Technology

[0005] Compound (I) is a hypoxia-inducible factor-2α (HIF-2α) inhibitor and is under development for the treatment of diseases mediated by abnormal HIF-2α activity, including cancers (such as renal cell carcinoma, glioblastoma, neuroblastoma, pheochromocytoma, paraganglioma, somatostatinoma, angioblastoma, gastrointestinal stromal tumor (GIST), pituitary adenoma, leiomyosarcoma, leiomyosarcoma, polycythemia vera, and retinal carcinoma) as well as non-cancer diseases (such as pulmonary arterial hypertension (PAH), reflux esophagitis, fatty liver, NASH, inflammatory diseases (such as inflammatory bowel disease), autoimmune diseases (such as graft-versus-host disease), and iron excess).

[0006] The synthesis of compound (I) is disclosed in Example 5 of PCT application publication number WO 2020 / 214853, filed April 16, 2020. An alternative method is needed that allows for the cost-effective large-scale synthesis of compound (I). The method disclosed herein addresses this need, as well as related requirements. Summary of the Invention

[0007] This document provides a method that makes it feasible to produce high-purity (including enantiomeric purity) compound (I) in a cost-effective manner, and the method is suitable for commercial-scale use. Methods for preparing certain intermediates used in this method are also provided.

[0008] On the one hand, a method for preparing compound (11) is provided.

[0009]

[0010] The method includes reducing the ketone moiety of compound (10):

[0011]

[0012] By using:

[0013] (a) Sodium borohydride in an organic solvent, said organic solvent being selected from the group consisting of: (i) ethanol containing acetic acid or trifluoroacetic acid, (ii) cyclic ethers, and (iii) mixtures of cyclic ethers and ethanol, wherein the cyclic ether in (ii) and the mixture of cyclic ethers and ethanol in (iii) optionally contain acetic acid or trifluoroacetic acid; or

[0014] (b) Lithium borohydride in a suitable organic solvent, wherein the suitable organic solvent optionally contains acetic acid or trifluoroacetic acid.

[0015] In the first embodiment of the second aspect, a method for preparing compound (I) is provided:

[0016]

[0017] The method includes:

[0018] (i) Preparation of compound (11):

[0019]

[0020] The method includes reducing the ketone moiety of compound (10):

[0021]

[0022] By using:

[0023] (a) Sodium borohydride in an organic solvent, said organic solvent being selected from the group consisting of: (i) ethanol containing acetic acid or trifluoroacetic acid, (ii) cyclic ethers, and (iii) mixtures of cyclic ethers and ethanol, wherein the cyclic ether in (ii) and the mixture of cyclic ethers and ethanol in (iii) optionally contain acetic acid or trifluoroacetic acid; or

[0024] (b) Lithium borohydride in a suitable organic solvent, said suitable organic solvent optionally comprising acetic acid or trifluoroacetic acid; and

[0025] (ii) Compound (11):

[0026]

[0027] Converted to compound (I):

[0028]

[0029] Compound (11) is reacted with a deoxyfluorinating agent in the presence of an organic base in a suitable organic solvent.

[0030] In a second embodiment of the second aspect, the method of the first aspect further includes: compound (11):

[0031]

[0032] Converted to compound (I):

[0033]

[0034] Compound (11) is reacted with a deoxyfluorinating agent in the presence of an organic base in a suitable organic solvent.

[0035] In the third aspect, a method for preparing compound (10) is provided:

[0036]

[0037] The method includes: compound (9):

[0038]

[0039] It reacts with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent other than dimethylformamide.

[0040] In the fourth aspect, each embodiment of the method of the first aspect and the second aspect further includes the preparation of compound (10):

[0041]

[0042] By using compound (9):

[0043]

[0044] It reacts with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent.

[0045] In the fifth aspect, a method for preparing compound (9) is provided:

[0046]

[0047] The method includes oxidative cleavage of the vinylidene moiety of compound (8):

[0048]

[0049] By using (i) sodium periodate in the presence of ruthenium chloride in aqueous acetonitrile, and (ii) sodium periodate in the presence of ruthenium chloride in a suitable organic solvent. Or (iii) in a suitable organic solvent

[0050] In the sixth aspect, the methods of the third and fourth aspects further include the preparation of compound (9):

[0051]

[0052] The vinylidene moiety of compound (8) was oxidatively cleaved using a suitable organic solvent or a suitable oxidant in an aqueous organic solvent:

[0053]

[0054] In the seventh aspect, a method for preparing compound (8) is provided:

[0055]

[0056] The method includes intramolecular cyclization between the olefin and the bromine group in compound (7):

[0057]

[0058] The compound (7) was treated with a palladium catalyst in the presence of a base in a suitable organic solvent other than dimethylformamide.

