A scalable method for the preparation of GLYT-1 inhibitors

Abstract

The present invention relates to a synthetic method for the preparation of compound (1) and its precursors. Compound (1) is prepared by reaction of isoxazole (2) with phenyl ether (R)-3-ONa. JPEG2025527633000018.jpg61144

Description

[Technical Field]

[0001] The present invention relates to a scalable synthetic method for preparing a specific bicyclo[3.1.0]hex-3-ylmethanone (Compound 1) that has inhibitory activity against glycine transporter 1 (GlyT-1). The method is suitable for producing Compound 1 on a multi-kilogram scale. [Background technology]

[0002] Dysfunction of glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors has been implicated in the pathogenesis of CIAS. Various strategies to enhance glutamatergic transmission have been investigated in patients with schizophrenia. One approach involves increasing synaptic levels of glycine, a coagonist required for NMDA receptor-mediated signaling. Inhibitors of glycine transporter-1 (GlyT1) are thought to increase synaptic glycine levels, thereby enhancing glutamatergic neurotransmission and downstream neuroplasticity processes. Therefore, activation of NMDA receptors by inhibiting GlyT1 may provide an option for treating psychosis, schizophrenia (positive symptoms, negative symptoms, and cognitive symptoms), dementia, and other diseases in which cognitive processes are impaired, such as attention deficit disorder, Alzheimer's disease, or other neurological and psychiatric disorders. Inhibition of GlyT1 is of particular interest for the cognitive impairment associated with schizophrenia.

[0003] Compound 1 is described in WO2013 / 017657. Compound 1 is a potent and selective GlyT1 inhibitor and is being investigated in patients with schizophrenia in a phase II trial. Compound 1: [ka] ([5-(methylsulfonyl)-2-{[(2R)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]{(1R,5R)-1-[5-(trifluoromethyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone) WO2013 / 017657 describes the preparation of compound 1, which has been prepared according to Scheme 1.

[0004] In the initial route, racemic isoxazole 2 and chiral (R)-3 were prepared as the two main building blocks and then coupled to give an equal mixture of diastereomers 1 and 4, which could only be resolved through laborious preparative HPLC chromatography. Example 1 of WO2008 / 107334 describes the synthesis (subkilogram scale) of (S)-3-OH by coupling 2-fluoro-5-methanesulfonyl-benzoic acid (10) with (S)-trifluoro-isopropanol in an autoclave using cesium carbonate as a base. Alternatively, a procedure is described using 10 and (S)-trifluoro-isopropanol in the presence of KOtBu in a double-jacket vessel. WO2008 / 107334 further describes the conversion of 2-fluorobenzoic acid to 10 in 45% overall yield via a two-step procedure via the corresponding sulfonyl chloride. Summary of the Invention

[0005] An object of the present invention is a safe, efficient, and scalable manufacturing process that provides for multi-kilogram scale production of Compound 1. This object has been achieved by providing the methods described herein. Scheme 1 [ka]

[0006] Show me how The method according to the invention is summarized in the following outline: A description of the individual steps follows. overview: [ka]

[0007] Rh-catalyzed asymmetric hydrogenation of 7 using the solid, air-stable ligand t-Bu-SMS-Phos·2HBF4 (8) afforded (R)-1,1,1-trifluoropropan-2-yl acetate (9) in excellent yield and enantioselectivity (99% yield and 98–99% ee) (Scheme 2) [J. Sieber, S. Rodriguez, R. Frutos, F. Buono, Y. Zhang, N. Li, B. Qu, A. Premasiri, Z. Li, Z. Han, Y. Xu, D. Byrne, N. Haddad, J. Lorenz, N. Grinberg, D. Kurouski, H. Lee, B. Narayanan, L. Nummy, J. Mulder, J. Brown, A. Granger, M. Krawiec, Z. Williams, S. Pennino, J. Song, A. Hossain, N. Yee, C. Busacca, F. Roschangar, Y. Xin, Z. Mao, X. Zhang, Y. Hong, C. H. Senanayake, J. Org. Chem. 2018, 83, 1448]. The product can be directly distilled from the hydrogenation reaction mixture, yielding a distillate containing exclusively 9 in THF, which can be used for further processing. Surprisingly, the residual Rh catalyst or phosphoryl ligand does not adversely affect the subsequent nucleophilic aromatic substitution, making it possible to use the hydration reaction mixture directly—without distillation—for the synthesis of phenyl ether (R)-3-OH). Purging of the residual Rh catalyst and phosphoryl ligand is possible in downstream processes without affecting the quality of the final API.

[0008] Scheme 2 [ka]

[0009] Step A: Synthesis of methyl sulfone 10 2-Fluorobenzoic acid is treated with chlorosulfonic acid in CH2Cl2, followed by an aqueous workup. The crude organic layer is treated with sodium sulfite and sodium bicarbonate, followed by the addition of diisopropylamine and chloroacetic acid. The crude methylsufone 10 is recrystallized from acetonitrile. Step 1: Synthesis of phenyl ether (R)-3-OH In situ deacetylation of acetate 9 with a strong base such as n-BuLi or KOH gave the alkoxide of trifluoropropanol, which was converted to 10 by S N Addition in the Ar mode gives 3 in good yield. The use of acetate 9 avoids the problems associated with isolating the volatile trifluoro-isopropanol (6). The crude solution of acetate 9 obtained from the hydrogenation of 7 is used without prior distillation of acetate 9.

[0010] Step 2: Synthesis of sodium salt 3-ONa The carboxylic acid (R)-3 can then be converted to its crystalline sodium salt (R)-3-ONa to eliminate possible impurities, ensure that the quality of the produced material is consistently within the required specifications, and in particular to further increase the enantiomeric excess of (R)-3-ONa, thereby reducing the formation of diastereoisomers of compound 1.

