Method for producing GLP1 RA and its intermediates

Abstract

The present invention relates to the synthesis of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one or a salt thereof, and related synthetic intermediate compounds.

Description

[Technical Field]

[0001] Disclosed herein are methods for the synthesis of the GLP-1 receptor agonist 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (herein GLP1RA), or a hydrate of a salt thereof. [Background technology]

[0002] GLP1RA is described and claimed in US Pat. No. 10,858,356.

[0003] U.S. Patent No. 10,858,356 describes a synthetic method for preparing GLP1RA. Nevertheless, there exists a need for alternative methods for preparing compounds. The methods described herein offer one or more advantages over known methods because they involve different intermediates. In one embodiment, the methods are more robust and efficient. In one embodiment, the methods are more scalable. In one embodiment, the methods provide higher yields. DETAILED DESCRIPTION OF THE INVENTION

[0004] GLP1RA can be prepared as a pharmaceutically acceptable salt. One salt of GLP1RA is the hemicalcium salt of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one (referred to herein as "GLP1RA(1 / 2)Ca"). 2+ ") and has the structure shown below.

[0005] [ka]

[0006] GLP1RAs can be prepared as hydrates of pharmaceutically acceptable salts. One hydrate of GLP1RA is hemicalcium hydrate of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one ("GLP1RA(1 / 2)Ca"). 2+ hydrate).

[0007] [ka]

[0008] In one embodiment, there is provided herein a compound having the following structure:

[0009] [ka] 1. A method for producing compound 6 of the formula: The following structure:

[0010] [ka] A method is disclosed that includes a multi-step chemical reaction starting from compound 1 of the formula:

[0011] In one embodiment, the above method comprises the step of:

[0012] [ka] Starting from compound 5:

[0013] [ka] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. via Compound 6:

[0014] [ka] This involves a multi-step chemical reaction that results in

[0015] In one embodiment, R is phenyl or benzyl. In another embodiment, R is phenyl. In another embodiment, R is benzyl.

[0016] In one embodiment, the above method comprises the reaction step of converting compound 1 into compound 2 as shown below:

[0017] [ka] Includes.

[0018] In one embodiment, the above method includes a reaction step of converting compound 2 to compound 3 as shown below:

[0019] [ka] Further includes:

[0020] In one embodiment, the above method comprises the reaction step of converting compound 3 to compound 4 as shown below:

[0021] [ka] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynylphenyl or benzyl. In one embodiment, R is phenyl or benzyl.

[0022] In one embodiment, R is phenyl. In another embodiment, R is benzyl.

[0023] In one embodiment of the reaction of compound 3 to compound 4, the method includes reacting compound 3 with CDI in a solvent, followed by coupling with (R)-4-benyl-2-oxazolidone in the presence of 1,8-doazabicyclo[5.4.0]undec-7-ene in a solvent.

[0024] In one embodiment of the reaction of compound 3 to compound 4, the method includes reacting compound 3 with CDI in a solvent, followed by coupling with (R)-4-phenyl-2-oxazolidone in the presence of 1,8-doazabicyclo[5.4.0]undec-7-ene in a solvent.

[0025] In one embodiment, the above method comprises the reaction step of converting compound 4 to compound 5 as shown below:

[0026] [ka] wherein R is phenyl or benzyl. In one embodiment, R is phenyl. In another embodiment, R is benzyl.

[0027] In one embodiment of the reaction of compound 4 to compound 5, the method comprises the copper-mediated addition of 2-methylallylmagnesium chloride to compound 4 in the presence of lithium chloride to provide compound 5.

[0028] In one embodiment, the above method includes the reaction step of converting compound 5 to compound 6 as shown below:

[0029] [ka] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. In one embodiment, R is phenyl or benzyl. In one embodiment, R is phenyl. In another embodiment, R is benzyl.

[0030] In one embodiment of the above process from compound 5 to compound 6, the reaction step comprises reducing compound 5 with lithium borohydride to give compound 6.

[0031] In one embodiment, the above method comprises the following multi-step reaction starting from compound 1 to arrive at compound 6:

[0032] [ka] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. In one embodiment, R is phenyl or benzyl. In one embodiment, R is phenyl. In another embodiment, R is benzyl.

[0033] In one embodiment, there is provided herein a compound having the following structure:

[0034] [ka] 12. A method for producing compound 12 of the formula: The following structure:

[0035] [ka] A method is disclosed that involves a multi-step chemical reaction starting from compound 6 of the formula:

[0036] In one embodiment, the above method comprises the step of:

[0037] [ka] Starting from compound 7:

[0038] [ka] via compound 10:

[0039] [ka] via compound 11:

[0040] [ka] via compound 12:

[0041] [ka] This involves a multi-step chemical reaction that results in

[0042] In one embodiment, the above method comprises the reaction step of converting compound 6 to compound 7 as shown below:

[0043] [ka] Includes.

[0044] In one embodiment, the above method comprises the reaction step of converting compound 10 to compound 11 as shown below:

[0045] [ka] Further includes:

[0046] In one embodiment, the above multi-step process from compound 6 to compound 12 comprises the following reactions: converting compound 6 to compound 7 and converting compound 10 to compound 11:

[0047] [ka] Includes.

[0048] In one embodiment, there is provided herein a compound having the following structure:

[0049] [ka] 20. A method for producing compound 20 of the formula: The following structure:

[0050] [ka] A method is disclosed that involves a multi-step chemical reaction starting from compound 19 of the formula:

[0051] In one embodiment, the above method comprises the step of:

[0052] [ka] Starting from compound 20:

[0053] [ka] This involves a multi-step chemical reaction that results in

[0054] In one embodiment, the above method comprises the reaction step of compound 19 to compound 20 as shown below:

[0055] [ka] and the reaction step comprises coupling compound 19 with (diphenylmethylene)hydrazine using a catalyst selected from Pd(OAc)2 and Xantphos to obtain compound 20.

[0056] In one embodiment, the above method comprises the reaction step of converting compound 20 to compound 21 as shown below:

[0057] [ka] Further includes:

[0058] In one embodiment, the above method comprises a multi-step reaction to produce compound 24 starting from compound 21 as shown below:

[0059] [ka] Includes.

[0060] In one embodiment, there is provided herein a compound having the following structure:

[0061] [ka] Compound 3 of the formula:

[0062] In one embodiment, there is provided herein a compound having the following structure:

[0063] [ka] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. Compound 4 of the formula:

[0064] In one embodiment, there is provided herein a compound having the following structure:

[0065] [ka] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. Disclosed is compound 5, wherein R is phenyl or benzyl. In one embodiment, R is phenyl. In another embodiment, R is benzyl.

[0066] In one embodiment, there is provided herein a compound having the following structure:

[0067] [ka] Compound 6 of the formula:

[0068] In one embodiment, there is provided herein a compound having the following structure:

[0069] [ka] Compound 20 of the formula is disclosed.

[0070] In one embodiment, there is provided herein a compound having the following structure:

[0071] [ka] The compound of formula (I) is disclosed.

[0072] Unless otherwise defined herein, certain abbreviations are as follows: ACN - acetonitrile; aq.-aqueous; Bn-benzyl; CDI-1,1'-carbonyldiimidazole; COMU-1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate; CSTR - Continuously Stirred Tank Reactor; DBU-1,8-diazabicyclo[5.4.0]undec-7-ene; DCM - dichloromethane; DEA - diethylamine; DIPEA-N,N-diisopropylethylamine; DMAc - dimethylacetamide; DMF - dimethylformamide; DMI-1,3-dimethyl-2-imidazolidinone; DMSO - dimethyl sulfoxide; DSC - Differential Scanning Calorimetry; ESI-electrospray ionization; EtOAc - ethyl acetate; EtOH - ethanol and ethyl alcohol; h-time HATU-1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; HPLC - High Performance Liquid Chromatography; HRMS-high resolution mass spectrometry; IPA - Isopropanol and isopropyl alcohol; IPAc - isopropyl acetate; KF - Karl Fischer titration; MeOH - methanol and methyl alcohol; 2-MeTHF-2-methyltetrahydrofuran; min-minutes mp-melting point MTBE - methyl tert-butyl ether; NMM - N-methylmorpholine; NMP-1-methyl-2-pyrrolidinone; NMR-Nuclear Magnetic Resonance; NMT - below; Ph - phenyl; Pd(OAc)2 - palladium(II) acetate; QNMR - quantitative nuclear magnetic resonance; TBAB - tetrabutylammonium bromide; TEA - triethylamine; THF - tetrahydrofuran; TOF-MS-Time-of-Flight Mass Spectrometer It is defined as follows:

[0073] Scheme 1

[0074] [ka] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. In one embodiment, R is benzyl or phenyl. In one embodiment, R is phenyl. In another embodiment, R is benzyl.

[0075] Scheme 1, Step A, shows the formation of the acid chloride of compound 1 using oxalyl chloride in a solvent such as ACN, followed by reaction with N-methylaniline to yield compound 2. Numerous methods exist for performing the amide coupling, whether by generating the acid chloride or by using an amide coupling reagent such as SOCl, AcO, PivCl, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), Boc anhydride, T3P, DCC, DIC, CDI, EDC, HATU, HBTU, TBTU, TPTU, TBTU, TPTU, cyanuric chloride, CDMT, or DMTMM. Additionally, various solvents can be used, such as toluene, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO, or CPME. The reaction can be carried out at temperatures ranging from −10°C to 100°C. In one embodiment, the reaction temperature ranged from 0°C to 40°C.

[0076] Step B shows the Heck coupling between compound 2 and acrylic acid to give compound 3. Numerous methods exist for performing the Heck coupling using various catalyst-ligand combinations, such as tetrakis(triphenylphosphine) [Pd(PPh3)4], palladium(0), palladium chloride (PdCl2), palladium(II) acetate [Pd(OAc)2], allylpalladium(II) chloride dimer [PdCl(C3H5)2], Pd(dppf)Cl2, and Pd(dtbpf)Cl2. Various solvents can be used, such as toluene, MeCN, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO, or CPME. The reaction can be carried out at temperatures ranging from -10°C to 150°C. In one embodiment, the reaction temperature was 40°C to 100°C.

[0077] Step C depicts the reaction of compound 3 with CDI in a solvent such as ACN, followed by coupling with the appropriate oxazolidinone in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent such as N,N-dimethylacetamide to give compound 4. Many additional methods exist for performing the amide coupling, whether by generating an acid chloride or by using an amide coupling reagent such as SOCl, AcO, PivCl, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), Boc anhydride, T3P, DCC, DIC, EDC, HATU, HBTU, TBTU, TPTU, TBTU, TPTU, cyanuric chloride, CDMT, or DMTMM. Also, various solvents such as toluene, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO, or CPME can be used. The reaction can be carried out at a temperature ranging from -10°C to 100°C. In one embodiment, the reaction temperature was 0°C to 40°C.