[0059] In the eighth aspect, the methods of the fifth and sixth aspects further include the preparation of compound (8):

[0060]

[0061] Intramolecular cyclization between the olefin and bromo group in compound (7) was achieved using a palladium catalyst in the presence of a base in a suitable organic solvent:

[0062]

[0063]

[0064] In the ninth aspect, a method for preparing compound (7) is provided:

[0065]

[0066] The method includes using 1,2-dibromo-1,1,2,2-tetrafluoroethane to brominate compound (6) in the presence of a deprotonating agent in a suitable organic solvent:

[0067]

[0068] In aspect ten, the methods of aspects seven and eight further include the preparation of compound (7):

[0069]

[0070] Compound (6) was treated with a brominating agent in the presence of a deprotonating agent in a suitable organic solvent:

[0071]

[0072] In the eleventh aspect, the methods of the ninth and tenth aspects further include the preparation of compound (6):

[0073]

[0074] Compound (5) was treated with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxane in a suitable organic solvent in the presence of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide and a base.

[0075]

[0076] In the twelfth aspect, the method of the eleventh aspect further includes the preparation of compound (5):

[0077]

[0078] Compound (4) was treated with an organolithium reagent in a suitable organic solvent:

[0079]

[0080] In aspect thirteen, the method of aspect twelf further includes the preparation of compound (4):

[0081]

[0082] Compound (3) is treated with a fluorinating agent in a suitable organic solvent:

[0083]

[0084] In aspect fourteen, the method of aspect thirteen further includes the preparation of compound (3):

[0085]

[0086] Compound (2) was treated with an oxidant in a suitable organic solvent:

[0087]

[0088] In aspect fifteen, the method of aspect fourteen further includes the preparation of compound (2):

[0089]

[0090] Compound (1) was treated with ethyl 2-bromo-2,2-difluoroacetate in a suitable organic solvent in the presence of zinc, trimethylchlorosilane, and 1,2-dibromoethane:

[0091] Detailed Implementation

[0092] definition:

[0093] Unless otherwise stated, the following terms used in this specification and claims are defined for the purposes of this application and have the following meanings:

[0094] As used herein, when describing a particular method, the terms “reaction” or “treatment” are used as known in the art and generally refer to a combination of chemical reagents in a manner that allows them to interact at the molecular level to achieve a chemical or physical transformation. The reaction steps described herein can be carried out at times and under conditions suitable for the preparation of the identified product.

[0095] "Suitable organic solvent" means an organic solvent that, under the reaction conditions of the methods disclosed herein and at the temperature at which the reaction is carried out, does not exhibit any significant reaction with the reactants, intermediates, and / or products. The given reactions disclosed herein can be carried out in organic solvents or mixtures 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, etc.; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, etc.; ethanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, n-butanol, tert-butanol, 1-, 2-, or 3-pentanol, neopentanol, etc.; hydrocarbons (including, for example, alkane solvents) such as benzene, toluene, xylene, cyclohexane, pentane, hexane, heptane, etc. Other organic solvents that can be used in the reactions described herein include polar organic solvents (including, but not limited to, acetonitrile, dimethylformamide, ethyl acetate, ethanol, etc.). When a polar organic solvent (e.g., ethanol, acetonitrile, DMF) contains water, it is referred to herein as an aqueous organic solvent. Depending on the reaction steps, those skilled in the art can readily select a solvent suitable for the specific reaction steps.

[0096] For example, in preparing compound (2), the reaction can be carried out in solvents other than THF, such as MTBE, 2-methylTHF, or toluene. In preparing compound (3), the reaction can also be carried out in a THF solvent. In preparing compound (4), the reaction can also be carried out in a CHCl3 solvent. In preparing compound (5), the reaction can also be carried out in a solvent of 2-methylTHF, n-heptane, or MTBE. In preparing compound (8), the reaction can also be carried out in a solvent of DMF, 1,4-dioxane, THF, 2-methylTHF, toluene, or acetonitrile. In preparing compound (9), the reaction can also be carried out in a mixture of DCM / ACN / water. In preparing compound (10), the reaction can also be carried out in a solvent of DMF, ACN, 2-methylTHF, or toluene. In preparing compound (11), the reaction can also be carried out in a solvent of THF, CH3OH, TFA / THF, or HOAc / THF. In preparing compound (I), the reaction can also be carried out in DCM, CH3CN, 2-methylTHF, ethyl acetate, DMF, MTBE or toluene solvent.

[0097] Furthermore, the reactions can be carried out at various temperatures. The reaction temperatures used to prepare compound (2) include 20°C, 40°C, and 60°C, with reflux. The reaction temperatures used to prepare compound (3) include 0-15°C and 15°C-25°C. The reaction temperatures used to prepare compound (4) include 0-10°C, 10°C-20°C, 20°C-30°C, and 30°C-40°C. The reaction temperatures used to prepare compound (5) include -30°C to -40°C, -40°C to -50°C, -50°C to -60°C, and -60°C to -70°C. The reaction temperatures used to prepare compound (6) include 35°C, 45°C, and 60°C. The reaction temperatures used to prepare compound (7) include -100°C to -80°C, -80°C to -60°C, and -60°C to -40°C. The reaction temperatures used to prepare compound (8) include 60°C and 70°C, with reflux. The reaction temperatures used to prepare compound (10) include 20°C to 30°C and 40°C. The reaction temperatures used to prepare compound (11) include 10°C to 20°C and -5°C to 5°C. And the reaction temperatures used to prepare compound (I) include 20°C to 30°C and -5°C to 5°C.