[0011] Scheme 3 [ka]

[0012] Step 3: Synthesis of enolate (R,R)-12 The carboxylic acid (R,R)-13 can be prepared by the reaction of (R)-epichlorohydrin with diethyl malonate according to a modification of the procedure described by Lee and coworkers (J. Org. Chem. 2007, 72, 7390), followed by in situ reduction with NaBH4 / ethanol to give the corresponding diol (WO2010 / 007032; Shuto et al. Org. Lett. 2013, 15, 1686), which can be converted to the corresponding bis-mesylate (WO2010 / 0070325; WO2016 / 0144637). Further elaboration with aqueous ammonia and protection with Boc anhydride gives the ethyl ester of (R,R)-13, which can be hydrolyzed with LiOH. Carboxylic acid (R,R)-13 is treated with MeLi to give the corresponding methyl ketone after protonation, which can be directly followed by deprotonation with lithium tert-butoxide and condensation with ethyl trifluoroacetate to give the enolate (R,R)-12, which is isolated as a solid.

[0013] Step 4: Synthesis of dihydroisoxazole (R,R)-14 Reaction of the enolate (R,R)-12 with hydroxylamine hydrochloride affords the dihydroisoxazole (R,R)-14 as a mixture of epimers. Step 5: Synthesis of isoxazole (R,R)-2 Dehydration of dihydroisoxazole (R,R)-14 with thionyl chloride directly affords the deprotected isoxazole (R,R)-2, which can be isolated as the hydrochloride salt ((R,R)-2·HCl) or as the free base ((R,R)-2). The use of the free base (R,R)-2 has the advantage that the synthesis is simplified (no further addition of HCl / HCl-containing solutions) and more cost-effective without adverse effects in terms of impurities or isolation.

[0014] Step 6: Coupling to Compound 1 WO 2013 / 017657 describes the use of HATU / EtN in DMF to achieve the final coupling of the two fragments (R,R)-2 and (R)-3-OH. However, other reagents, such as isobutyl chloroformate (IBCF), propanephosphonic anhydride (T3P), or SOCl2, have been found to mediate the coupling efficiently and at lower cost. Scheme 4 [ka]

[0015] Step A: The coupling of (R,R)-2·HCl with (R)-3-OH was carried out on a pilot plant scale using T3P (50% solution in EtOAc) in DMF. The resulting product could be isolated after crystallization from isopropanol and heptane. Steps B and C: Thionyl chloride is added to a suspension of the sodium salt of the phenyl ether (R)-3-ONa in toluene, the suspension is heated to 80° C., further stirred, and then concentrated under vacuum to give the acid chloride (R)-3-Cl. Isoxazole (R,R)-2 is dissolved in Me-THF in a separate reaction vessel and NEt3 is added. The resulting solution is mixed with the acid chloride solution. After the reaction is complete, the mixture is poured into water and the two phases are separated. The organic phase is concentrated. Isopropanol is added and concentrated again. The remaining solution is heated to about 70° C. Heptane (or alternatively isopropanol / heptane) and seed crystals are added and slowly cooled to give compound 1 in crystalline form. DETAILED DESCRIPTION OF THE INVENTION

[0016] Step A: Synthesis of methyl sulfone 10 According to a first aspect of the present invention, there is provided a process for preparing methyl sulfone 10, which comprises reacting 2-fluorobenzoic acid with chlorosulfonic acid, followed by treatment with sodium sulfite and chloroacetic acid. The process is preferably carried out without isolation of any intermediates, e.g., preferably without isolation of the corresponding sulfonyl chloride. The crude methyl sulfone 10 can be recrystallized from acetonitrile.

[0017] Step 1: Synthesis of phenyl ether 3-OH According to a further aspect of the present invention, there is provided a method for preparing (R)- or (S)-5-(methylsulfonyl)-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid, which comprises reacting (R)- or (S)-1,1,1-trifluoropropan-2-yl acetate (9) with methyl sulfone 10 in the presence of a strong base. In one embodiment, the strong base is selected from the group consisting of n-BuLi, KOH, NaOH, KOtBu. In certain embodiments, the strong base is KOH. In one embodiment, DMSO, THF, NMP or a mixture thereof is used as the solvent. Preferably, DMSO or a mixture of DMSO and THF is used as the solvent. In one embodiment, a solution of methyl sulfone 10 in DMSO is added to a solution of (R)- or (S)-1,1,1-trifluoro-2-propanol 6, which is prepared in situ by adding acetate (R)- or (S)-9 to a solution of strong base (preferably KOH) in DMSO and THF.

[0018] With n-BuLi, the formation of 5-methyl-5-nonanol is observed as a by-product, which may interfere with the isolation process. The above method using KOH as the base completes the conversion of methyl sulfone 10 and allows for the removal of KF and / or KOAc by simple filtration after cooling the mixture to 20° C. Thus, the formation of HF during workup (acidification) is largely avoided. According to a preferred embodiment, the crude solution of acetate 9 obtained from the hydrogenation of 7 is used, i.e., the reaction mixture obtained from the Rh-catalyzed asymmetric hydrogenation of 7 is subjected to coupling with methyl sulfone 10 without distillation of acetate 9 or other treatment to reduce the Rh content. Step 2: Synthesis of sodium salt (R)-3-ONa According to a further embodiment, the phenyl ether (R)-3 is converted to the sodium salt (R)-3-ONa and isolated as a crystalline compound. In one embodiment, NaOH is used in the conversion. In a particular embodiment, the conversion is carried out using NaOH in iPrOH. Due to the conversion to the sodium salt (R)-3-ONa, this method allows for the easy isolation of the crystalline compound, effectively eliminating possible impurities and enriching for the desired enantiomer.

[0019] Step 3: Synthesis of enolate 12 In a further embodiment, carboxylic acid 13 is reacted with MeLi, followed by quenching, deprotonation, and addition of ethyl trifluoroacetate to give enolate 12. In one embodiment, MeLi in diethoxymethane is used. In one embodiment, aqueous NH4Cl is used for quenching. In one embodiment, LiOtBu or LiN(TMS)2 are used for deprotonation, preferably LiOtBu is used. Step 4: Synthesis of dihydroisoxazole 14 In a further embodiment, the enolate 12 is converted to the dihydroisoxazole 14 using hydroxylamine. In one embodiment, the hydroxylamine is applied in the form of its hydrochloride salt. In one embodiment, the conversion to 14 is carried out in iPrOH, in MeOH, or in a mixture of iPrOH and water. Step 5: Synthesis of isoxazole 2 In a further embodiment, dihydroisoxazole 14 is converted to isoxazole (R,R)-2 as the free base. In one embodiment, the dehydrating agent is selected from the group consisting of SOCl2 and (COCl)2. In certain embodiments, the dehydrating agent is SOCl2. In one embodiment, the solvent is selected from CH3CN, H2O, MTBE, or a mixture thereof.