[0078] Step D depicts the copper-mediated addition of 2-methylallylmagnesium chloride to compound 4 in the presence of lithium chloride to give compound 5. Combinations of other Grignard reagents, such as 2-methylallylmagnesium bromide and 2-methylallylmagnesium iodide, can be used with salts such as LiBr or LiI and Cu reagents such as CuBr or CuI in solvents such as EtO, MTBE, THF, 2-MeTHF, or CPME. The reaction in Step D can be carried out at temperatures ranging from -80°C to 20°C. In one embodiment, the reaction temperature was -60°C to -10°C.

[0079] Step E depicts the reduction of compound 5 with lithium borohydride to give compound 6. Many other reducing agents exist, such as NaBH, BH, LAH, H, DIBAl, or Red-Al, and suitable solvents are selected from toluene, THF, 2-MeTHF, DCM, MTBE, and CPME. The reaction of Step E can be carried out at a temperature ranging from -80°C to 80°C. In one embodiment, the temperature was -40°C to 80°C.

[0080] Step F depicts the cyclization of compound 6 to compound 7 using p-toluenesulfonic acid monohydrate in a solvent such as cyclopentyl methyl ether. This step can be carried out using MsOH, TsOH, H2SO4, HCl, or TFA, as well as other acid / solvent combinations such as toluene, MeCN, MTBE, THF, 2-MeTHF, DCM, or dioxane. The reaction in Step E can be carried out at temperatures ranging from -10°C to 100°C. In one embodiment, the temperature was 20°C to 80°C.

[0081] Step G depicts the alkylation of compound 7 with chloroacetonitrile using a suitable base such as potassium hydroxide and catalytic tetrabutylammonium chloride hydrate in a solvent such as toluene to give compound 8.

[0082] Step H depicts the reaction of compound 8 and (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide using a suitable base such as potassium bis(trimethylsilyl)amide or lithium t-butoxide in a suitable solvent such as THF to give compound 9.

[0083] Step I depicts the addition of hydroxylamine to compound 9 to give compound 10 in a suitable solvent such as IPA or THF.

[0084] Step J depicts the intramolecular cyclization of compound 10 to give compound 11 using CDI and a suitable base such as DBU in a solvent such as THF. This cyclization can be carried out using other reagents such as DCC, DIC, EDC, phosgene, diphosgene, triphosgene, dimethyl carbonate, diethyl carbonate, PivCl, ethyl chloroformate, isobutyl chloroformate, Boc anhydride, EEDQ, oxalyl chloride, CO2, along with other bases such as pyridine, pyrrolidine, pyrrole, triethylamine, DIPEA, methylamine, diethylamine, ethyldimethylamine, imidazole, diisopropylamine, Barton's base, NaOH, NaOMe, NaOEt, NaOtBu, in other solvents such as 2-MeTHF, toluene, IPA, isopropyl acetate, DMF, DMI, EtOAc, EtOH, MeOH, acetonitrile, DMAc, dioxane, iBuOAc, MTBE, DCM, CPME, DMSO, NMP, and the like, at temperatures ranging from 0° C. to 150° C. In one embodiment, the temperature was 5° C. to 40° C.

[0085] Step K depicts the hydrolysis of compound 11 using a base such as sodium t-butoxide in the presence of water in a solvent such as DMI, followed by acidification with aqueous H2SO4 to give compound 12.

[0086] Scheme 2

[0087] [ka] Scheme 2, Step A, depicts the reaction of compound 13 with methanesulfonic anhydride using a base such as TEA in a solvent such as DCM to give compound 14. Step B depicts the nucleophilic substitution of compound 14 using sodium cyanide and a phase transfer catalyst such as TBAB in a solvent such as DMF to give compound 15. Step C depicts the acidic deprotection of compound 15 with HCl in a solvent such as DCM to give compound 16. Step D depicts the addition of compound 16 to ethyl acrylate using a suitable base such as TEA in a solvent such as EtOH, followed by protection with di-tert-butyl dicarbonate to give compound 17. Step E depicts the cyclization of compound 17 using a base such as potassium t-butoxide in a solvent such as THF to give compound 18.

[0088] Scheme 3

[0089] [ka] Scheme 3, Step A, depicts the coupling of compound 19 and (diphenylmethylene)hydrazine using a suitable catalyst / ligand system such as Pd(OAc)2 and Xantphos, a base such as NaOH, and a solvent system such as tert-amyl alcohol or toluene and water to give compound 20. Step B depicts the acidic deprotection of compound 20 with HCl in a solvent such as dioxane to give compound 21. Alternatively, deprotection can be carried out using acetic acid and water.

[0090] Scheme 4

[0091] [ka] Scheme 4, Step A, depicts the coupling of compounds 18 and 21, followed by cyclization using a suitable base such as NMM in a solvent such as NMP to give compound 22. Step B depicts the addition of (N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide) to compound 22 using a base such as potassium t-butoxide in a solvent such as DMAc to give compound 23. Step C depicts the intramolecular cyclization of compound 23 using methanesulfonic acid in a solvent such as THF to give compound 24.

[0092] Scheme 5

[0093] [ka] Scheme 5, Step A, depicts the lithiation of compound 25 followed by reaction with DMF in a solvent such as 2-MeTHF to give compound 26. Step B depicts the addition of methylhydrazine to compound 27 in a solvent such as EtOH to give compound 27. Step C depicts the intramolecular cyclization of compound 27 using CuCl and a base such as DBU in a solvent such as DMI to give compound 28.

[0094] An alternative route to compound 28 begins with Step A1, in which compound 29 is treated with acetic anhydride in a solvent such as toluene to give compound 30. Step B1 depicts the cyclization of compound 30 using isoamyl nitrite in a solvent such as toluene to give compound 31. Step C1 depicts the methylation of compound 31 using methyl iodide, a base such as potassium carbonate, and a solvent such as DMF to give compound 28.

[0095] Scheme 6

[0096] [ka] Scheme 6, Step A, depicts the coupling of compounds 24 and 28 using a base such as potassium carbonate and a catalyst / ligand system such as CuCl and trans-N,N'-dimethylcyclohexane-1,2-diamine in a solvent such as DMI to give compound 32. Step B depicts the deprotection of compound 32 with methanesulfonic acid in a solvent such as ACN to give compound 33.

[0097] Scheme 7

[0098] [ka] Scheme 7, Steps A and B, show that when compound 12 is treated with a coupling reagent such as HATU or COMU and a base such as DIPEA in a solvent such as THF, DMI, and DMAc, compound 34 is formed, followed by an amide coupling between compounds 34 and 33 to give compound 35. Step C shows that compound 35 is treated with NaOH and calcium acetate dihydrate in a solvent system such as water and EtOH to give a compound of Formula I.

[0099] There are many possible combinations of solvents, bases, and calcium salts that can be used to carry out this reaction. In one embodiment, suitable solvents were selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, toluene, dichloromethane, dimethyl sulfoxide, tert-butyl methyl ether, dimethylacetamide, and 1,4-dioxane. Suitable bases were selected from sodium ethoxide, sodium tert-butoxide, potassium hydroxide, potassium ethoxide, potassium tert-butoxide, sodium tert-amylate, sodium hydride, and sodium bis(trimethylsilyl)amide. Suitable calcium salts were selected from calcium acetate, calcium citrate, calcium lactate, calcium gluconate, calcium chloride, calcium sulfate, calcium nitrate, calcium iodide, and tricalcium phosphate. This process can be carried out at temperatures ranging from 0°C to 150°C. In one embodiment, the temperature was 0°C to 50°C.

[0100] Preparation 1 5-Bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0101] [ka] A reactor was charged with ACN (7951 kg), 5-bromo-1H-indole-2-carboxylic acid (991 kg, 4.13 kmol), and oxalyl chloride (654 kg, 5.15 kmol). A solution of DMF (151 kg, 2.07 kmol) in ACN (958 kg) was added dropwise at 20°C to 30°C, and the mixture was stirred at 20°C to 30°C for 45 minutes. N-methylaniline (550 kg, 5.13 kmol) was added at 0°C to 20°C and stirred for 2 hours. TEA (1080 kg, 10.67 kmol) was added at 0°C to 20°C and stirred for 2 hours. Water (1456 kg) was added, and the mixture was stirred at 20°C to 30°C for 2 hours, then filtered. The resulting wet cake was rinsed sequentially with ACN (2907 kg) and water (4845 kg), then dried under vacuum at 50-80°C to constant weight to give the title compound as a solid (1288.4 kg, 92%). Melting point (DSC): 259.2°C. 1 H NMR(DMSO-d6)δ 3.39(br s,3 H),5.27(s,1 H),7.23(dd,J=8.78Hz,1.76Hz,1 H),7.34-7.52(m,7 H),11.81(s,1 H). 13 C NMR (DMSO-d6) δ 38.91, 105.25, 112.48, 114.60, 123.99, 126.51, 128.08, 128.47, 128.87, 130.16, 131.89, 134.60, 144.48, 161.56. TOF-MS (ESI) m / z calculated: 328.0211, found: 329.0308 (M+H).

[0102] Alternative preparation 1 A reactor was charged with 5-bromo-1H-indole-2-carboxylic acid (4.96 g, 20.66 mmol), DMF (0.81 mL, 10.5 mmol), and ACN (50 mL). A solution of oxalyl chloride (2.38 mL, 27.46 mmol) in ACN (10 mL) was added at a rate such that the temperature remained below 30°C. After the addition, the reaction was vigorously stirred at ambient temperature for 60 minutes. The reaction temperature was then adjusted to 5°C, and N-methylaniline (2.75 mL, 25.4 mmol) was added slowly, maintaining the internal temperature below 10°C. After stirring for 10 minutes, TEA (7.0 mL, 50 mmol) was added slowly to the mixture, maintaining the internal temperature below 30°C. The mixture was stirred at ambient temperature for 2 hours and quenched with water (5 mL). The resulting slurry was stirred at ambient temperature for 1 hour, filtered, and the resulting wet cake was washed sequentially with ACN (15 mL) and water (25 mL). The wet cake was dried in vacuo at 70° C. for approximately 24 hours to give the title compound as a solid (6.50 g, 96%). Analytical data were consistent with those collected from Preparation 1.

[0103] Preparation 2 (E)-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)acrylic acid

[0104] [ka] A reactor was charged with 5-bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (60 kg, 182.3 mol) and N,N-dimethylacetamide (329 kg). The mixture was heated to 50-60°C and purged with nitrogen. Tri-tert-butylphosphonium tetrafluoroborate (0.64 kg, 2.2 mol) and allylpalladium(II) chloride dimer (0.17 kg, 0.46 mol) were added under a nitrogen atmosphere, and the mixture was purged with nitrogen. N,N-dicyclohexylmethylamine (142 kg, 726.9 mol) and acrylic acid (19.4 kg, 273.4 mol) were added. The reaction was purged with nitrogen and stirred at 50-70°C for 18 hours. 1 M aqueous sulfuric acid (410 kg) was added at 50-70°C until the pH reached 3.68. Water (181 kg) was added and the temperature was adjusted to 5-15°C over 5 hours. The mixture was stirred for 1-3 hours, filtered, and the resulting wet cake was rinsed with water (420 kg) and then dried under vacuum at 50-80°C to constant weight to give the title compound as a solid (52.7 kg, 87%). Melting point (DSC): 293.2°C. 1 H NMR(DMSO-d6)δ 3.39(s,3 H),5.31(s,1 H),6.36(d,J=15.81Hz,1 H),7.38-7.62(m,9 H). 13 C NMR (DMSO-d6) δ 38.91, 106.69, 113.18, 116.31, 123.35, 123.98, 126.70, 127.36, 128.18, 128.52, 130.21, 131.69, 137.04, 144.56, 145.86, 161.57, 168.36. TOF-MS (ESI) m / z calculated: 320.1161, found: 321.1260 (M+H).