[0098] In addition, the bases used to prepare compound (8) include NaOAc, KOAc, and K2CO3;

[0099] The brominating agents used to prepare compound (7) include CBr4 and CF2BrCF2Br;

[0100] The catalysts used to prepare compound (8) include Pd(dppf)Cl2, Pd2(dba)3 / XPhos, Pd(OAc)2 / PPh3, and Pd(PPh3)Cl2;

[0101] The fluorinating agents used to prepare compound (4) include DAST, 4-tert-butyl-2,6-dimethylphenyl trifluoride, and HF / SF4;

[0102] Fluoriding agents used to prepare compound (I) include DAST, PyFluor, AlkylFluor, and SulfoxFluor;

[0103] The oxidizing agents used to oxidize compounds (2) to (3) include 2-iodobenzoic acid (IBX), RuCl3 / NaBrO3; TEMPO / NaClO, MnO2, and TPAP / NMO.

[0104] Oxidizing agents used to oxidize compounds (8) to (9) include RuCl3 / NaIO4, And O3; and

[0105] The reducing agents used to reduce compounds (10) to (11) include LiBH4 and NaBH4.

[0106] The reactions described herein can be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are fully reactive with air can be carried out using air-sensitive synthesis techniques well known to skilled technicians.

[0107] The method described herein can be monitored according to any suitable method known in the art. For example, it 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 to monitor product formation. The compound obtained by the reaction can be purified by any suitable method known in the art, such as chromatography (medium pressure) on a suitable adsorbent (e.g., silica gel, alumina, etc.), HPLC, or preparative thin-layer chromatography; distillation; sublimation, grinding, or recrystallization. Typically, the purity of the compound is determined by physical methods such as measuring the melting point (in the case of a solid), obtaining an NMR spectrum, or performing HPLC separation.

[0108] "Cyclic ethers" refer to tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane.

[0109] "Ethanol" refers to aliphatic hydrocarbon compounds carrying a hydroxyl group. Representative examples include, but are not limited to, methanol, ethanol, propanol, and butanol.

[0110] As used herein, “about” means ±10%, preferably ±5%, of the listed values. For example, the reaction is carried out at about 10°C (inclusive of 9°C and 11°C), and all temperatures included are between 9°C and 11°C.

[0111] Example:

[0112] 1. In Example 1, a method for preparing compound (11) is provided.

[0113]

[0114] The method includes reducing the ketone moiety of compound (10):

[0115]

[0116] By using:

[0117] (a) Sodium borohydride in an organic solvent, said organic solvent being selected from the group consisting of: (i) ethanol containing acetic acid or trifluoroacetic acid, (ii) cyclic ethers, and (iii) mixtures of cyclic ethers and ethanol; wherein the cyclic ether in (ii) and the mixture of cyclic ethers and ethanol in (iii) optionally contain acetic acid or trifluoroacetic acid; or

[0118] (b) Lithium borohydride in a suitable organic solvent, wherein the suitable organic solvent optionally contains acetic acid or trifluoroacetic acid.

[0119] 2. In Example 2, a method for preparing compound (I) as described in the first and second examples of the second aspect of the invention is provided.

[0120] 2a. In Example 2a, a method for preparing compound (I) as described in the first embodiment of the second aspect of the invention is provided.

[0121] 2b. In Example 2b, a method for preparing compound (I) as described in the second embodiment of the second aspect of the invention is provided.

[0122] 3. In Example 3, the method described in Examples 2, 2a, or 2b is wherein the deoxidizing fluorinating agent is diethylaminosulfur trifluoride, Phenofluor. TM N-Toluenesulfonyl-4-chlorobenzene-sulfonylimide fluoride, pyridine-2-sulfonyl fluoride, or AlkylFluor.

[0123] 4. In Example 4, the method described in Examples 2, 2a (in step (ii)), 2b, or 3 is such that the organic solvent is a halogenated hydrocarbon, a cyclic ether, an ether, an aromatic hydrocarbon, or a polar solvent. Preferably, the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethylformamide, methyl tert-butyl ether, or toluene.

[0124] 5. In Example 5, the method described in Examples 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-1,5,7-triazabicyclo[4.4.0]dec-1-ene.

[0125] 6. In Example 6, the method described in Example 1, 2a, 2b or 2b is wherein the ketone group of compound (10) is reduced by sodium borohydride in tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran or a mixture of 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.

[0126] 7. In Example 7, the method as described in Example 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.

[0127] 8. In Example 8, the method as described in Example 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.

[0128] 9. In Example 9, the method as described in Example 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.

[0129] 10. In Example 10, the method described in Example 5 or 9 is such that the reaction is carried out at 20°C to about 30°C.