[0020] Step 6: Coupling to Compound 1 Step A: According to a further embodiment, a solution of T3P in EtOAc is added to a solution of the phenyl ether (R)-3-ONa-OH in DMF, followed by the addition of a solution of the isoxazole 2 in DMF. Steps B and C: According to one embodiment, acid chloride (R)-3-Cl is used in reaction with isoxazole 2 to give compound 1. According to a further embodiment, the sodium salt (R)-3-ONa is converted to the corresponding acid chloride ((R)-3-Cl) and then coupled with isoxazole 2 to give compound 1. In one embodiment, SOCl is used for the conversion to the acid chloride. Toluene, DMF, THF, or CHCl may be used as a solvent. Toluene is preferably used as the solvent for the conversion to the acid chloride. In one embodiment, a solution of isoxazole 2 is added to a solution of acid chloride in toluene. In a more particular embodiment, a solution of isoxazole 2 in Me-THF is added to a solution of acid chloride (optionally in the presence of triethylamine).

[0021] List of abbreviations δ chemical shift br wide line 13C carbon 13 d double line DEM Diethoxymethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide ESI electrospray ionization 1 H proton HRMS high-resolution mass spectrometry LC / MSD Liquid Chromatography / Mass Selective Detector m multiplet m / z mass-to-charge ratio Me-THF 2-Me-THF MHz Megahertz MS mass spectrometry MTBE Methyl tert-butyl ether NMP N-methylpyrrolidinone NMR nuclear magnetic resonance spectroscopy q quartet RT room temperature s single line t triple line T3P Propanephosphonic Anhydride THF tetrahydrofuran TMS Tetramethylsilane

[0022] Synthesis Examples and Experimental Data All reactions were carried out under a nitrogen atmosphere unless otherwise noted. NMR spectra were recorded on a 400 MHz NMR spectrometer. Chemical shifts are reported in ppm relative to tetramethylsilane. Coupling constants (J) are reported in Hertz and are referred to as apparent peak multiplicities, which may not necessarily reflect true coupling constants. High-resolution mass spectrometry data were obtained by flow injection using an LC / MSD TOF (time-of-flight) mass spectrometer in electrospray positive ionization mode. Commercially available starting materials were used as received without further purification. Step A: Preparation of methyl sulfone 10 Vessel 1 is charged with 2-fluorobenzoic acid (126 kg) and dichloromethane, stabilized with amylene (335 kg). The resulting suspension is heated to reflux. Chlorosulfonic acid is mixed into the reaction mixture. First, a small amount of chlorosulfonic acid (90 kg) is charged, followed by a sufficient amount (277 kg) under reflux conditions. In parallel, dichloromethane is distilled off to reach a reaction temperature above 90°C (between 90°C and 100°C) at the end of the chlorosulfonic acid addition. The contents of the vessel are stirred for at least 60 minutes at a preferred internal temperature of 95°C. The reaction mixture is then cooled to an internal temperature of 10-20°C.

[0023] In Vessel 2, a mixture of water (1008 kg) and dichloromethane (922 kg) is cooled to 0-10°C. The contents of Vessel 1 are combined in Vessel 2 at an internal temperature below 25°C, and dichloromethane (512 kg) is flushed into Vessel 1, with the residue being transferred to Vessel 2. The contents of Vessel 2 are stirred for approximately 15 minutes at 15-25°C. The layers are then separated, and the aqueous layer is re-extracted with dichloromethane (461 kg). The organic layers are combined and transferred to Vessel 3. Water (504 kg), sodium sulfite (101 kg), and sodium bicarbonate (151 kg) are charged to vessel 4 and heated to a preferred internal temperature of 55°C. The contents of vessel 3 are mixed into vessel 4 over at least 60 minutes, while maintaining the internal temperature of vessel 4 at a preferred temperature of about 55°C. Vessel 3 is rinsed with dichloromethane (169 kg) and the residue is charged to vessel 4 (during the mixing of the dichloromethane solution and stirring at 50-60°C, dichloromethane is distilled off in parallel). The reactor contents of vessel 4 are stirred at 50-60°C for at least 60 minutes. The reactor contents of vessel 4 are heated to 65°C and diisopropylamine (130 kg) is charged to vessel 4 at an internal temperature between 50-80°C. A solution of water (148 kg) and chloroacetic acid (112 kg) is mixed in vessel 4 at an internal temperature between 50 and 80°C, water (108 kg) is drained into the chloroacetic acid vessel, and the residue is charged to vessel 4. The reaction mixture is heated to above 100°C and stirred at this temperature for more than 10 hours. The reactor contents are then cooled to 75 to 85°C. After the internal temperature of the reaction mixture is brought to 70 to 80°C, 36% hydrochloric acid (209 kg) is charged while maintaining the internal temperature between 70 and 80°C. The reaction mixture is cooled to 55 to 65°C and stirred for at least 15 minutes, after which it is cooled, preferably to 20°C. The suspension is isolated by centrifugation, and water (756 kg) is drained onto the wet cake. The product is dried under vacuum at a maximum temperature of 60°C to yield 123.9 kg (63.1%) of crude dried product 10.

[0024] A vessel is charged with crude methyl sulfone 10 (109.4 kg) and acetonitrile (259.3 kg). The suspension is heated to reflux and stirring is continued at reflux for at least 30 minutes. The contents of the vessel are cooled from the reflux temperature to an internal temperature between 13 and 23°C. The suspension is stirred at this temperature for at least 30 minutes. The product is isolated by centrifugation and the wet cake is washed with acetonitrile (109 kg). The product is dried under vacuum at a maximum temperature of 60°C to yield 94.7 kg (86.5%) of dried product 10.