[0105] Preparation 3 (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0106] [ka] The reactor was charged with (E)-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)acrylic acid (585 kg, 1.83 kmol) and ACN (5646 kg). CDI (360 kg, 2.22 kmol) was added, followed by an ACN (342 kg) rinse. The reaction was stirred at 5°C to 10°C for 2 hours, filtered, and the resulting wet cake was rinsed with ACN (3440 kg). The wet cake, N,N-dimethylacetamide (4002 kg), (R)-4-benzyl-2-oxazolidinone (401 kg, 2.26 kmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (718 kg, 4.72 kmol) were added sequentially to the reactor. The reaction was stirred at 10°C to 25°C for 1 hour and then quenched with 5N HCl (867.5 kg) to pH 4. The resulting suspension was stirred for 6 to 12 hours and filtered. The wet cake was rinsed with water (2925 kg) and dried under vacuum at 50°C to 80°C to constant weight to give the title compound as a solid (742 kg, 75%). Melting point (DSC): 236.6°C. 1 H NMR(DMSO-d6)δ 2.95-3.12(m,2 H),3.39(s,3 H),4.20(dd,J=8.78Hz,2.76Hz,1 H),4.36(t,J=8.41Hz,1 H),4.72-4.79(m,1 H),5.35(s,1 H),7.18-7.33(m,5 H),7.38-7.52(m,7 H),7.62-7.72(m,2 H),7.79-7.88(m,1 H),11.93(s,1 H). 13 C NMR (DMSO-d6) δ 37.18, 38.89, 55.00, 66.52, 106.85, 113.47, 114.63, 123.16, 124.74, 126.81, 127.31, 127.47, 128.18, 128.56, 129.01, 129.93, 130.21, 131.93, 136.16, 137.33, 144.52, 146.98, 153.98, 161.53, 165.11. TOF-MS (ESI) m / z calculated: 479.1845, found: 480.1945 (M+H).

[0107] Preparation 4 5-((R)-1-((R)-4-benzyl-2-oxooxazolidin-3-yl)-5-methyl-1-oxohex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0108] [ka] The reactor was charged with 0.5 M 2-methylallylmagnesium chloride in THF (1250 kg, 683 mol) and lithium chloride (30 kg, 707.6 mol). The mixture was stirred at 10°C to 25°C for 30 to 90 minutes and cooled to -80°C to -40°C. Copper(I) iodide (134 kg, 703.6 mol) was added at <-30°C, followed by a THF rinse (94 kg). The reaction was stirred at -50°C to -30°C for 10 minutes, and (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (95 kg, 198 mol) was added below -30°C, followed by a THF (143 kg) rinse. The reaction was stirred at -40°C to -20°C for 4 hours and then quenched below 0°C with 10% aqueous ammonium chloride (500 kg). MTBE (232 kg) was added and the layers were separated. Ethylenediamine (31 kg) was added to the organic layer, and the mixture was stirred at 20°C to 30°C for 1 to 3 hours. 10% aqueous ammonium chloride (398 kg) was added and stirred at 20-30°C for 30-60 minutes. The layers were separated, and the organic phase was filtered through a pad of diatomaceous earth. The pad was rinsed with THF (95 kg), and the combined filtrate was washed sequentially with 1% aqueous acetic acid (315 kg) and 10% aqueous ammonium chloride (408 kg). The organics were concentrated to 3-5 volumes and solvent-exchanged under reduced pressure into approximately 39 volumes of EtOH at less than 50°C. The resulting mixture was heated at approximately 80°C until a clear solution was obtained, after which the mixture was cooled to 5-10°C at a rate of 10°C / hr. The resulting suspension was stirred at 5-10°C for 1-3 hours and then filtered. The filter cake was added back to the reactor along with EtOH (2634 kg). The mixture was heated at 78°C until a clear solution was obtained, after which the mixture was cooled to 5-10°C at a rate of 10°C / hr. The resulting suspension was stirred at 5-10°C for 1-3 hours and filtered. The filter cake was dried under vacuum at 55-80°C to constant weight to give the title compound as a solid (81.54 kg, 77%). Melting point (DSC): 158.3°C. 1H NMR(DMSO-d6)δ 1.61(s,3 H),2.25-2.42(m,2 H),2.74-2.89(m,2 H),2.99-3.19(m,2 H),3.35-3.45(m,4 H),4.05-4.14(m,2 H),4.42-4.48(m,1 H),4.58(br d,J=16.56Hz,2 H),5.17(s,1 H),7.05(d,J=8.53Hz,1 H),7.10-7.15(m,3 H),7.22-7.48(m,9 H),11.46(s,1 H). 13 C NMR (DMSO-d6)δ 22.45, 37.07, 38.89, 40.62, 42.30, 45.07, 54.65, 66.42, 105.88, 112.31, 112.87, 120.23, 124.23, 127.17, 127.28, 128.25, 128.43, 128.97, 129.81, 130.15, 130.57, 134.92, 135.70, 136.14, 143.81, 144.74, 153.67, 161.86, 171.69. TOF-MS (ESI) m / z calculated value: 535.2471, measured value: 536.2572 (M+H).

[0109] Replace Modulation 4 The reactor was charged with 0.5 M 2-methylallylmagnesium chloride in THF (1320 kg, 721 mol) and lithium chloride (31 kg, 731.3 mol). The mixture was cooled to −42° C., after which copper(I) iodide (140 kg, 735.1 mol) and (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (100 kg, 208.5 mol) were added at below −30° C. The reaction was stirred at −40° C. to −20° C. for 8 hours and then quenched with 10% aqueous ammonium chloride solution (480 kg). MTBE (220 kg) was added, the contents were stirred for 1 hour, and the layers were separated. Ethylenediamine (63 kg) was added to the organic layer, and the mixture was stirred at 20°C to 30°C for 2 hours. 10% aqueous ammonium chloride solution (400 kg) was added, and the mixture was stirred at 20°C to 30°C for 30 to 60 minutes. The layers were separated, and the organic phase was filtered through a pad of diatomaceous earth. The pad was rinsed with THF (89 kg), and the combined filtrate was washed with 10% aqueous ammonium chloride solution (300 kg). The organic phase was concentrated in vacuo and solvent exchanged to 5 volumes under reduced pressure below 50°C with EtOH (948 kg). EtOH (2370 kg) was added, and the resulting mixture was heated at 80°C until a clear solution was obtained. The mixture was then cooled to 5°C to 10°C over 3 hours. The resulting suspension was filtered, and the filter cake was rinsed with EtOH (100 kg). The solid was dried under vacuum at 50° C.-80° C. to constant weight to give the title compound as a solid (85.8 kg, 76%). Analytical data were consistent with that collected from Preparation 4.

[0110] Alternative Preparation 4-CSTR Process Feed preparation Pump A Feed: A dry 3000 L glass-lined reactor (FLR1) was charged with 0.5 M 2-methylallylmagnesium chloride THF solution (1381.3 kg, 750.7 mol) and LiCl (31.8 kg, 750.7 mol) at 10 °C to 30 °C and stirred for 0.5 h to 1 h as Feed A.

[0111] Pump B Feed: CuI (3 kg, 15.75 mol) in THF (6 L) in a 50 L stirred vessel (FLR5) was used as material B (prepared approximately every 40 min, total CuI: 143.0 kg, 750.1 mol).

[0112] Starting material mixture: A dry 5000 L stainless steel reactor (FLR4) was charged with (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (150 kg, 312.8 mol) and THF (1201.5 kg) at −45° C. to −35° C. The reaction mixture was stirred as Charge C.

[0113] Quench solution: A dry 5000 L stainless steel reactor (FLR6) was charged with citric acid monohydrate (79.5 kg, 378.3 mol) and water (750 kg, 5.0 vol) at 15° C. to 30° C. The solution was stirred for 0.5 to 1 hour.

[0114] Pump and CSTR configuration: Pump 1 was connected from the Material A reactor (FLR1) to CSTR1 (FLR2, 100 L). Pump 2 was connected from the CuI / THF stirred tank (FLR5) to CSTR1 (FLR2), then to CSTR1 (FLR2, 100 L, Cu complex), CSTR2 (FLR3, 100 L, Cu complex), reaction reactor (FLR4), and quench reactor (FLR6). The flow rate of Pump 1 was set to 800 mL / min by the automatic control system. (Residence time in FLR2: 87.5 min, residence time in FLR3: 37.5 min).

[0115] Preparation of CSTR system: Agitation was started in FLR2 and FLR3. THF (150 kg) was pumped through all CSTR stages, after which the pumps were stopped and the THF in CSTR4 was analyzed for residual water by KF until the KF was 500 ppm or less. The two CSTRs (FLR2 and FLR3) were cooled to -45°C to -20°C.

[0116] Start-up and shutdown of the CSTR system: Pump 1 was started to pump Feed A solution into CSTR1 (FLR2). After approximately 40 minutes, Feed B was pumped into CSTR1, and then Feed B was pumped every 40 minutes. The copper complex mixture after CSTR2 was transferred to the 5000 L stainless steel reactor (FLR4) containing (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide / THF with stirring at -45°C to -35°C. The reaction was monitored by HPLC analysis in the reaction reactor (FLR4) for the conversion of (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (IPC spec: 1.0% or less of (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide). The reaction mixture in FLR4 was then transferred to FLR6 for quenching at -10°C to 25°C.

[0117] Workup and isolation: The quenched mixture was diluted with MTBE (600 L, 4 vol). The layers were separated, and the organic layer was washed with 10% aqueous NH4Cl (750 L, 5 vol). Ethylenediamine (94.5 kg, 1.57 kmol) was added to the mixture and stirred at ambient temperature for 1 hour. The mixture was washed three times with 10% aqueous NH4Cl (750 L, 5 vol) and then with 5% aqueous Na2SO4 (750 L, 5 vol). The mixture was solvent-switched to EtOH (3000 L, 20 vol), and the resulting mixture was heated to 80°C and stirred for 2 hours. The batch temperature was adjusted to 5°C over 3 hours and stirred for an additional 3 hours. The resulting suspension was filtered, and the filter cake was rinsed with EtOH (600 L, 4 vol). The compound was dried under vacuum at 70°C to provide the title compound as a solid (130 kg, 80%). Analytical data were consistent with that collected from Preparation 4.