[0130] 11. In Example 11, a method for preparing compound (10) is provided:

[0131]

[0132] The method includes: compound (9):

[0133]

[0134] It reacts with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent other than dimethylformamide.

[0135] 12. In Example 12, the method as described in any one of Examples 1 to 10 further comprises the preparation of compound (10):

[0136]

[0137] By using compound (9):

[0138]

[0139] It reacts with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable organic solvent.

[0140] 13. In Example 13, the method described in Example 11 or 12 is wherein the base is an inorganic base.

[0141] 14. In Example 14, the method described in Example 13 is wherein the inorganic base is cesium carbonate or potassium carbonate.

[0142] 15. In Example 15, the method of any one of Examples 11 to 14 is wherein the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, acetonitrile, or toluene.

[0143] 16. In Example 16, the method as described in Example 15 is wherein the organic solvent is tetrahydrofuran.

[0144] 17. In Example 17, the method of any one of Examples 11 to 16 is such that the reaction is carried out at about 20°C to about 40°C.

[0145] 18. In Example 18, the method as described in any one of Examples 11 to 17 further comprises crystallizing compound (10) from a mixture of ether and alkane solvent.

[0146] 19. In Example 19, the method described in Example 18 is wherein compound (10) is crystallized from a mixture of methyl tert-butyl ether and n-heptane.

[0147] 20. In Example 20, a method for preparing compound (9) is provided:

[0148]

[0149]

[0150] The method includes oxidative cleavage of the vinylidene moiety of compound (8):

[0151]

[0152] By using (i) sodium periodate in the presence of ruthenium chloride in aqueous acetonitrile, and (ii) ruthenium chloride in a suitable organic solvent or aqueous organic solvent. Or (iii) ozone in a suitable organic solvent or aqueous organic solvent.

[0153] 21. In Example 21, the method as described in any one of Examples 11 to 19 further comprises the preparation of compound (9):

[0154]

[0155] The vinylidene moiety of compound (8) was oxidatively cleaved using a suitable organic solvent or a suitable oxidant in an aqueous organic solvent:

[0156]

[0157] 22. In Example 22, the method described in Example 21 is wherein (i) sodium periodate in the presence of ruthenium chloride or Or (ii) ozone oxidizes and cracks vinylidene.

[0158] 23. In Example 23, the method described in Example 21 is wherein the solvent is a mixture of dichloromethane, acetonitrile and water or the solvent is aqueous acetonitrile.

[0159] 24. In Example 24, the method as described in any one of Examples 20 to 23 involves oxidative cracking of vinylidene using sodium periodate in the presence of a catalytic amount of ruthenium chloride in aqueous acetonitrile.

[0160] 24a. In Example 24a, the method as described in any one of Examples 20 to 24 further comprises purifying the compound (9) from a mixture of ether and alkane solvent.

[0161] 24b. In Example 24b, the method described in Example 24a is wherein compound (9) is purified from a mixture of methyl tert-butyl ether and n-heptane.

[0162] 25. In Example 25, a method for preparing compound (8) is provided:

[0163]

[0164] The method includes intramolecular cyclization between the olefin and the bromine group in compound (7):

[0165]

[0166] The compound (7) was treated with a palladium catalyst in the presence of a base in a suitable organic solvent other than dimethylformamide.

[0167] 26. In Example 26, the method as described in any one of Examples 20 to 24 further comprises the preparation of compound (8):

[0168]

[0169] Intramolecular cyclization between the olefin and bromo group in compound (7) was achieved using a palladium catalyst in the presence of a base in a suitable organic solvent:

[0170]

[0171] 27. In Example 27, the method as described in Example 25 or 26 is wherein 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(diphenylphosphine)ethane)(OAc)2, and the organic solvent is acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, 1,4-dioxane, or dimethylformamide.

[0172] 28. In Example 28, the method described in Example 27 is wherein the base is sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, or cesium carbonate.

[0173] 29. In Example 29, the method of any one of Examples 25, 26, or 28 is wherein the palladium catalyst is Pd(PPh3)2Cl2, the base is potassium acetate, and the solvent is acetonitrile.

[0174] 30. In Example 30, the method described in Example 29 is such that the reaction is carried out between about 60°C and about 80°C.

[0175] 31. In Example 31, a method for preparing compound (7) is provided:

[0176]

[0177] The method includes using 1,2-dibromo-1,1,2,2-tetrafluoroethane to brominate compound (6) in the presence of a deprotonating agent in a suitable organic solvent:

[0178]

[0179] 32. In Example 32, the method as described in any one of Examples 25 to 30 further comprises the preparation of compound (7):

[0180]

[0181]

[0182] Compound (6) was treated with a brominating agent in the presence of a deprotonating agent in a suitable organic solvent:

[0183]

[0184] 33. In Example 33, the method described in Example 32 is wherein the brominating agent is carbon tetrabromide or 1,2-dibromo-1,1,2,2-tetrafluoroethane.