[0025] Example 1 (Step 1): Preparation of phenyl ether (R)-3-OH (R)-5-(methylsulfonyl)-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid Step A n-BuLi in hexane (10.6 L, 2.5 M solution, 26.4 mol) was added to crude 9 (11.3 kg, 19.0% w / w To a solution of 10 (2.38 kg, 96.8% by weight; 13.7 mol) in THF was slowly added, maintaining the internal temperature below 30°C, and the resulting mixture was stirred at ambient temperature for 1 h. A solution of 10 (2.38 kg, 96.8% by weight; 10.6 mol) in THF (9.2 L) and NMP (2.3 L) was charged to the reactor originally containing the solution of 9 and n-BuLi, and the resulting mixture was stirred under reflux (63-65°C) for a minimum of 1 h. The mixture was quenched with 2 N HCl (14.0 L, 28.0 mol) and concentrated by distillation under reduced pressure at 40-45°C to a total volume of approximately 18-19 L. The mixture was then extracted with ethyl acetate (23.0 L), washed with 5% aqueous NaCl (7.0 kg), and distilled to a minimum stirrable volume (7-8 L). Methanol (18.0 L) was charged, and distillation was continued until the volume was approximately 10-11 L. Water (9.0 L) was charged at 40-45°C and distillation was continued until the volume reached approximately 6-7 L. The mixture was allowed to reach ambient temperature and the resulting solid was collected by filtration, rinsed sequentially with water (18.0 L) and heptane (18.0 L), and then dried in a vacuum oven at 45-50°C for a minimum of 10 hours to give 2.9 kg (88.0% yield) of (R)-3-OH as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.47 (d, J = 6.4 Hz, 3H), 3.25 (s, 3H), 5.50 (m, 1H), 7.59 (d, J = 8.8 Hz, 1H), 8.07 (dd, J = 2.4, 8.8 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 13.3 (br, 1H); 13C NMR (75 MHz, DMSO-d6) δ 13.7, 44.1, 72.6 (q, J = 23.8 Hz), 116.2, 124.0, 124.9 (q, J = 209.5 Hz), 129.11, 130.5, 132.3, 134.4, 158.9, 166.2.

[0026] Step B The hydrogenation vessel 1 is charged with 3,3,3-trifluoropropenyl-2-acetate 7 (77 kg). A separate portable stirred tank, inertized with argon, is charged with the catalyst Rh(nbd)2BF4 (280 g) and the ligand t-Bu-SMS-Phos·2HBF48 (644 g), flushed with tetrahydrofuran (231 kg), and the contents are then charged to the hydrogenation vessel. Potassium tert-butylate (20%) in THF (924 g) is charged to the separate portable stirred tank, inertized with argon, flushed with tetrahydrofuran (42.5 kg), and the contents are then charged to the hydrogenation vessel. Hydrogenation is carried out at an internal temperature of 20-40 °C and at p = 1.5 bar of hydrogen until completion. The acetate 9 solution is filtered into a portable tank and poured into the hydrogenation vessel using 17.2 kg of THF. Dimethyl sulfoxide (149 kg) is charged to vessel 2 and heated to an internal temperature of 45-55°C. Methyl sulfone 10 (90 kg) is then charged to vessel 2 at an internal temperature of 45-55°C and stirred until a clear solution is obtained.

[0027] Dimethyl sulfoxide (98 kg), potassium hydroxide (84 kg), and tetrahydrofuran (121 kg) are then placed in vessel 3, and the internal temperature is adjusted to 25-35° C. Then, acetate 9 solution (345 kg) is mixed into vessel 3 at an internal temperature of 25-35° C., and tetrahydrofuran (18 kg) is poured into the transfer vessel, and the residue is placed in vessel 3. The contents of vessel 2 are then mixed into vessel 3 at an internal temperature of 20-60°C for 15-35 minutes. Dimethyl sulfoxide (50 kg) is poured into vessel 2, and the residue is poured into vessel 3. The resulting solution is stirred for at least 60 minutes at an internal temperature of 45-60°C. The reaction solution is then cooled to an internal temperature of 15-25°C. The reaction solution is filtered through a filter cascade and poured into vessel 4. Tetrahydrofuran (81 kg) is poured through the filter and poured into vessel 4. The reaction solution in vessel 4 is heated to an internal temperature of 50-65°C, and the solvent is distilled off under vacuum (100 mbar or more) at an internal temperature of 50-65°C. Water (180 kg) is added to vessel 4 at an internal temperature of 50-65°C, followed by the addition of 36% aqueous HCl (73 kg) while maintaining the internal temperature in the 50-65°C range, and finally, water (34 kg) is added while maintaining the internal temperature in the same range. The contents of the vessel are stirred at 50-65°C for 15-30 minutes, and water (146 kg) is mixed within at least 15 minutes at an internal temperature of 50-65°C. The resulting mixture is stirred for 15-30 minutes and then cooled linearly to 15-25°C over 60-90 minutes. The suspension is isolated by centrifugation, and water (900 kg) is poured onto the wet cake. The product is dried under vacuum at a maximum temperature of 60°C to yield 106 kg (82%). The EE value of the product (R)-3-OH is 99.38%.