[0118] Preparation 5 (R,E)-N-methyl-5-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-N-phenyl-1H-indole-2-carboxamide

[0119] [ka] The reactor was charged with (E)-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)acrylic acid (20 g, 62.4 mmol) and DMAc (140 mL), and the contents were stirred for 20 minutes to form a clear solution. The internal temperature was cooled to 5 °C, and CDI (11.7 g, 72.2 mmol) was added. The reaction was stirred for 2-4 hours, after which (R)-4-phenyloxazolidin-2-one (17.7 g, 109.4 mmol) and DBU (27.5 g, 180.6 mmol) were added, followed by a DMAc (20 mL) rinse. The reaction was stirred at 20 °C for 4 hours and quenched with 5 N HCl (70 mL) below 40 °C to adjust the pH to 3-5. The resulting suspension was cooled to 0 °C and stirred for an additional 12 hours. The suspension was filtered and the solid was slurried in a mixture of DMAc (140 mL) and water (60 mL). The suspension was filtered and the solid was dried under vacuum at 60° C. for 16 hours to constant weight to give the title compound as a solid (25 g, 80%). 1 H NMR(DMSO-d6)δ 11.94(s,1 H),7.79-7.65(m,2 H),7.62(s,1 H),7.51-7.24(m,12 H),7.58(dd,J=8.5,3.75Hz,1 H),5.35(s,1H),4.79(t,J=8.63Hz,1 H),4.19(dd,J=8.5,3.75Hz,1 H),3.4(s,3 H). 13C NMR (DMSO-d₆) δ 164.6, 161.5, 154.4, 147.1, 144.5, 140.4, 137.4, 131.9, 130.2, 129.3, 128.6, 128.4, 128.2, 127.5, 126.8, 126.3, 124.9, 123.1, 114.7, 113.5, 106.9, 70.6, 57.7, 38.9. TOF-MS (ESI) m / z calculated: 466.1761, found: 466.1774 (M+H).

[0120] Preparation 6 (R)-5-(1-hydroxy-5-methylhex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0121] [ka] A reactor was charged with 5-((R)-1-((R)-4-benzyl-2-oxooxazolidin-3-yl)-5-methyl-1-oxohex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (525 kg, 0.98 kmol) and THF (2658 L). The reaction temperature was adjusted to 20-30 °C, and the mixture was stirred until a clear solution was obtained. Glacial acetic acid (5.4 kg, 89.9 mol), water (10 kg, 555.6 mol), and EtOH (154 kg, 3.34 kmol) were added. The mixture was cooled to -20 °C, and a 2 M solution of lithium borohydride in THF (450 kg, 1 kmol) was added below -5 °C, followed by stirring at 0-10 °C for 15 h. The reaction was quenched with 10% aqueous ammonium chloride solution (2603 L) below 10°C. The mixture was diluted with MTBE (1056 L), the aqueous layer was removed, and the organic layer was washed with water (1570 L). The organic phase was concentrated in vacuo and solvent exchanged twice with MeOH (5498 L) under reduced pressure below 50°C to approximately 10 volumes. The resulting mixture was heated at 65°C until a clear solution was obtained, after which the mixture was cooled to 5-10°C over 5 hours and filtered. The filter cake was rinsed with water (525 L) and dried to constant weight under vacuum at 50-80°C to give the title compound as a solid (279 kg, 74%). Melting point (DSC): 180.5°C. 1 H NMR(DMSO-d6)δ 1.40-1.62(m,4 H),1.64-1.82(m,1 H),2.14-2.33,(m,2 H),2.75-2.95(m,1 H),3.04-3.22(m,2 H),3.38(s,3 H),4.25(t,J=5.14Hz,1 H),4.53(br d,J=12.30Hz,2 H),5.15-5.20(m,1 H),7.00(d,J=8.54Hz,1 H),7.05(s,1 H),7.27-7.34(m,1 H),7.36-7.52(m,5 H),11.46(s,1 H). 13C NMR (DMSO-d6) δ 22.53, 38.91, 39.84, 40.61, 45.74, 59.29, 105.82, 112.30, 120.14, 124.07, 127.24, 128.29, 128.43, 130.18, 130.43, 134.82, 136.68, 144.27, 144.77, 161.89. TOF-MS (ESI) m / z calculated value: 362.1994, measured value: 363.2091 (M+H).

[0122] Replace Modulation 6 A 12,500 L reactor was charged with 5-((R)-1-((R)-4-benzyl-2-oxooxazolidin-3-yl)-5-methyl-1-oxohex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (550 kg, 1.03 kmol) and EtOH (5,500 L). The internal temperature was adjusted to −15° C. and MgCl (100 kg, 1.05 kmol) was charged to the reactor at −15° C. A solution of lithium borohydride in THF (636 kg, 1.41 kmol) was charged at −15° C., and the reaction was stirred at −15° C. for 20 hours, at which point HPLC analysis indicated consumption of starting material [5-((R)-1-((R)-4-benzyl-2-oxooxazolidin-3-yl)-5-methyl-1-oxohex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide: <0.5%]. The reaction was quenched with 10% aqueous NH4Cl (2716 L, 5 vol) and the mixture was concentrated to 4 vol at <50° C. The mixture was extracted with 2-MeTHF (4128 L, 7.5 vol), and the organic layer was washed with water (2756 L, 5 vol). The organic phase was concentrated to approximately 1.5 vol, and MeOH (2758 L, 5 vol) was charged. The contents were concentrated under reduced pressure (-0.09 MPa to 0.1 MPa) to 1.5 volumes below 65°C, and MeOH (2763 L, 5 volumes) was charged. The contents were concentrated under reduced pressure (-0.09 MPa to 0.1 MPa) to 1.5 volumes below 65°C, and MeOH (4408 L, 8 volumes) and water (1728 L, 3 volumes) were added sequentially, and the mixture was heated to 65°C. The mixture was stirred for 2 hours and cooled to 55°C over 1 hour. Seed crystals (2.76 kg, 0.5 wt%) were added, and the resulting suspension was cooled to 5°C over 5 hours, stirred for 8 hours, and filtered. The resulting wet cake was rinsed with water (1650 L, 3 volumes) and dried to constant weight under vacuum at 65°C to provide the title compound as a solid (297 kg, 77%). Analytical data were consistent with those collected from Preparation 6.

[0123] Preparation 7 N-methyl-5-((R)-5-methyl-1-oxo-1-((R)-2-oxo-4-phenyloxazolidin-3-yl)hex-5-en-3-yl)-N-phenyl-1H-indole-2-carboxamide

[0124] [ka] The reactor was charged with (2-methylallyl)magnesium chloride (0.5 M solution in THF, 1381 g, 754.6 mmol) and LiCl (31.8 g, 750.1 mmol). The mixture was adjusted to 25° C. and stirred for 30 minutes. The mixture was cooled to −45° C. and CuI (143.2 g, 751.9 mmol) was added while maintaining the temperature below −40° C. The reaction was further stirred at −45° C. for 30 minutes, after which (R,E)-N-methyl-5-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-N-phenyl-1H-indole-2-carboxamide (100 g, 214.8 mmol) was added. The reaction was adjusted to −35° C. and stirred at −35° C. for 4.5 hours. Aqueous citric acid (0.5 N, 500 mL) was charged over 1 h below 0 °C. The mixture was diluted with MTBE (300 mL), and the layers were separated. The aqueous layer was extracted with THF (500 mL), and the combined organics were washed with 10% aqueous NH4Cl (500 mL). The organics were treated with ethane-1,2-diamine (65 g, 1.08 mol) at 25 °C for 2 h and washed with 10% aqueous NH4Cl (500 mL × 2). The organics were concentrated to 1 to 2 volumes and solvent switched to methyl ethyl ketone (600 mL). The resulting mixture was heated to 75 °C to give a clear solution, which was cooled to 65 °C and seeded. The resulting suspension was stirred at 65 °C for an additional 2 h, after which n-heptane (600 mL) was added at 65 °C over 1.5 h. The slurry was cooled to 25° C. over 2.5 hours and stirred for an additional 8 hours. The suspension was filtered, and the filter cake was rinsed with n-heptane (200 mL) and dried under vacuum at 60° C. for 16 hours to constant weight to give the title compound as a solid (84 g, 80%). 1H NMR(CDCl3)δ 9.40(s,1 H),7.44-7.42(m,3 H),7.28-7.24(m,2 H),7.21-7.19(m,4 H),7.10-7.07(m,3 H),7.02(dd,J=8.5,1.63Hz,1 H),5.10-5.06(m,2 H),4.52(d,J=11.6Hz,2 H),4.29(t,J=8.7Hz,1 H),4.05(dd,J=8.8,3.4Hz,1 H),3.43(s,3 H),3.35-3.31(m,1 H),3.03-3.00(d,J=12.3Hz,1 H),2.23-2.21(d,J=7.0Hz,2 H), 1.51(s,3 H). 13 C NMR (CDCl) δ 171.54, 161.98, 153.68, 144.09, 143.29, 138.99, 135.83, 134.27, 130.02, 129.75, 129.04, 128.61, 128.55, 128.04, 127.74, 125.85, 124.71, 120.69, 112.79, 111.45, 107.06, 69.80, 57.50, 45.68, 41.56, 39.33, 38.98, 22.16. TOF-MS (ESI) m / z calculated: 522.2415, found: 522.2387 (M+H).

[0125] Preparation 8 (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0126] [ka] A reactor was charged with (R)-5-(1-hydroxy-5-methylhex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (147 kg, 405.6 mol), p-toluenesulfonic acid monohydrate (190 kg, 1.0 kmol), and cyclopentyl methyl ether (600 kg). The reaction was heated to 60-70°C for 12 hours and then quenched with 1N aqueous sodium hydroxide solution (1072 L). IPA (147 kg) and n-heptane (1080 L) were added sequentially, and the mixture was cooled to 5-10°C at a rate of 10°C / hour. The resulting suspension was filtered, and the filter cake was rinsed with IPA (147 kg). The wet cake was slurried in a mixture of water (1892 kg) and IPA (218 kg) at 60-70°C for 1 hour and cooled to 20-30°C. The reaction mixture was stirred at 20-30°C for 2 hours and filtered. The filter cake was dried under vacuum at 50-80°C to constant weight to give the title compound as a solid (128.4 kg, 87%). Melting point (DSC): 220.1°C. 1 H NMR(DMSO-d6)δ 0.75-1.75(m,12 H),2.72-2.99(m,1 H),3.54-3.70(m,3 H),5.21(br s,1 H),7.04(s,1 H),7.09(s,1 H),7.21-7.41(m,3 H),7.46(br s,3 H)11.48(br s,1 H). 13 C NMR (DMSO-d6) δ 22.03, 31.99, 34.09, 36.94, 38.82, 44.86, 61.24, 71.65, 105.90, 112.41, 118.77, 123.81, 127.28, 128.17, 128.31, 130.08, 130.56, 134.78, 137.85, 144.75, 161.94. TOF-MS (ESI) m / z calculated: 362.1994, found: 363.2098 (M+H).