[0185] 33a. In Example 33a, the method described in Example 32 is such that the brominating agent is trichlorobromomethane, 1,2-dibromo-1,1,2,2-tetrachloroethane, 1,2-dibromo-1,1,2,2-tetrafluoroethane, carbon tetrabromide, N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, N-bromoacetamide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, Sodium bromide isocyanurate, dimethyl sulfide bromide, 5,5-dibromomelinic acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate; and bromine and its equivalents, such as bromo-1,4-dioxane complexes, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, and 1-butyl-3-methylimidazolium tribromide.

[0186] 34. In Example 34, the method as described in Example 31 or 32 is wherein the brominating agent is 1,2-dibromo-1,1,2,2-tetrafluoroethane, the deprotonating agent is lithium diisopropylaminodimethylamine, and the solvent is tetrahydrofuran.

[0187] 35. In Example 35, the method as described in Example 34 is such that the reaction is carried out at about -100°C to about -20°C.

[0188] 36. In Example 36, the method as described in any one of Examples 31 to 35 further comprises the preparation of compound (6):

[0189]

[0190] Compound (5) was treated with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxane in a suitable organic solvent in the presence of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide and a base.

[0191]

[0192] 37. In Example 37, the method as described in Example 36 is wherein the base is sodium tert-butoxide and the organic solvent is a mixture of methanol and toluene.

[0193] 38. In Example 38, the method described in Example 36 or 37 further comprises preparing compound (5):

[0194]

[0195] Compound (4) was treated with an organolithium reagent in a suitable organic solvent:

[0196]

[0197] 39. In Example 39, the method as described in Example 38 is wherein the organolithium reagent is n-butyllithium and the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, n-heptane, and methyl tert-butyl ether.

[0198] 40. In Example 40, the method as described in Example 38 or 39 is wherein the solvent is tetrahydrofuran.

[0199] 41. In Example 41, the method as described in any one of Examples 38 to 40 further comprises the preparation of compound (4):

[0200]

[0201] Compound (3) is treated with a fluorinating agent in a suitable organic solvent:

[0202]

[0203] 42. In Example 42, the method as described in Example 41 is wherein the fluorinating agent is diethylaminosulfur trifluoride, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride, or sulfur tetrafluoride and hydrofluoric acid.

[0204] 43. In Example 43, the method as described in Example 42 is wherein the fluorinating agent is sulfur tetrafluoride and hydrofluoric acid and the solvent is dichloromethane.

[0205] 44. In Example 44, the method as described in any one of Examples 41 to 43 further comprises the preparation of compound (3):

[0206]

[0207] Compound (2) was treated with an oxidant in a suitable organic solvent:

[0208]

[0209] 45. In Example 45, the method described in Example 44 is wherein the oxidant is dimethyl sulfoxide / oxalyl chloride, 2-iodobenzoic acid, RuCl3 / NaBrO3, MnO2, NaBrO3 / NaHSO3, or TPAP / NMO.

[0210] 46. ​​In Example 46, the method as described in Example 45 is wherein the oxidant is TPAP / NMO and the reaction is carried out in dichloromethane, acetonitrile, or tetrahydrofuran, preferably dichloromethane.

[0211] 47. In Example 47, the method as described in any one of Examples 44 to 46 further comprises the preparation of compound (2):

[0212]

[0213] Compound (1) was treated with ethyl 2-bromo-2,2-difluoroacetate in a suitable organic solvent in the presence of zinc, trimethylchlorosilane, and 1,2-dibromoethane:

[0214]

[0215] 48. In Example 48, the method as described in Example 47 is wherein the organic solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

[0216] Example

[0217] abbreviation:

[0218] ACN: Acetonitrile

[0219] AcOH or HOAc: Acetic acid

[0220] AlkylFluor: CAS Registration No. 2043361-32-4

[0221] Cs2CO3: Cesium carbonate

[0222] DAST: Diethylaminosulfuric acid

[0223] DCM: Dichloromethane

[0224] HF: hydrofluoric acid

[0225] HCl: hydrochloric acid

[0226] KOAc: Potassium acetate

[0227] LDA: Lithium diisopropylamide

[0228] MTBE: Methyl tert-butyl ether

[0229] NMO: N-methylmorpholine N-oxide

[0230] MeOH: Methanol

[0231] NaBH4: Sodium borohydride

[0232] NaIO4: Sodium periodate

[0233] n-BuLi: n-Butyllithium

[0234] Pd(PPh3)2(OAc)2:bis(acetic acid)bis(triphenylphosphine)palladium(II)

[0235] Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium(II) dichloride

[0236] Pd2(dba)3:tris(dibenzylacetone)dipalladium(0)

[0237] PyFluor: 2-Pyridinesulfonyl fluoride

[0238] RuCl3·3H2O: Ruthenium(III) chloride hydrate

[0239] SF4: Sulfur tetrafluoride

[0240] SulfoxFluor: [methyl(oxo){1-[6-(trifluoromethyl)-3-pyridyl]ethyl ester}-λ 6 -Thionyl]cyanamide