[0028] Example 2 (Step 2): Preparation of sodium salt (R)-3-ONa Sodium (R)-5-(methylsulfonyl)-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoate Step A The carboxylic acid (R)-3-OH (20.1 kg, 63.1 mol) was charged to a jacketed reactor under nitrogen, followed by 2-propanol (225 L), and the resulting mixture was stirred at 70-75°C for a minimum of 0.5 hours (homogeneous solution). 50% sodium hydroxide solution (5.35 kg, 66.9 mol) was charged, and stirring was continued at 70-75°C for a minimum of 1 hour. A suspension of (R)-3-ONa seed crystals (0.2 kg, 0.59 mol) in 2-propanol (10.0 L) was added, and the batch was stirred at 65-70°C for a minimum of 2 hours. The batch was then linearly cooled to 20-25°C over approximately 4 hours. The resulting solid was collected by filtration, rinsed with 2-isopropanol (50 L), and then dried in a vacuum oven at 45-50° C. for a minimum of 10 hours to give 18.6 kg (98.8% by weight) of product, 86.3% yield. 1 H NMR (400 MHz, DMSO-d6) δ 1.42 (d, J = 6.4 Hz, 3H), 3.16 (s, 3H), 5.32 (m, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 2.4, 8.8 Hz, 2H), 7.87 (d, J =2.4 Hz, 1H); 13 C NMR (75 MHz, DMSO-d6) δ 14.2, 44.3, 73.3 (q, J = 23.0 Hz), 118.4, 125.4 (q, J = 210.3 Hz), 127.2, 128.8, 134.5, 136.0.

[0029] Step B Vessel 1 is charged with phenyl ether (R)-3-OH (140 kg) and isopropanol (964 kg). The mixture is heated to an internal temperature of 65-75°C and stirring is continued until a clear solution is obtained. 45% sodium hydroxide solution (40 kg) is added at an internal temperature of 65-75°C, followed by seed crystals (0.5 kg), and stirring is continued at this temperature for 10-60 minutes. The vessel contents are cooled to 15-25°C within 45-120 minutes. The product is isolated by centrifugation, and the wet cake is washed with isopropanol (310 kg). The product is dried under vacuum at a maximum temperature of 80°C to yield 138.5 kg (92%). The EE value of the product, 3-ONa, increases to 99.82%, compared to 99.38% for the (R)-3-OH step.

[0030] Example 3 (Step 3): Preparation of enolate (R,R)-12 Carboxylic acid (R,R)-13 (175 kg) is dissolved in THF (467 kg) and cooled to -20 °C. A solution of MeLi (8% in diethoxymethane, 487 kg) is added at -25 to -10 °C, and the reaction mixture is stirred at this temperature for 3 h. The reaction mixture is poured into a solution of ammonium chloride (26 kg) and water (499 kg) at 10 to 35 °C. THF is removed by vacuum distillation at a maximum temperature of 60 °C. Methyl tert-butyl ether (648 kg) is added to the residue, and the phases are separated. The organic layer is concentrated by vacuum distillation at a maximum temperature of 60 °C. THF (467 kg) is added to the residue, and the solution is concentrated by vacuum distillation at a maximum temperature of 60 °C. Lithium tert-butoxide (20% in THF, 309 kg) is added at -5 to 10°C, followed by ethyl trifluoroacetate (115 kg) at -5 to 10°C. The mixture is stirred at 15 to 25°C for at least 60 minutes. The reaction mixture is poured into a solution of ammonium chloride (18 kg) in water (333 kg) at 15 to 35°C. The organic solvent is removed by vacuum distillation at a maximum temperature of 60°C. Methyl tert-butyl ether (882 kg) is added to the residue and the phases are separated. The organic layer is concentrated by vacuum distillation at a maximum temperature of 60°C. Methanol (455 kg) is added to the residue and seed crystals are added at a temperature of 30°C. The suspension is cooled to 20°C and stirred at this temperature for 60 minutes. Water (980 kg) is added and stirred at 20°C for 30 minutes. The suspension is cooled to 10°C and stirred at this temperature for 60 minutes. The product is isolated by centrifugation, washed with water (320 kg), and then dried under vacuum at a maximum temperature of 60° C. to yield 173.9 kg (69%).

[0031] Example 4 (Step 4): Preparation of dihydroisoxazole (R,R)-14 Vessel 1 is charged with enolate 12 (149 kg) and isopropanol (317 kg). The resulting suspension is stirred for approximately 20 minutes at 20-30°C. An aqueous solution of hydroxylamine hydrochloride (180 kg, 23.2% aqueous solution) is mixed into the reaction mixture over 20-40 minutes, maintaining the internal temperature between 20-30°C. The reaction mixture is stirred for a preferred period of 3 hours at 20-30°C. Water (932 kg) is then charged to vessel 1 over 20-35 minutes. The suspension is stirred for 12-15 hours at 15-25°C. The suspension is isolated by centrifugation, and water (394 kg) is drained onto the wet cake. The product is dried under vacuum at a maximum temperature of 60°C to yield 129.1 kg (84.4%) of dried product.

[0032] Alternative synthetic routes Preparation of tert-butyl (1R,5R)-1-acetyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (enolate (R,R)-12): Carboxylic acid (R,R)-13 (22.4 kg, 94.8%, 93.4 mol) and THF (105 L) were charged to a reactor under nitrogen. The mixture was cooled to -15±5°C, and a solution of MeLi in diethoxymethane (3.0 M, 71.6 L, 215 mol) was slowly charged while maintaining an internal temperature of -10 to -15°C. The batch was then stirred for an additional 2 hours at -10°C, and upon completion, a 5% solution of ammonium chloride (3.3 kg in 62 L of water) was charged. The mixture was distilled under reduced pressure at approximately 40-50°C to a minimum stirrable volume to remove most of the THF and DEM (diethoxymethane). tert-Butyl methyl ether (149 L) was then charged, and the mixture was stirred at 20-25°C for 5-10 minutes. The layers were allowed to settle, the bottom aqueous layer was discarded, and the organic portion was washed with 5% ammonium chloride solution (3.3 kg of ammonium chloride in 62 L of water). The mixture was then concentrated by distillation under reduced pressure at 40-45°C to a minimum stirrable volume. Tetrahydrofuran (105 L) was then charged. The mixture was then concentrated by distillation under reduced pressure at 40-45°C to a minimum stirrable volume to give 30 kg of crude ketone (52.9 wt% solution, 75.2% yield), which was used in the next chemical step. For characterization purposes, an analytical sample was prepared by purification by silica gel chromatography. 1 H NMR (400 MHz, CDCl3) δ 0.93-0.97 (m, 1H), 1.45 (s, 9H), 1.61 (dd, J = 4.8, 8.4 Hz, 1H), 2.04-2.11 (m, 4H), 3.40-3.43 (m, 1H), 3.56-3.81 (m, 3H); 13 C NMR (75 MHz, CDCl3, rotamer mixture) δ 19.4, 19.9, 25.6, 26.7, 27.4, 28.4, 28.6, 47.3, 47.4, 47.5, 47.6, 79.8, 154.9, 205.1. HRMS (ESI) [C 12 H 20 NO3] + Calculated value: 226.14377, observed value: 226.14385.