[0127] Alternative preparation 8 (R)-5-(1-hydroxy-5-methylhex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0128] [ka] A reactor was charged with N-methyl-5-((R)-5-methyl-1-oxo-1-((R)-2-oxo-4-phenyloxazolidin-3-yl)hex-5-en-3-yl)-N-phenyl-1H-indole-2-carboxamide (20 g, 38.4 mmol), EtOH (160 mL), THF (40 mL), and MgCl (1.85 g, 19.4 mmol). The mixture was cooled to −15° C., and a 2N solution of LiBH in THF (19 mL, 38.0 mmol) was added at −15° C. The reaction was stirred for 16 h and then quenched below 0° C. with 10% aqueous NH4Cl (100 mL). The mixture was warmed to 10° C.-20° C. and concentrated to 5-7 volumes. The remaining mixture was extracted with 2-MeTHF (200 mL x 2). The organic layers were combined and washed with water (100 mL). The organics were solvent exchanged with MeOH (800 mL) and diluted with water (200 mL). The mixture was heated to 60 °C to give a clear solution, which was cooled to 20 °C over 2 hours. The resulting suspension was stirred for an additional 16 hours and filtered. The filter cake was rinsed with water (100 mL) and dried to constant weight under vacuum at 60 °C for 16 hours to give the title compound as a solid (10 g, 70%). Analytical data were consistent with those collected from Preparation 8.

[0129] Preparation 9 (S)-1-(Cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0130] [ka] A reactor was charged with (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (100 g, 0.27 mol) and toluene (1200 mL). The mixture was heated at 50°C for 2 hours and cooled to ambient temperature. Potassium hydroxide (50% by weight, 61.93 g, 1.1 mol) and tetrabutylammonium chloride hydrate (7.35 g, 0.025 mol) were added, and the mixture was cooled to 0°C. A solution of chloroacetonitrile (26.04 g, 0.345 mol) in toluene (200 mL) was added slowly with vigorous stirring, and the reaction was stirred for an additional 2 hours after addition. The aqueous layer was separated, and the organic layer was washed with 5% aqueous sodium bicarbonate solution (300 mL x 5). The organic layer was treated with activated carbon, filtered, and crystallized from a mixture of MTBE (100 mL) and n-heptane (1100 mL). The resulting suspension was filtered, and the filter cake was dried under vacuum at 50° C. to give the title compound (100 g, 90%). Melting point (DSC): 84.3° C. 1 H NMR(CDCl3)δ 1.28(d,J=19.6Hz,6 H),1.54-1.72(m,4 H),2.91-2.95(m,1 H),3.53(s,2 H),3.75-3.86(m,2 H),5.55(s,2 H),5.91(s,1 H),7.17-7.47(m,8 H). 13 C NMR (CDCl) δ 21.76, 31.73, 32.44, 33.83, 37.39, 38.52, 44.73, 61.79, 71.88, 109.15, 110.76, 115.48, 119.86, 124.88, 126.61, 127.01, 127.60, 129.70, 130.18, 135.97, 139.41, 144.64, 162.58. TOF-MS (ESI) m / z calculated: 402.2176, found: 402.2249 (M+H).

[0131] Preparation 10 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0132] [ka] (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (100 g, 0.24 mol) was dissolved in DMF (633 g) and labeled as Solution 1. (R)-4-Methyl-1,3,2-dioxathiolane 2,2-dioxide (110 g, 0.77 mol) was dissolved in THF (200 mL) and labeled as Solution 2.

[0133] A CSTR with four reactors, Reactor A, Reactor B, Reactor C, and Reactor D, was prepared. Solution 1 (5.73 mL / min), Solution 2 (1.71 mL / min), and a 1.0 M solution of potassium bis(trimethylsilyl)amide in THF (6.04 mL / min) were simultaneously pumped into Reactor A at the indicated flow rates while maintaining the internal temperature at -10 °C. The reaction mixture in Reactor A (residence time: 2 min) was continuously pumped into Reactor B. Then, the reaction mixture in Reactor B (residence time: 2 min) was pumped into Reactor C at the same flow rate, and the mixture in Reactor C (residence time: 2 min) was pumped into Reactor D at the same flow rate. After the reaction, the mixture was pumped into a vessel and quenched with 50% aqueous acetic acid to a pH of 5–7 (residence time: 17 min). The quenched mixture was concentrated to remove THF and diluted with ACN (200 mL). Water (330 mL) was added at ambient temperature to precipitate the crude product, and the filter cake was crystallized from a mixture of ACN (400 mL) and water (400 mL). The wet cake was dissolved in ACN (400 mL) at 45° C., filtered to remove sticky material, and water (400 mL) was slowly added to the filtrate. The resulting suspension was slowly cooled to ambient temperature and filtered. The filter cake was dried under vacuum at 50° C. to give the title compound (71 g, 65%). Melting point (DSC): 180.9° C. 1H NMR(CDCl3)δ 1.29(d,J=19.6Hz,6 H),1.76-1.53(m,10 H),1.94-1.80(m,2 H),3.01-2.89(m,1 H),3.54(s,3 H),3.88-3.75(m,2 H),5.89(s,1 H),7.45-7.10(m,8 H). 13 C NMR (CDCl) δ 15.45, 21.77, 24.89, 31.35, 31.75, 33.87, 37.39, 38.40, 44.79, 61.81, 71.89, 109.81, 110.61, 118.28, 119.77, 124.35, 126.59, 126.76, 127.37, 129.57, 132.00, 136.29, 139.34, 144.51, 162.00. TOF-MS (ESI) m / z calculated: 442.2489, found: 442.2526 (M+H).

[0134] Alternative preparation 10 A reactor was charged with (S)-1-(cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (100 g, 0.24 mol), (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (68.8 g, 0.49 mol), and THF (500 mL) at 0 °C. A 2N solution of lithium t-butoxide in THF (805 g, 1.92 mol) was slowly added, and the reaction was stirred for an additional 20 h. The mixture was quenched with 50% aqueous acetic acid (240 g) and diluted with n-heptane (500 mL). The layers were separated, and the organic layer was washed with water (2 × 500 mL). The organic layer was solvent-switched to ACN (500 mL), and water (420 mL) was added. The suspension was filtered and the solid was recrystallized from a mixture of ACN (400 mL) and water (330 mL). The suspension was filtered and the filter cake was dried in vacuo at 50° C. to give the title compound as a solid (78 g, 71%). Analytical data were consistent with those collected from Preparation 10.

[0135] Alternative preparation 10 A reactor was charged with (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (100 g, 275.9 mmol) and toluene (1200 mL). Potassium hydroxide (50 wt%, 123.85 g, 1.1 mol) and tetrabutylammonium chloride hydrate (7.35 g, 24.8 mmol) were added, and the mixture was cooled to 0 °C. A solution of chloroacetonitrile (26 g, 344 mmol) in toluene (200 mL) was added slowly, and the reaction was stirred for an additional hour after the addition. 5 wt% aqueous sodium bicarbonate solution (300 mL) was charged at 0 °C. The mixture was warmed to 20 °C and stirred for 30 minutes. The layers were separated, and the organic layer was washed with 5 wt% aqueous sodium bicarbonate solution (300 mL × 5). Toluene (500 mL) was added to the organic layer, and the resulting organics were filtered through a pad of diatomaceous earth. The pad was rinsed with toluene (300 mL), and the filtrate was allowed to settle, separated, and the aqueous layer removed. The organic layer was circulated through a CUNO column, and the CUNO pad was rinsed with toluene (300 mL). The combined filtrate was azeotroped with toluene to 2 volumes until the KF was 0.1% or less. THF (800 mL) was added, and the mixture was cooled to 0°C. (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (68.81 g, 498 mmol) was added at 0°C, and the resulting mixture was stirred at 0°C for 20 minutes. Lithium t-butoxide (152.39 g, 1.9 mol) was added slowly, and the mixture was stirred for 19 hours. The mixture was quenched with 50% aqueous acetic acid (239 g) and then diluted with n-heptane (500 mL) and water (500 mL). The layers were separated, and the organic layer was washed with water (500 mL). The organic layer was concentrated to approximately 200 mL and solvent-switched to ACN (500 mL). The mixture was heated to 50° C., and water (167 mL) was added. The resulting suspension was stirred at 50° C. for 1.5 hours, cooled to 20° C. over 4 hours, and stirred at 20° C. for 13 hours. Water (280 mL) was added over 3 hours, and the suspension was stirred at 20° C. for 16 hours. The suspension was filtered, and the solid was recrystallized from a mixture of ACN (500 mL) and water (340 mL) to give the title compound as a solid (75.65 g, 62%) after drying under vacuum at 55° C. to constant weight.Analytical data were consistent with that collected from Preparation 10.

[0136] Preparation 11 (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate

[0137] [ka] A vessel was charged with tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate (200 g, 1.14 mol) and DCM (400 mL). The mixture was cooled to 0°C to 5°C. TEA (173.24 g, 1.71 mol) was added over 20 minutes, maintaining the internal temperature below 10°C. A solution of methanesulfonic anhydride (218.71 g, 1.26 mol) dissolved in DCM (600 mL) was added to the reaction over 4 hours, maintaining the internal temperature below 5°C. The reaction contents were stirred at this temperature for an additional 30 minutes. Once the reaction was complete (approximately 30 minutes), water (400 mL) was added over 30 minutes, maintaining the internal temperature below 8°C. The aqueous phase was separated and further extracted with DCM (800 mL). The organic phases were combined and washed sequentially with 10% aqueous citric acid (800 mL), 8% NaHCO3 (800 mL), and 10% aqueous NaCl (800 mL). The organic layer was concentrated in vacuo to approximately 400 mL, and n-heptane (400 mL) was added. The suspension was cooled to 0°C to 10°C and stirred for 2 hours. The resulting mixture was filtered and dried to give the title compound as a solid (290 g, 99% yield). 1 H NMR(CDCl3)δ 4.74-4.62(m,1H),4.25(d,J=9.9Hz,1H),4.16(ddd,J=10.1,4.2,2.0Hz,1 H),3.99(s,1H),3.05(q,J=1.8Hz,3H),1.46(s,9H),1.25(d,J=7.1Hz,3H).

[0138] Preparation 12 tert-Butyl (S)-(1-cyanopropan-2-yl)carbamate

[0139] [ka] A vessel was charged with DMF (1.2 L), NaCN (75.45 g, 1.54 mol), and TBAB (38.178 g, 0.118 mol). The mixture was heated to 35°C to 45°C, and then (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (300 g, 1.184 mol) dissolved in DMF (300 mL) was added, followed by stirring for 18 hours. The mixture was cooled to 15°C to 25°C, and water (4.5 L) and MTBE (6 L) were added. The aqueous phase was separated and further extracted with MTBE (6 L). The organic phases were combined and washed with water (1.8 L x 3) and then once with saturated aqueous sodium chloride solution (1.8 L). The organic layer was concentrated in vacuo to approximately 300 mL, and MTBE (900 mL) was added. The organic layer was concentrated in vacuo to approximately 300 mL, and n-heptane (1.2 L) was added. The resulting mixture was filtered and dried to give the title product as a solid (160 g, 73.3%). 1 H NMR(CDCl3)δ 4.65(s,1H),3.95(s,1H),2.80-2.69(m,1H),2.56-2.49(m,1H),1.44(d,J=3.3Hz,9H),1.32(dd,J=6.7,3.0Hz,3H).