[0241] TEMPO: (2,2,6,6-tetramethylpiperidin-1-yl)oxy or (2,2,6,6-tetramethylpiperidin-1-yl)oxoalkyl

[0242] TFA: Trifluoroacetic acid

[0243] THF: Tetrahydrofuran

[0244] TPAP: Tetrapropylammonium perruthenium

[0245] t-BuONa: Sodium tert-butoxide

[0246] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0247] Example 1

[0248] Synthesis of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

[0249]

[0250] Step 1: Ethyl 3-(2-bromo-4-fluorophenyl)2,2-difluoro-3-hydroxypropionate

[0251]

[0252] A mixture of zinc (211.36 g, 3.23 mol, 1.31 equivalents) in THF (1.50 L) was added in a single addition of 1,2-dibromoethane (13.88 g, 73.89 mmol, 0.030 equivalents) and TMSCl (53.52 g, 492.59 mmol, 0.20 equivalents). The mixture was stirred at 25 °C for 0.5 h, and then, under reflux for 1 h, a solution of 2-bromo-4-fluorobenzaldehyde (500 g, 2.46 mol, 1.00 equivalents) and ethyl 2-bromo-2,2-difluoroacetate (549.93 g, 2.71 mol, 1.10 equivalents) in THF (1.50 L) was added dropwise to the mixture, and the reaction mixture was continuously stirred under reflux for 1 h. The reaction mixture was cooled, filtered, and the filter cake was washed with ethyl acetate. The filtrate was quenched with 1.0 M aqueous HCl (800 mL), then adjusted to pH 5-6, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with 10% brine, dried over Na₂SO₄, and concentrated under vacuum to give the title compound as a yellow oil (857.0 g, 88.8% purity, 94.5% yield), which was used for the next step without further purification.

[0253] Step 2: Ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropionate

[0254]

[0255] NMO (297.86 g, 2.54 mol, 1.40 equivalents), TPAP (15.96 g, 45.41 mmol, 0.025 equivalents) and The mixture of 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-hydroxypropionate (669.00 g, 1.82 mol, 88.8% determination, 1.00 equivalent) in DCM (1000 mL) was added dropwise at 0–5 °C for 1.5 h. The resulting mixture was further stirred for 2 h at 25 °C under N2 atmosphere, then filtered through a silica gel pad and the filter cake pad was washed with MTBE. The combined filtrates were washed with 1.0 M aqueous HCl. The combined aqueous phases were extracted with MTBE. The combined MTBE organic phase was washed with H2O, filtered through a silica gel pad, and the filter cake pad was washed with MTBE. The combined filtrates were concentrated to give the title compound (561.0 g, 95.1% yield) as a yellow oil, which was used for the next step without further purification.

[0256] Alternative methods:

[0257] At 20-30°C, NaH₂PO₄ (63.0 g, 0.525 mol, 0.60 equivalent) and RuCl₃ (1.81 g, 8.726 mmol, 0.010 equivalent) were successively added to a stirred mixture of ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropionate (285.9 g, adjusted for determination, 0.874 mol, 1.00 equivalent) in acetonitrile (900 mL) and water (900 mL) at a stirring temperature. Then, at 20-30°C, NaBrO₃ (158.27 g, 1.049 mol, 1.20 equivalent) was added in one step. After further stirring at 20-30°C for 2 h, the reaction mixture was diluted with EtOAc and then washed 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 in the next step without further purification.

[0258] Step 3: Ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropionate

[0259]

[0260] Ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropionate (550.00 g, 1.69 mol, 1.00 equivalent) and DCM (55.5 mL) were packed into an autoclave. The mixture was cooled to -78 °C and HF (33.85 g, 1.69 mol, 1.00 equivalent) was packed in, followed by SF4 (202.00 g, 1.87 mol, 1.11 equivalent). The reaction mixture was heated to room temperature and stirred at this temperature for 16 h. The reaction mixture was quenched by slow addition of saturated aqueous Na2CO3 (2.5 L) and then extracted with petroleum ether. The combined organic layers were washed with 10% brine, dried over Na2SO4, filtered, and concentrated. The residue was further purified by vacuum distillation to provide the title compound (474.0 g, 81.1% yield) as a yellow oil.

[0261] Step 4: 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

[0262]

[0263] A stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropionate (100.0 g, 288.11 mol, 1.00 equivalent) in 1.0 L THF was cooled to -65 °C and n-BuLi (2.5 M, 138.0 mL, 345.0 mol, 1.20 equivalent) was added dropwise at -60 °C to -70 °C for 1 h under a nitrogen atmosphere. The resulting mixture was further stirred at -65 °C for 1 h, then quenched with saturated aqueous NH4Cl at -30 °C 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 layers were washed with 10% brine, dried over Na2SO4, filtered, and concentrated to give the residue. The residue was purified by vacuum distillation, and the distillate was ground with petroleum ether at low temperature to give the title compound as a white solid (41.0 g, 64.1% yield).