[0033] tert-Butyl (1R,5R)-1-(5-hydroxy-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate ((R,R)-14): LiN(TMS)2 (79.7 L, 79.7 mol of a 1.0 M solution in THF) was charged to a reactor under nitrogen and then cooled to -20 to -15 °C. Crude ketone in THF (28.6 kg, 66.5 mol of a 52.4% solution in THF) was then added slowly, maintaining the internal temperature below -10 °C. The mixture was stirred at -15 to -10 °C for approximately 1 hour, and ethyl trifluoroacetate (11.9 L, 99.8 mol) was added slowly, maintaining the internal temperature at -15 to -5 °C. The reaction mixture was then allowed to reach ambient temperature (20 to 25 °C) over 2 hours. The batch was cooled to 0 to 5 °C, and 5% aqueous NH4Cl (45.8 kg) was slowly charged, maintaining the internal temperature below 35 °C. The mixture was concentrated by distillation under reduced pressure at 30 to 35 °C until a volume of approximately 83 to 85 L was reached. The mixture was then cooled to 20-25°C, MTBE (150 L) was charged, and the batch was stirred at 20-25°C for approximately 15 minutes. The layers were then separated, and the aqueous layer was discarded. The organic layer was then washed with 5% aqueous NH4Cl (45.8 kg) and then concentrated by distillation under reduced pressure at 35-40°C until the volume was reduced to approximately 37-38 L. Methanol (150 L) was charged, and the batch was filtered through a charcoal cartridge (12" x 9" activated carbon), and after rinsing the filter cartridge with methanol (60 L), the batch was concentrated by distillation under reduced pressure at 35-40°C until the volume was reduced to approximately 80-85 L. The crude diketone (protonated enolate (R,R)-12, ([C 14 H 18 F3NO4] +The resulting solution, containing HRMS (ESI) calculated 322.12607, found 322.12626, was cooled to 20-25°C and a 47% solution of hydroxylamine hydrochloride (5.54 kg in 7.45 L of water) was charged, and the mixture was stirred for 1 h. Water (90 L) was slowly charged over approximately 30 min, the mixture was stirred for 4 h, and the resulting solid was collected by filtration. The filter cake was rinsed sequentially with water (60 L) and heptane (30 L) and then dried in a vacuum oven at 45-50°C for a minimum of 8 h to give 22.4 kg (99.2% by mass, 99.3% yield) of the (R,R)-14 product as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 0.72 (m, 1H), 1.8 (obs m, 1H), 1.33 (s, 9H), 1.95-2.041 (m, 1H), 2.90 (m, 1H), 3.28-3.60 (m, 5H); 13 C NMR (75 MHz, DMSO-d6, rotamer mixture) δ 16.0, 16.5, 23.6, 24.0, 24.4, 24.9, 25.9, 26.8, 42.8, 42.9, 47.7, 48.0, 48.4, 48.5, 48.6, HRMS (ESI) [C 14 H 20 F3N2O4] + Calculated value 337.13697, observed value 337.13696

[0034] Example 5 (Step 5): Preparation of isoxazole (R,R)-2 3-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(trifluoromethyl)isoxazole hydrochloride ((R,R)-2) Dihydroisoxazole (R,R)-14 (18.7 kg, 99.2% by weight, 55.2 mol) was charged to a reactor at ambient temperature, followed by acetonitrile (37.0 L). The mixture was heated to 35-40°C and thionyl chloride was charged. The mixture was heated to 40-45°C and stirred for 2 hours. Isopropyl acetate (223 L) was charged, and the mixture was concentrated by distillation under vacuum at 40-45°C to a minimum stirrable volume to remove the acetonitrile. The mixture was cooled to 20-25°C, and an additional 130 L of isopropyl acetate was charged, followed by 60.3 kg of 2N sodium hydroxide solution. After stirring for 5-10 minutes, the layers were allowed to settle, the aqueous layer was collected and discarded, and the organic layer was washed with water (18.5 L). The organic layer was filtered through a charcoal cartridge (12" x 9" activated carbon). After rinsing the filter cartridge with isopropyl acetate (37.1 L), the batch was concentrated by distillation under reduced pressure at 35-45°C to a volume of approximately 55 L. Hydrochloric acid (13.8 L, 82.7 mol, 5-6 N solution in isopropanol) was then charged over 15 minutes, maintaining the internal temperature at approximately 35-40°C. The internal temperature was raised to 50-55°C, and seed crystals of isoxazole 2 (185 g) were added. The mixture was heated to 50-55°C, and heptane (148 L) was slowly charged over approximately 2 hours. The mixture was cooled linearly to 20-25°C, and the resulting solid was collected by filtration to give 13.2 kg (94% yield) of product 2 as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (t, J = 7.6 Hz, 1H), 1.73 (t, J = 5.8 Hz, 1H), 2.33 (m, 1H), 3.40 (d, J = 11.2 Hz, 1H), 3.47 (dd, J = 4.0, 11.6 Hz, 1H), 3.64 (d, J = 11.2, 1H), 3.70 (d, J = 11.6 Hz, 1H), 7.52 (d, J = 0.8 Hz, 1H), 10.0 (br, 2H); 13C NMR (75 MHz, DMSO-d6) δ 15.6, 24.5, 25.8, 46.7, 46.9, 105.8, 118.2 (q, J = 201 Hz), 157.2 (m), 164.9; 10 F3N2O] + Calculated value: 219.07397, observed value: 219.07415.