[0140] Preparation 13 (S)-3-Aminobutanenitrile Hydrochloride

[0141] [ka] A vessel was charged with tert-butyl (S)-(1-cyanopropan-2-yl)carbamate (235 g, 1.276 mol) and DCM (1.88 L). HCl gas (139.67 g, 3.827 mol) was added while maintaining the reaction temperature between 15 and 25°C. The contents were stirred for 6 hours, then the mixture was cooled to 0 to 5°C and stirred for 2 hours. The resulting mixture was filtered and dried to afford the title compound as a white solid (150 g, 97.5%). 1H NMR(D2O)δ 3.79-3.72(m,1H),2.93(dq,J=5.8,2.8Hz,2H),1.44-1.40(m,3H).

[0142] Preparation 14 Ethyl (S)-3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate

[0143] [ka] A vessel was charged with EtOH (4.4 L) and (S)-3-aminobutanenitrile hydrochloride (879 g, 7.3 mol). TEA (999 g, 9.9 mol) was added dropwise, followed by ethyl acrylate (918 g, 9.5 mol), while maintaining the temperature between 15 and 25°C. The mixture was then heated to 70 and 85°C and stirred for 24 hours. After this time, the mixture was cooled to 15 and 25°C, and TEA (852.6 g, 8.4 mol) was added dropwise, followed by di-tert-butyl dicarbonate (2160.7 g, 9.9 mol) at 15 and 25°C. The mixture was stirred at 15 and 25°C for 10 hours, then quenched with N-methylpiperazine (73.1 g, 0.8 mol) at 15 and 25°C and stirred for 2 hours. The mixture was concentrated in vacuo to 2.64 L, followed by the addition of EtOAc (4.4 L) and HO (1.76 L). 2N aqueous HCl was added until the pH of the aqueous layer was 2-3. The aqueous phase was separated, and the organic phase was washed with 15% aqueous NaCl (4.4 L). The organic phase was concentrated under reduced pressure to 2.64 L. THF (1.76 L) was added to give a solution of the title compound (4101 g, 82%). 1 H NMR(CDCl3)δ 4.02-4.18(m,2H),3.37-3.45(m,2H),2.48-2.58(m,4H),1.44(s,9H),1.29-1.30(d,3H,J=7Hz),1.21-1.24(t,3H,J=7Hz).

[0144] Preparation 15 tert-Butyl (S)-5-cyano-4-hydroxy-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate

[0145] [ka] A vessel was charged with THF (12 L) and potassium t-butoxide (1042 g, 9.3 mol) and cooled to 0-5°C. Ethyl (S)-3-((tert-butoxycarbonyl)(1-cyanopropan-2-yl)amino)propanoate in THF (1200 g, 4.2 mol) was added dropwise, maintaining the temperature at 0-5°C. The mixture was stirred at 0-5°C for 4 hours and then quenched with 2N HCl until the pH reached 2-3. IPAc (6 L) was added. The organic phase was separated and then washed with 15% aqueous NaCl (3.6 L). The mixture was concentrated in vacuo to 2-3 L, then IPAc (3.6 L) was added, and the organic phase was washed with 15% aqueous NaCl (3.6 L). The mixture was treated with 5% activated carbon (60 g), filtered, and concentrated in vacuo to 2-3 L. Heptane (7.2 L) was added, and the mixture was again concentrated in vacuo to 2-3 L. IPAc (3.6 L) was added, and the mixture was heated to 50-60 °C. Heptane (1.2 L) was added, and the contents were then cooled to 15-25 °C. Heptane (6.0 L) was added over 1 h, and the mixture was then stirred at 0-5 °C for 12 h. The resulting solid was filtered and washed with IPAc / heptane (0.2:1.8, 2.4 L). The solid was dried under N2 to give the title compound (858 g, 85%). IR (cm-1): 3171 (broad), 2982 (sharp), 2932 (sharp), 2881 (sharp), 2219 (sharp), 1701 (sharp), 1697 (sharp), 1663 (sharp). 1 H NMR(CDCl3)δ 10.88(s,1H),4.50(s,1H),3.97(s,1H),2.97(s,1H),2.29~2.37(m,1H),2.18-2.22(m,1H),1.41(s,9H),1.21-1.22(d,3H,J=6.5Hz).

[0146] Preparation 16 1-(diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl)hydrazine

[0147] [ka] A vessel was charged with distilled tert-amyl alcohol (1.5 L), water (200 mL), 5-bromo-2-fluoro-1,3-dimethylbenzene (500 g, 2.46 mol), (diphenylmethylene)hydrazine (507 g, 2.59 mol), and NaOH (394 g, 9.85 mol). The mixture was degassed with nitrogen for 30 minutes, and then Pd(OAc) (0.55 g, 24.62 mmol) and Xantphos (1.4 g, 24.62 mmol) were added. The mixture was degassed with nitrogen for 30 minutes and then heated to 100-106°C for 1 hour. After completion of the reaction, the mixture was cooled to 85-95°C, and water (500 mL) was added dropwise over 1 hour. The mixture was stirred at 85-95°C for 1-2 hours, cooled to 65-75°C and stirred for 1-2 hours, then continued to cool to 15-25°C and stirred for 2-4 hours. The resulting cake was filtered and washed with tert-amyl alcohol (500 mL) and water (1 L). Water (2.5 L) and the wet cake were added to a vessel and slurried at 15-30°C. The contents were stirred at 15-30°C for 2-4 hours, then filtered and washed with water (1 L). The resulting solid was dried at below 60°C using a nitrogen stream until the water content was 5.0% or less to give the title compound (715 g, 90%). IR (cm -1 ):3344(Sharp), 3341(Sharp), 3055(Sharp), 2952(Sharp), 2920(Sharp), 1660(Sharp), 1604(Sharp), 1579(Sharp). 1 H NMR(CDCl3)δ 7.59-7.44(m,5H),7.29(d,J=7.1Hz,6H),6.69(d,J=6.1Hz,2H),2.20(s,6H). 13C NMR(DMSO-d6)δ 143.16,139.16,133.52,129.94,129.49,129.42,128.72,128.07,126.39,124.37,124.19,113.42,113.39,113.35,15.10,15.06. 19 F NMR (DMSO-d6) δ -134.24. TOF-MS (ESI) m / z calculated: 319.2, found 318.9 (M+H).

[0148] Preparation 17 (4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride hydrate

[0149] [ka] Dioxane (1.05 L) was charged to the vessel, and HCl gas was added at 0°C to 30°C until the concentration reached 20.0% or greater. Water (98.9 g, 5.50 mol) was added to the reaction solution at 0°C to 30°C, followed by heating to 35°C to 45°C. 1-(Diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl)hydrazine (700 g, 2.20 mol) was added portionwise over 2 hours. Upon completion, the mixture was cooled to 15°C to 25°C and stirred for 2 to 4 hours. After filtration, the resulting cake was washed with dioxane (1.4 L) and then dried at ≦30°C until the dioxane concentration reached 1.0% or less to give the title compound (403 g, 87%). IR (cm -1 ):3224(Broad), 2855(Broad), 2684(Broad), 1574(Sharp). 1 H NMR(DMSO-d6)δ 10.22(s,3H),6.73(d,J=6.0Hz,2H),6.05(d,J=1.3Hz,1H),3.66(s,4H),2.12(d,J=2.2Hz,6H). 13 C NMR(DMSO-d6)δ 156.19,153.84,141.62,141.59,124.59,124.40,115.79,115.75,66.81,15.00,14.97. 19F NMR (DMSO-d6) δ -127.90. Thermogravimetric analysis (TGA) determined percent weight loss from 50 °C to 160 °C: 8.759%. TOF-MS (ESI) m / z calculated: 155.1, found: 155.0 (M+H).

[0150] Preparation 18 tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0151] [ka] The vessel was charged with NMP (1350 mL) and then degassed with nitrogen for 0.5 hours. Afterwards, (4-fluoro-3,5-dimethylphenyl)hydrazine hydrochloride hydrate (274 g, 1.31 mol) and NMM (279 g, 2.77 mol) were added. The mixture was stirred at 15°C to 25°C for 1 hour. tert-Butyl (S)-5-cyano-4-hydroxy-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate (300 g, 1.26 mol) was added, and the mixture was heated to 70°C to 80°C for 30 minutes. Upon completion, the mixture was cooled to 15°C to 25°C, and MTBE (3 L) and 20% NH4Cl (330 g NH4Cl in 1.2 L water) were added. The mixture was stirred for 0.5 hours, and the layers were separated. The aqueous layer was extracted with MTBE (1.5 L). The combined layers were washed twice with 15% aqueous NaCl (247.5 g NaCl in 1.275 L water). The organics were concentrated in vacuo to 600 mL at ≦40° C. Heptane (2.4 L) was added dropwise to the mixture, which was then heated to 50-60° C. and stirred for 6 hours. The mixture was then cooled to 0-5° C. over 6 hours and then held at 0-5° C. for 16 hours. The mixture was filtered and the resulting cake was washed with MTBE / n-heptane: 0.5 V / 3.8 V. The product was dried at 25° C. using a nitrogen stream to give the title compound (419.6 g, 89%). IR (cm -1):3448,3375,3129,2960,2926,1682,1637,1589. 1 H NMR(DMSO-d6)δ 7.21(d,J=6.4Hz,2H),5.18(s,2H),5.06(d,J=43.5Hz,1H),4.21-3.95(m,1H),2.94(d,J =13.5Hz,1H),2.47-2.36(m,2H),2.23(d,J=2.2Hz,6H),1.42(s,9H),1.27-1.17(m,3H). 13 C NMR(DMSO-d6)δ 158.93,156.53,154.22,141.97,135.16,135.13,124.98,124.79,124.16,124.11,79.16,44.56,37.85,28.63,24.07,14.80,14.76. 19 F NMR (DMSO-d6) δ -125.12. TOF-MS (ESI) m / z calculated: 375.2, found: 375.1 (M+H). Chiral purity by HPLC = 100% area.

[0152] Preparation 19 N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide

[0153] [ka] The vessel was charged with DMAc (750 mL) and CDI (181.8 g, 1.12 mol) and then cooled to 0-5°C. 2,2-Dimethoxyethylamine (109.5 g, 1.04 mol) was added dropwise over 2 h at 0-5°C and then stirred at this temperature for 3 h. The reaction was monitored by NMR until no starting material remained. This solution was used directly in the subsequent step. 1 H NMR(CDCl3)δ 8.46(t,J=5.9Hz,1H),7.86(d,J=1.2Hz,1H),7.24(d,J=1.5Hz,1H),6.53( d,J=1.3Hz,1H),4.08(t,J=5.4Hz,1H),2.98(t,J=5.6Hz,2H),2.89(s,6H).