[0264] Example 2

[0265] Synthesis of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]inden-1-one

[0266]

[0267] Step 1: (R)-1-Allyl-2,2,3,3,6-Pentafluoro-2,3-Dihydro-1H-Indene-1-ol

[0268]

[0269] Add 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxane (94.57 g, 562.78 mmol, 1.21 equivalents), (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethyl-butanamide (36.51 g, 119.14 mmol, 0.26 equivalents), t-BuONa (4.33 g, 45.06 mmol, 0.097 equivalents), toluene (900 mL), and MeOH (28.8 g, 898.88 mmol, 1.94 equivalents) to a dry three-necked flask. Stir the mixture at 20 °C under a nitrogen atmosphere until a clear solution is formed. The reaction mixture was heated to 60 °C, and a solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (103.09 g, 464.14 mmol, 1.00 equivalent) in toluene (100 mL) was slowly added at 60 °C for 2 h. The resulting mixture was stirred continuously at 60 °C for 16 h, then cooled to room temperature, quenched with water, and extracted with MTBE. The organic layer was cooled to 0 °C and washed 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 (146.71 g, 73.5% determination purity, 87.9% determination yield, 90.7% ee).

[0270] Step 2: (R)-1-Allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol

[0271]

[0272] Add THF (500 mL) and LDA (356.82 g, 25%, 832.76 mmol, 2.21 equivalents) to a dry 3-necked flask and then cool the solution to -50 °C under a nitrogen atmosphere. At -50 °C, slowly add a solution of (R)-1-allyl-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (100.00 g, 378.50 mmol, 1.00 equivalents) in THF (200 mL). Stir the resulting mixture at -50 °C for 1 h, then cool to -80 °C to form solution A.

[0273] Add dibromotetrafluoroethane (196.66 g, 756.91 mmol, 2.00 equivalence) and THF (100 mL) to another dry 3-necked flask, and cool the solution to -80 °C. While stirring, slowly add solution A while maintaining the reaction temperature at approximately -80 °C. At -80 °C, stir the mixture again for 30 min, and then slowly quench the reaction at a temperature below -60 °C by slowly adding a solution of AcOH (75.00 g, 1248.96 mmol, 3.30 equivalence) in THF (75 mL). Slowly heat the mixture to room temperature and dilute with water. Extract the mixture with MTBE, and wash the combined organic layers with water and 10% brine. Concentrate the organic layers to give the title compound as a solution in THF (204.40 g, 50.4% determination purity, 79.3% determination yield).

[0274] Step 3: (R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopentane[cd]indene-2a-ol

[0275]

[0276] Under a nitrogen atmosphere, KOAc (86.50 g, 881.39 mmol, 3.03 equivalents) and Pd(PPh3)2Cl2 (10.30 g, 14.67 mmol, 0.050 equivalents) were added to a solution of (R)-1-allyl-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-indene-1-ol (100.00 g, 291.47 mmol, 1.00 equivalents) in acetonitrile (1.50 L). The mixture was stirred at 80 °C for 4 h and then concentrated under vacuum to approximately 1 / 3 of the 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 washed with MTBE / n-heptane = 1 / 3 to elute the product. The eluent was concentrated and the solvent was replaced with acetonitrile to give the title compound as a solution in acetonitrile (120.15 g, 51.7% purity determined, 81.3% yield determined, 90.6% ee).

[0277] Step 4: (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indone

[0278]

[0279] RuCl3·3H2O (4.00 g, 15.30 mmol, 0.050 equivalent) was added to a mixture of (R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-cyclopentane[cd]indene-2a-ol (80.00 g, 305.13 mmol, 1.00 equivalent) in ACN (1200 mL) and H2O (3200 mL), followed by a one-time addition of NaIO4 (456.87 g, 2.14 mol, 7.01 equivalent) while maintaining the reaction temperature between 10 °C and 20 °C. After further stirring for 1 h at 10 °C to 20 °C, MTBE (800 mL) was added to the mixture, and the mixture was filtered through a diatomaceous earth layer. The diatomaceous earth solid filter 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 layers were washed with 5% aqueous Na₂SO₃ and 10% aqueous Na₂SO₄. The organic layers were concentrated, and the residue was dissolved in MTBE and n-heptane. The solution was filtered through a silica gel pad (200 g), and the solid filter cake pad was washed with MTBE / n-heptane = 1 / 3. The combined eluent was concentrated to approximately 3V to precipitate the product, which was then filtered and dried to give the title compound as a white solid (70.62 g, 88.4% determination purity, 77.5% determination yield, approximately 91.7% ee).

[0280] Example 3

[0281] 3-Fluoro-5-(((1R,2aR)-3,3,4,4-Tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopentane[cd]

[0282] Synthesis of indene-7-yl)oxy)benzonitrile

[0283]

[0284] Step 1: (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopentan[cd]indene-7-yl)oxy)benzonitrile

[0285]

[0286] At room temperature, 3-fluoro-5-hydroxybenzonitrile (57.10 g, 416.45 mmol, 1.10 equivalent) and Cs₂CO₃ (74.01 g, 227.15 mmol, 0.60 equivalent) were added to a stirred solution of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-1-one (100.00 g, 378.57 mmol, 1.00 equivalent) in THF (500 mL). 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 layers were washed with 5% aqueous Na₂CO₃ and then with 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% purity determined, 85.2% yield determined, 98.4% ee).