[0035] Example 5b (Step 5): Preparation of isoxazole (R,R)-2 as the free base 3-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(trifluoromethyl)isoxazole ((R,R)-2 as the free base) Thionyl chloride (63 kg) was added in three portions to a stirred suspension of dihydroisoxazole (R,R)-14 (155 kg) in acetonitrile (367 kg) at 10–20°C. After each addition, the reaction mixture was stirred for 1–2 h at 10–20°C. The reaction mixture was then stirred for 5 h at 15–25°C. It was then poured into water (450 kg) at 15–25°C. The acetonitrile was removed by vacuum distillation at a maximum temperature of 70°C. MTBE (217 kg) was then added, the phases were separated, and the organic layer was discarded. Residual MTBE was removed from the aqueous layer by vacuum distillation at a maximum temperature of 50°C. After the addition of water (503 kg), 45% aqueous NaOH (97 kg) was added at a temperature of 10–25°C to obtain a suspension. The suspension was cooled to 15°C and stirred at this temperature for 60 minutes. The product was isolated by centrifugation, washed with water (580 kg), and then dried under vacuum at a maximum temperature of 30° C. to give 87.5 kg (87%).

[0036] Example 6 (Step 6): Preparation of Compound 1 ([5-(methylsulfonyl)-2-{[(2R)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]{(1R,5R)-1-[5-(trifluoromethyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone)

[0037] Step A: Isoxazole (R,R)-2 (14.4 kg, 343 mol) and DMF (22.0 L) were charged to a reactor at ambient temperature under nitrogen. The internal temperature was adjusted to 10-15°C, and a 50% solution of T3P in ethyl acetate (30.9 L, 51.8 mol) was charged over 30 minutes while maintaining the internal temperature at 10-15°C. The mixture was then stirred for approximately 20 minutes. A solution of (R)-3-OH (11.0 kg, 254.6 mol) in DMF (17.6 L) was prepared and slowly charged to the reactor over approximately 30 minutes while maintaining the internal temperature at 10-15°C. The vessel containing the (R)-3-OH / DMF solution was rinsed with DMF (4.4 L) to transfer the residue to the reactor, and the mixture was stirred for approximately 3 hours. The internal temperature was adjusted to 10-15°C, and triethylamine (15.1 L, 108 mol) was slowly charged to the reactor over approximately 45 minutes, maintaining the internal temperature at 10-15°C. The mixture was stirred for 20 minutes, the temperature was adjusted to 20-25°C, and the mixture was stirred at 20-25°C for 12 hours. Water (55.0 L) was charged, and the mixture was extracted twice with ethyl acetate (55.0 L per extraction). The combined organic layers were washed first with 8.0% aqueous NaHCO3 (55.0 L) and then with water (55.0 L). The mixture was concentrated by distillation (40-50°C, reduced pressure) to approximately 30 L, isopropanol (101 L) was added, and the mixture was then concentrated by distillation (50-55°C, reduced pressure) to a minimum stirrable volume. Additional isopropanol (101 L) was added, and the mixture was then concentrated (50-55°C, reduced pressure) to give 73.4 kg of a solution containing 27.8% by mass of product 1 (20.4 kg). Additional isopropanol (9.9 L) was charged to bring the concentration of the solution of compound 1 in isopropanol to 25% by mass, and the temperature was raised to 65-75°C. Heptane (51.0 L) was then charged, followed by a suspension of seed crystals of 1 (154 g) in heptane (1.54 L), maintaining the temperature at 65-75°C. The mixture was then linearly cooled to ambient temperature (20-25°C) over 6 hours, and the resulting solid was collected by filtration, and the reactor and cake were washed with heptane (44.0 L).The material was then dried in a vacuum oven under reduced pressure at 45-50° C. for 12 hours to give 19.1 kg (98.7% by weight, 85.2% yield) of product as a white solid. 1 H NMR (400 MHz, CDCl3, 1:1 mixture of rotamers at ambient temperature) δ 1.15 (t, J = 5.2 Hz, 1H), 1.42 (q, J = 7.6 Hz, 1H), 1.56 (m, 3H), 1.99-2.12 (m, 2H), 3.07 (d, J = 1.6 Hz, 3H), 3.34 (d, J = 10.8 Hz, 0.5H), 3.55 (d, J = 11.2 Hz, 0.5 H), 3.60-3.68 (m, 1H), 3.91-4.04 (m, 1H), 4.25 (d, J = 12.0 Hz, 0.5H), 4.47 (d, J = 12.0 Hz, 1H), 4.86 (m, 1H), 6.50 (d, J = 0.8 Hz, 0.5H) 6.38 (d, J = 0.8 Hz, 0.5H), 7.13 (d, J = 8.8 Hz, 1H), 7.90 (t, J = 2.4 Hz, 1H), 7.98 (dt, J = 8.8 Hz, 2.4 Hz, 1H); 13 C NMR (75 MHz, CDCl3, 1:1 mixture of rotamers at ambient temperature) δ 13.7, 17.4, 23.2, 24.2, 25.1, 25.8, 44.6, 47.3, 48.6, 49.6, 72.7, 73.0, 73.3, 73.6, 102.7, 103.2, 114.1, 116.3, 119.0, 122.5, 125.3, 18.3, 129.1, 130.6, 135.0, 155.9, 158.9, 159.3, 163.8, 165.7; HRMS (ESI) [C 20 H 19 F6N2O5S] + Calculated value: 513.09134, observed value: 513.09164.

[0038] Step B Thionyl chloride (17.40 kg, 146.3 mol) was slowly added to the sodium salt (R)-3-ONa (19.55 kg, 58.49 mol) in toluene (61.0 kg) at 55° C. The mixture was heated to 80° C. within 30 minutes, stirred for at least 30 minutes, and then cooled to 50° C. Toluene was removed by distillation at 50° C. to a minimum stirrable volume. Toluene (101.7 kg) was added and distilled off again. Me-THF (28.54 kg) was added.