[0154] Preparation 20 tert-Butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0155] [ka] tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (300 g, 0.8 mol) in DMAc (750 mL) was added dropwise to a solution of (N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide) at −5° C. to 5° C. Potassium t-butoxide (449.4 g, 4.0 mol) was added in three equal portions, followed by stirring at −5° C. to 10° C. for 18 hours. Water (2400 mL) was added to the mixture over 2 hours at −5° C. to 10° C. t-Butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3 g) was added as seed material and stirred at -5 to 10°C for 18 hours. Water (1.2 L) was added to the reaction mixture over 2 hours at -5 to 10°C, and the slurry was then stirred at -5 to 10°C for 4 hours. The mixture was filtered and the resulting wet cake was washed with water (1.8 L). The product was dried below 50°C to give the title compound (321.0 g, 84%). IR (cm -1 ):3283,3103,2977,2938,2872,2841,~1700,1680,1626. 1H NMR(DMSO-d6)δ 8.10(s,1H),7.19(d,J=6.4Hz,2H),6.42(s,1H),5.08(d,J=31.3Hz,1H),4.30(t,J=5.3Hz,1H),4.18(d,J=35.0Hz,1H),3.31 (s,1H),3.24(s,6H),3.14(s,1H),3.06(s,1H),2.65-2.51(m,2H),2.23(d,J=2.2Hz,6H),1.41(s,9H),1.19(d,J=6.6Hz,3H). 13 C NMR(DMSO-d6)δ 155.69,155.63,146.29,134.74,132.64,124.95,124.76,124.61,124.56,114.69,102.85,79.39,53.70,41.41,28.58,14.79,14.75. 19 F NMR (DMSO-d6) δ -123.68. TOF-MS (ESI) m / z calculated: 506.3, found 505.9 (M+H). Chiral purity = 100% (by HPLC).

[0156] Preparation 21 tert-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0157] [ka] A vessel was charged with THF (3.5 L) and tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (350 g, 0.69 mol). Methanesulfonic acid (73.2 g, 0.76 mol) was added dropwise to the mixture at 15°C to 25°C. The mixture was heated to 40°C to 50°C and stirred for 18 hours; HPLC showed a mixture of the title compound and the deprotected title compound. The mixture was cooled to 15-25°C, quenched with aqueous KPO (147 g, dissolved in 1.4 L of water), and di-tert-butyl dicarbonate (51 g, based on the amount of deprotected intermediate obtained by HPLC) was added at 15-25°C. The mixture was then stirred for 18 h. The aqueous phase was separated, and the organic phase was concentrated in vacuo to 1 L-1.4 L. IPAc (1.4 L) and 15% aqueous NaCl (1.05 L) were added. The organic phase was separated and concentrated in vacuo to 0.7 L-1 L. The mixture was heated to 50-60°C, and n-heptane (2.1 L) was added dropwise over 3 h. The mixture was then cooled to 10-30°C, stirred for 16 h, filtered, and the resulting wet cake was washed with IPAc / n-heptane at 0.2 V / 1.8 V. The resulting material was dried below 50° C. to give the title compound (240 g, 78.5%).

[0158] For further purification, tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (160 g) was dissolved in EtOH (800 mL). The mixture was stirred at 20°C to 25°C for 2 hours to obtain a solution. Water (800 mL) was added dropwise at 20°C to 25°C, followed by the addition of 1% seed crystals to the solution. The suspension was stirred for 16 hours, followed by the addition of water (800 mL) over 4 to 10 hours at 20°C to 25°C. The suspension was stirred for an additional 2 to 4 hours, filtered, and the resulting solid was washed with water (800 mL). The material was dried below 50°C to give the title compound as a solid (150g, 94%). IR (cm-1 ):3220,3107,2982,2933,2858,1699,1670,1602. 1 H NMR(CDCl3)δ10.74(s,1H),7.03(s,2H),6.54-6.59(d,2H,J=25Hz),5.07(s,1H) ,4.21(s,1H),3.10(s,1H),2.68(s,2H),2.20(s,6H),1.47(s,9H),1.14(s,3H). 13 C NMR(DMSO-d6)δ 159.76,157.34,154.00,153.18,146.92,134.14,134.11,130.27,125.26,125. 07,124.30,124.25,112.83,111.31,111.17,79.68,28.54,24.15,14.81,14.77. 19 F NMR (DMSO-d6) δ -122.60 enantiomer <0.10%; chiral purity: >99.9% by HPLC.

[0159] Preparation 22 3,6-Dibromo-2-fluorobenzaldehyde

[0160] [ka] A solution of 1,4-dibromo-2-fluorobenzene (249 kg, 981 mol) was prepared in 2-MeTHF (1749 L) under nitrogen protection, and the solution was polish filtered to remove insoluble material and transferred to a holding vessel.

[0161] A solution of n-butyllithium (697 L, 1.6 M in THF) was polish filtered to remove insoluble material as it was transferred to a holding vessel.

[0162] A solution of diisopropylamine in 2-MeTHF was prepared by adding diisopropylamine (135 kg, 1334 mol) and 2-MeTHF (300 L). The mixture was stirred and controlled at 10°C to 30°C. The solution was then polish filtered to remove insoluble material and transferred to a separate holding vessel.

[0163] A solution of DMF in 2-MeTHF was prepared by dissolving DMF (156 kg, 2134 mol) in 2-MeTHF (499 L) and polish filtering as the solution was transferred to a holding vessel.

[0164] An aqueous citric acid solution was prepared by dissolving citric acid monohydrate (748 kg, 3560 mol) in water (1830 kg), and the solution was polish filtered to remove insoluble material and transferred to a holding vessel.

[0165] Flow reaction: A plug flow reactor consisting of a pre-cooling loop for a solution of 1,4-dibromo-2-fluorobenzene, diisopropylamine, and DMF, and a main reactor tube for lithiation and addition to DMF, was constructed and placed in a cooling bath controlled at -45°C to -40°C. After the reaction feed exited the low-temperature zone, it was quenched with aqueous citric acid in another plug flow reactor and collected for batch workup. (Example flow rates: 1,4-dibromo-2-fluorobenzene = 5.13 mL / min; n-butyllithium = 2.35 mL / min; diisopropylamine = 3.93 mL / min; DMF = 1.81 mL / min; citric acid = 6.5 mL / min)

[0166] To the quenched reaction mixture (4244 kg) was added heptane (124 kg), the mixture was stirred, and then allowed to settle. The aqueous layer was removed, and the organic layer was washed with water (530 kg). The mixture was allowed to settle, and the aqueous layer was removed. The organic layer was recirculated through a CUNO cartridge containing activated carbon for 8 hours. The organic layer was then concentrated in vacuo to 340 L and heated to 55-65°C. After stirring at 55-65°C for 4 hours, heptane (736 kg) was slowly added at 55-65°C, and after the heptane addition was complete, the mixture was stirred at this temperature for an additional 1.5 hours. The slurry was then gradually cooled to 0-5°C over 7 hours and stirred at that temperature for an additional 3 hours. The solid was then isolated by filtration, and the product cake was washed with heptane (120 kg). The solid product was then dried under vacuum to give the title compound as a solid (160.85 kg, 58%). 1H NMR(DMSO-d6)δ 10.15(s,1H),7.93(td,J=7.8,1.3Hz,1H),7.62(dd,J=8.6,1.6Hz,1H). 19 F NMR(DMSO-d6)δ-109.24(d,J=7.1Hz). 13 C NMR(DMSO-d6)δ 188.41(d,J=1.7Hz),158.71(d,J=262.6Hz),138.98(d,J=2.1Hz),131.53(d, J=4.4Hz), 123.89(d,J=11.0Hz),123.75(d,J=2.3Hz),109.73(d,J=21.2Hz). HRMS m / z calculated value: 279.8535; actual value 279.8528 (M+H).

[0167] Preparation 23 (E)-1-(3,6-dibromo-2-fluorobenzylidene)-2-methylhydrazine

[0168] [ka] The reactor was charged with anhydrous EtOH (2298 L) followed by 3,6-dibromo-2-fluorobenzaldehyde (574 kg, 2036 mol), and the mixture was controlled at 15°C to 25°C. An aqueous solution of methylhydrazine (40% w / w, 258 kg, 2240 mol) was added slowly over 4 hours, after which the mixture was stirred at 15°C to 25°C for an additional 9 hours. Heptane (1172 kg) was then added over 4 hours, after which time the mixture was cooled to -5°C to 5°C over 6 hours and then held at that temperature for 3 hours. The solid was isolated by filtration, and the cake was washed with heptane (576 L). The solid was dried under vacuum at 25°C to 35°C for 8 hours to give the title compound as a solid (443.5 kg, 70%). 1 H NMR(CD3CN)δ 7.49-7.30(m,3H),6.72(s,1H),2.95(dd,J=4.5,1.0Hz,3H).19F NMR(CD3CN)δ-106.22(d,J=4.9Hz). 13C NMR(CD3CN)δ 156.13(d,J=254.6Hz),131.52,129.61(d,J=4.4Hz),126.05(d,J=14.1Hz), 125.74(d,J=4.7Hz),121.76(d,J=3.4Hz),108.98(d,J=22.4Hz),32.75.HRMS m / z calculated value: 308.9033; actual value 308.9036 (M+H).

[0169] Preparation 24 5-Bromo-4-fluoro-1H-indazole

[0170] [ka] To a solution of 4-bromo-3-fluoro-2-methylaniline (50 g, 0.245 mol) in anhydrous toluene (435 g), acetic anhydride (75 g, 0.735 mol) was added dropwise at 0°C to 15°C. After stirring for 2 to 4 hours at 15°C to 30°C, a solution of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide was produced. The temperature was adjusted to 35°C to 40°C, and isoamyl nitrite (57.4 g, 0.490 mol) was added dropwise below 40°C. The reaction temperature was then adjusted to 75°C to 80°C, and the contents were stirred for 16 to 20 hours to yield a solution of 1-(5-bromo-4-fluoro-1H-indazol-1-yl)ethan-1-one. The mixture was cooled to 0°C to 10°C, and 35% hydrochloric acid (350 g) was added while maintaining the temperature below 10°C. The temperature was adjusted to 57-63°C and stirred for 6-10 hours. The contents were cooled to 20-25°C and the slurry was stirred for 2-4 hours. After filtration, the resulting wet cake was rinsed with toluene (87 g). The wet cake was then added to a vessel containing water (250 g). While stirring the contents and maintaining the temperature below 30°C, a 10% NaOH solution was added to adjust the pH to 11-13. The slurry was cooled to 0-5°C, stirred for 1-2 hours, filtered, and the resulting wet cake was washed with water (150 g). The resulting solid was dried under vacuum at 35-40°C to give the title compound (34 g, 65%). Melting point (DSC) 161.04°C. 1H NMR(DMSO-d6)δ 7.37-7.39(dd,J=8.8,1.0Hz,1 H),7.50-7.54(dd,J=8.8,6.4Hz,1 H),8.22(d,J=0.8Hz,1 H). 13 C NMR(DMSO-d6)δ 152.13,149.65,142.01,141.93,130.06,129.40,113.75,113.51,108.48,108.44,96.69,96.50. 19 F NMR(DMSO-d6) δ-121.04.

[0171] Preparation 25 5-Bromo-4-fluoro-1-methyl-1H-indazole

[0172] [ka] The reactor was charged with DMI (63 kg), degassed by sparging with nitrogen gas, and then transferred to a holding drum. (£)-1-(3,6-dibromo-2-fluorobenzylidene)-2-methylhydrazine (15 kg, 48.4 mol) was added to the vessel and dissolved in degassed DMI (32 kg), which was then transferred to a holding drum.