[0287] Step 2: 3-Fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopentan[cd]indene-7-yl)oxy)benzonitrile

[0288]

[0289] At -5°C to 0°C, NaBH4 (1.84 g, 48.64 mmol, 0.37 equivalent) was added in a single batch to a stirred solution of (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-7-yl)oxy)benzonitrile (50.00 g, 131.14 mmol, 1.00 equivalent) in MeOH (53.0 mL, 1.31 mol, 10.00 equivalent) and THF (500 mL). The reaction mixture was stirred for another 1 hour at -5°C to 0°C, then quenched to pH 5–7 with 2.0 M aqueous HCl (approximately 30.0 g) at below 5°C and diluted with water. The mixture was extracted with MTBE, and the combined organic layers were washed with water and 10% brine. The organic layer was concentrated and the solvent was exchanged for THF to obtain a THF solution of the title compound (286.66 g, 16.6% purity, 94.7% yield, 97.7% ee). 1H NMR(400MHz, CDCl3)δ=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).

[0290] Example 4

[0291] 3-Fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopentane[cd]indene

[0292] Synthesis of 7-yl)oxy)benzonitrile

[0293]

[0294] Under a nitrogen atmosphere, at 20°C–30°C, for 2 hours, a solution of pyridine-2-sulfonyl fluoride (32.00 g, 198.57 mmol, 1.40 equivalent) in THF (200 mL) was added dropwise to a stirred solution of 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cd]indene-7-yl)oxy)benzonitrile (54.30 g, 141.68 mmol, 1.00 equivalent) and DBU (43.14 g, 283.37 mmol, 2.00 equivalent) in THF (1200 mL). The resulting mixture was further stirred for 20 hours at 20°C–30°C and quenched with 0.5 N aqueous NaOH (600 mL). After stirring at 20°C–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 layers were washed with water, 0.5N aqueous HCl, water, and 10% brine. The organic layers were concentrated, and the residue was purified by silica gel column chromatography, eluting with n-heptane / ethyl acetate = 4 / 1 to give a crude product (49.0 g), which was further recrystallized from MTBE / n-heptane = 1 / 9 to give the title product (42.0 g, 76.9% yield). The HPLC purity of the title compound was 95.4%. 1 HNMR (400MHz, CDCl3) δ=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 method for preparing compound (10): The method includes: compound (9): It reacts with 3-fluoro-5-hydroxybenzonitrile in the presence of an inorganic base in an organic solvent. The inorganic base is cesium carbonate or potassium carbonate, and the organic solvent is tetrahydrofuran.

2. The method of claim 1, wherein the inorganic base is cesium carbonate.

3. The method of claim 1, further comprising crystallizing the compound (10) from a mixture of ether and alkane solvent.

4. The method of claim 3, wherein the compound (10) is crystallized from a mixture of methyl tert-butyl ether and n-heptane.

5. The method according to any one of claims 1-4, the method further comprising preparing compound (9): The vinylidene moiety of compound (8) was oxidatively cleaved using a suitable organic solvent or a suitable oxidant in an aqueous organic solvent: 。 6. The method of claim 5, wherein the vinylidene moiety is oxidatively cracked with sodium periodate in the presence of a catalytic amount of ruthenium chloride in aqueous acetonitrile.

7. The method of claim 6, further comprising preparing compound (8): Intramolecular cyclization between the olefin and bromine group in compound (7) was achieved by using a palladium catalyst in the presence of a base in a suitable organic solvent: 。 8. The method of claim 7, wherein 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(diphenylphosphine)-ethane)(OAc)2, and the organic solvent is acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, 1,4-dioxane, or dimethylformamide.

9. The method of claim 8, wherein the palladium catalyst is Pd(PPh3)2Cl2, the base is potassium acetate, and the solvent is acetonitrile.

10. The method of any one of claims 7 to 9, wherein the method further comprises preparing compound (7): Compound (6) was treated with a brominating agent in the presence of a deprotonating agent in a suitable organic solvent: 。 11. The method of claim 10, wherein the brominating agent is 1,2-dibromo-1,1,2,2-tetrafluoroethane, the deprotonating agent is lithium diisopropylaminodimethylamine, and the solvent is tetrahydrofuran.

12. The method of claim 10, further comprising preparing compound (6): Compound (5) was treated with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxane in a suitable organic solvent in the presence of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide and a base. 。 13. The method of claim 11, further comprising preparing compound (6): Compound (5) was treated with 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxane in a suitable organic solvent in the presence of (S)-2-((3-(tert-butyl)-2-hydroxybenzyl)amino)-N,N,3-trimethylbutanamide and a base. 。 14. The method of claim 12 or 13, wherein the base is sodium tert-butoxide and the organic solvent is a mixture of methanol and toluene.

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