[0039] To a solution of isoxazole (R,R)-2 (12.75 kg, 58.44 mol, as free base) in Me-THF (65.57 kg) in a separate vessel, triethylamine (7.12 kg, 70.36 mol) was added. The resulting solution was slowly added to the acid chloride solution, maintaining the temperature below 30°C. The solution was further stirred for at least 30 min. Water (117.3 kg) was added at 20°C and further stirred for at least 15 min. The organic layer was concentrated by distillation at 50°C to a minimum stirrable volume. Isopropanol (60.6 kg) was added and distilled off (twice). The mixture was heated to 70°C, stirred for 15 min, and isopropanol / n-heptane (1 / 5 v / v, 206.6 kg) was slowly charged. Seed crystals (0.12 kg) were added, and the mixture was cooled to 55°C within 1.5 h and then cooled to 20°C. The resulting solid was collected, washed with isopropanol / heptane, and dried under reduced pressure to give Compound 1 (23.95 kg of crude product as a white solid, 80% mass recovery).

[0040] Step C Thionyl chloride (43.7 kg) is added to the sodium salt (R)-3-ONa (80.5 kg) in toluene (453 kg) at 55-80°C over 10-30 minutes. The mixture is heated to 80°C within 30 minutes and stirred at this temperature for 3 hours. The reaction mixture is concentrated by vacuum distillation at a maximum of 70°C. Toluene (418 kg) is added and distilled off again. 2-MeTHF (193 kg) is then added. In a separate reactor, 29.5 kg of triethylamine is added to a solution of isoxazole 2 (50.0 kg) in 2MeTHF (260 kg) at 15-25°C. The resulting solution is slowly added to the solution of acid chloride at 15-35°C, and the reaction mixture is stirred at 20°C for 40 minutes. It is then added to water (724 kg). The phases are then separated, and the organic layer is concentrated under vacuum at a maximum of 70°C. 2-Propanol (652 kg) is then added, and the reaction mixture is concentrated again under vacuum at up to 70°C, followed by the addition of another portion of 2-propanol (652 kg). n-Heptane (695 kg) is added to this solution at 60-70°C, followed by the addition of seed crystals (0.5 kg). The resulting suspension is cooled to 20°C over 2 hours. It is then warmed to 65°C and stirred at this temperature for at least 30 minutes, after which it is cooled again to 20°C over 2 hours. The product is isolated by centrifugation, washed with n-heptane (360 kg), and dried at up to 60°C to yield 99.8 kg (85%) of compound 1.

Claims

1. A method for preparing compound 1, comprising reacting a phenyl ether (R)-3-OH, its sodium salt (R)-3-ONa, or the corresponding acid chloride ((R)-3-Cl) with an isoxazole (R,R)-2 or (R,R)-2.HCl to obtain compound 1, preferably by reacting (R)-3-Cl or (R)-3-OH with an isoxazole (R,R)-2 or (R,R)-2.HCl to obtain compound 1. 【Chemical 1】

2. 2. The process according to claim 1, characterized in that T3P in EtOAc is added to a solution of the phenyl ether (R)-3-OH or (R)-3-ONa, preferably to a solution of (R)-3-ONa, followed by the addition of a solution of the isoxazole 2.

3. 2. The method of claim 1, wherein the acid chloride (R)-3-Cl is reacted with dissolved isoxazole 2.

4. 4. The method according to claim 3, characterized in that the acid chloride (R)-3-Cl is prepared from the sodium salt of phenyl ether (R)-3-ONa.

5. 5. The process of claim 4, wherein a solution of isoxazole 2, for example a solution of isoxazole 2 in Me-THF, is added to the solution of the acid chloride (R)-3-Cl.

6. Phenyl ether (R)-3-OH 【Chemistry 2】 2. A method for preparing a compound comprising the steps of: 【Chemistry 3】 Methyl sulfone 10 【Chemistry 4】 in the presence of KOH to obtain (R)-3-OH.

7. 7. The method of claim 6, wherein the reaction is carried out using a solvent selected from the group consisting of dimethyl sulfoxide (DMSO) or a mixture of DMSO and THF.

8. 8. The method of claim 6 or 7, characterized in that the methyl sulfone 10 is prepared by reacting fluorobenzoic acid with chlorosulfonic acid, followed by reaction with sodium sulfite and chloroacetic acid.

9. 9. A process according to any one of claims 6 to 8, characterized in that the phenyl ether (R)-3-OH is further converted to the sodium salt (R)-3-ONa, preferably by use of NaOH, for example by use of NaOH in iPrOH.

10. 10. The process according to claim 6, wherein 3,3,3-trifluoropropenyl-2-acetate (7) is converted to acetate 9 in a Rh-catalyzed hydrogenation reaction, and the crude hydrogenation solution is subjected to the process according to claim 6.

11. Enolate (R,R)-12 【Chemistry 5】 1. A method for preparing a carboxylic acid (R,R)-13 【Chemistry 6】 with methyllithium and CF 3 CO 2 A method for preparing the enolate (R,R)-12 comprising reacting with Et.

12. The product of the reaction of (R,R)-13 with methyllithium is quenched and reacted with, for example, NH 4 quenched with aqueous Cl, then deprotonated and converted to, for example, LiOtBu or LiN(TMS) 2 and then deprotonated with CF 3 CO 2 The method of claim 11 , wherein the reactant is reacted with Et.

13. The enolate (R,R)-12 was converted to the dihydroisoxazole (R,R)-14 using hydroxylamine. 【Chemistry 7】 13. The method of claim 11 or 12, further comprising converting

14. Isoxazole (R,R)-2 【Chemistry 8】 2. A method for preparing a compound according to claim 1, wherein the dihydroisoxazole (R,R)-14 is reacted with SOCl 2 and (COCl) 2 A method for preparing isoxazole (R,R)-2, comprising treating the compound with a reagent selected from the group consisting of:

15. Isoxazole (R,R)-2 is dihydroisoxazole (R,R)-14 【Chemistry 9】 with a reagent selected from the group consisting of thionyl chloride and oxalyl chloride to obtain (R,R)-2.

16. 16. The method of any one of claims 1 to 5 or 15, characterized in that the phenyl ether (R)-3-OH is prepared as described in any one of claims 6, 7 or 8.

17. 【Catalog 10】 A compound selected from the group consisting of:

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