[0173] Fresh DMI (30 kg) was added to the vessel and degassed by sparging with nitrogen gas. CuCl (1.3 kg, 13.1 mol) was added, followed by DBU (11.1 kg, 72.9 mol), and the mixture was further degassed using vacuum / nitrogen cycles (3x). The mixture was heated to 70-80°C, and then the (E)-1-(3,6-dibromo-2-fluorobenzylidene)-2-methylhydrazine solution was added over 4 hours. The mixture was held at 70-80°C for 11 hours, then cooled to 40-50°C; analysis indicated the reaction was incomplete. The mixture was heated to 70-80°C for 4 hours, then cooled to 40-50°C, at which point analytical samples indicated consumption of starting material, and the mixture was cooled to 20-30°C. 2M aqueous HCl (124 kg, 248 mol) was added over 6 hours, and the mixture was then stirred for 4 hours, which resulted in crystallization. The solid was isolated by filtration, and the cake was washed with water (59.4 kg). The solid was dried under vacuum at 35°C to 45°C for 25 hours to give a batch of 5-bromo-4-fluoro-1-methyl-1H-indazole.

[0174] Crude 5-bromo-4-fluoro-1-methyl-1H-indazole from several production batches was pooled (471 kg, 2056 mol) and EtOAc (3296 L) was added. The reactor walls were rinsed with additional EtOAc (178 kg). Aqueous ammonium hydroxide (25% w / w, 850 kg) was added and rinsed with water (approximately 10 kg). The mixture was controlled at 20-30°C and stirred for 4 hours, after which time it was filtered through diatomaceous earth. The diatomaceous earth was washed with additional EtOAc (118 kg) to reduce product loss. The aqueous layer was separated, and fresh aqueous ammonium hydroxide (25% w / w, 850 kg) was added along with water (938 L). The mixture was held at 20-30°C and stirred for 1.5 hours. After settling, the aqueous layer was removed. The organic phase was circulated through a CUNO filter packed with activated carbon for 7 hours, after which the CUNO was rinsed with EtOAc (140 kg). The CUNO filtration was repeated a total of three times for each batch. The resulting solution was then concentrated under vacuum to approximately 1650 L. DMF (1414 L) was added, and the mixture was concentrated to approximately 1650 L. Water (1422 L) was added over 5 hours at 45-55°C. The mixture was cooled to 15-25°C and stirred for 3 hours. The solid product was isolated by filtration, and the cake was washed with water (1421 kg). The product cake was dried under vacuum at 30-40°C for 8 hours, then at 35-45°C for 16 hours to give the title compound as a solid (234.1 kg, 50%). 1 H NMR(DMSO-d6)δ 8.08(s,1H),7.46(dd,J=8.9,6.2Hz,1H),7.37(d,J=8.9Hz,1H),4.03(s,3H). 19 F NMR(DMSO-d6)δ-112.88(d,J=6.3Hz). 13 C NMR(DMSO-d6)δ 151.11(d,J=250.3Hz),141.73(d,J=9.0Hz),130.29,128.65(d,J=2.6Hz),1 14.44(d,J=23.5Hz),108.14(d,J=4.4Hz),97.30(d,J=18.8Hz),36.23.HRMS m / z calculated value: 228.9771; actual value: 228.9772 (M+H).

[0175] Alternative preparation 25 To a solution of 435 g of DMF was added 20 g (0.093 mol) of 5-bromo-4-fluoro-1H-indazole and 20 g (0.145 mol) of K2CO3 at 25-30°C. After stirring for 30-60 minutes at 25-30°C, the temperature was adjusted to 0-10°C, and then methyl iodide (17 g, 0.120 mol) was added dropwise while maintaining the temperature below 10°C. After stirring for 4-6 hours at 25-30°C, water (320 g) was added while maintaining the temperature below 30°C, and then stirred for 2-4 hours at 25-30°C. After filtration, the resulting solid was washed with 40 g of water. The wet cake was added to a vessel containing 38 g of DMF, and the mixture was heated to 40-50°C and then stirred for 1-2 hours. Water (80 g) was added to the mixture while maintaining the temperature below 50°C, and then cooled to 25-30°C over 2-3 hours. Stirred at 25-30°C for 1-2 hours, filtered, and the wet cake was washed with water (60 g). The solid was dried under vacuum at 35-45°C for 12-16 hours to give the title compound as a solid (12.31 g, 57.8%). Melting point (DSC) 106.90°C; 1 H NMR(CDCl3)δ ppm 4.05(s,3 H),7.03-7.06(dd,J=8.8,0.8Hz,1 H),7.40-7.44(dd,J=8.8,6.2Hz,1 H),8.00(d,J=0.6Hz,1 H). 13 C NMR(CDCl3)δ ppm 153.29,150.71,141.70,141.62,130.75,129.04,129.02,113.75,115.34,115.11,106.21,106.16,98.10,97.91,36.04. 19 F NMR(CDCl3)δ ppm-111.32

[0176] Preparation 26 tert-Butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0177] [ka] A vessel was charged with tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.034 g, 11.40 mmol), 5-bromo-4-fluoro-1-methyl-1H-indazole (3.084 g, 13.2 mmol), and powdered potassium carbonate (2.387 g, 17.27 mmol). To a separate vial was added trans-N,N'-dimethylcyclohexane-1,2-diamine (0.758, 5.22 mmol) and copper(I) chloride (0.229 g, 2.31 mmol) or alternatively copper(I) iodide (0.446 g, 2.34 mmol). The vessel was degassed and placed in a glove box. The vessel was equipped with a mechanical stirrer, a heating mantle, and a thermocouple. Degassed 1,3-dimethyl-2-imidazolidinone (20 mL) was added to the vessel along with trans-N,N'-dimethylcyclohexane-1,2-diamine and copper(I) chloride or copper(I) iodide. The mixture was heated to 100 °C and held for 15 hours. After this time, the mixture was removed from the glove box and assayed, which indicated the reaction was complete. To the mixture was added EtOAc (30 mL), 12% aqueous ammonium chloride solution (30 mL), and methylcyclohexane (10 mL). The mixture was stirred, allowed to settle, and the aqueous phase was separated from the organic phase. The organic phase was washed sequentially with another 12% aqueous ammonium chloride solution (30 mL) and 0.5 N aqueous hydrochloric acid (20 mL). The organic phase was stirred with activated carbon (345 mg, 7 wt%) and filtered. The flask was washed with EtOAc (10 mL), which was then used to wash the filter. The combined filtrate was washed sequentially with 5% aqueous sodium bicarbonate solution (30 mL) and water (20 mL). The final organic phase was vacuum distilled to 15 mL in a 250 mL three-neck flask at 40 °C. ACN (25 mL) was added, and the mixture was vacuum distilled again to 15 mL. ACN (25 mL) was added, and the mixture was vacuum distilled again to 15 mL. ACN (40 mL) was added, and the mixture was vacuum distilled again to 15 mL. After distillation, ACN (30 mL) was added to the resulting mixture. This solution was used as is for the subsequent preparation. FTIR (cm -1):2974.51,1686.89,1626.44,1604.35,1577.26,1528.12,1495.10,1476.23,1411.03,1391.27,1363.64,1323.18,1295.00,1250.88,1203.68,1158.15,1109.83,1054.75,983.02,881.02,860.40,796.52,769.36,750.36,719.98,691.98,680.53,655.48. 1 H NMR(DMSO-d6)δ 8.3(s,1 H),7.65(d,1 H,J=16.3Hz),7.4-7.5(m,1 H),7.14(br d,J=6.1Hz,1 H),7.05(d,J=2.9Hz,1 H),6.9-7.0(m,1 H),5.2(brs,1 H),4.3(brs 1 H),4.1(s,3 H),2.2(s,6 H),1.4(s,9 H),1.23(d,J=5.6Hz,3 H). 13 C NMR(DMSO-d6)δ 158.5(d,J=243Hz),154.0,151.3,149.4(d,J=256Hz),147.1,141.8(d,J=8.8Hz), 134.0(d,J=3.7Hz),129.7,128.9(d,J=2.2Hz),127.6(d,J=8.1Hz),126.7,125.4(d ,J=19.8Hz),124.1,123.9,115.6,114.9,114.8,114.0(d,J=21.3Hz),113.2,107. 2,107.1,106.8(d,J=4.4Hz),104.9(d,J=18.3Hz),79.8,36.3,28.5,14.75,14.71. 19 F NMR(DMSO-d6)δ-118.89,-122.46,-126.59.HRMS m / z calculated value: 590.2686; measured value: 590.2791 (M+H).

[0178] Instead of mixing 26 A vessel was charged with tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (5.007 g, 11.34 mmol), 5-bromo-4-fluoro-1-methyl-1H-indazole (3.084 g, 13.2 mmol), and powdered potassium carbonate (2.356 g, 17.05 mmol). To a separate vial, trans-N,N'-dimethylcyclohexane-1,2-diamine (0.768 g, 5.29 mmol) and copper(I) chloride (0.226 g, 2.28 mmol) or copper(I) iodide (0.479 g, 2.52 mmol) were added. The vessel was degassed and placed in a glove box. The vessel was equipped with a mechanical stirrer, a heating mantle, and a thermocouple. Degassed N-methylpyrrolidone was added to the vessel along with trans-N,N'-dimethylcyclohexane-1,2-diamine and copper(I) chloride or copper(I) iodide. The mixture was heated to 100 °C and held for 15 h. After this time, the mixture was removed from the glove box and assayed, indicating completion of the reaction. To the mixture was added EtOAc (30 mL), 12% aqueous ammonium chloride solution (30 mL), and methylcyclohexane (10 mL). The mixture was stirred, allowed to settle, and the aqueous phase was separated from the organic phase. The organic phase was washed sequentially with another 12% aqueous ammonium chloride solution (30 mL) and 0.5 N aqueous hydrochloric acid (20 mL). The organic phase was washed with water (20 mL). The final organic phase was vacuum distilled to 15 mL in a 250 mL three-neck flask at 40° C. ACN (25 mL) was added, and the mixture was vacuum distilled again to 15 mL. ACN (25 mL) was added, and the mixture was vacuum distilled again to 15 mL. ACN (40 mL) was added, and the mixture was vacuum distilled again to 15 mL. After distillation, ACN (40 mL) was added to the resulting mixture. This solution was used directly in subsequent preparations. Analytical data were consistent with those collected from Preparation 26.

[0179] Preparation 27 (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one

[0180] [ka] A vessel containing the ACN solution of tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate from Preparation 26 was equipped with a mechanical stirrer, heating mantle, thermocouple, and N2 inlet. Methanesulfonic acid (2.054 g, 21.37 mmol) was combined with ACN (10 mL), taken via syringe, and added over 0.5 h at 21 °C. After the addition, the reaction mixture was heated from 21 °C to 55 °C at 30 °C / h. The reaction mixture reached 55 °C in 1.5 h and was held at 55 °C for an additional 0.5 h. After that, an assay by HPLC showed complete consumption of the intermediate tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate. After cooling to 22°C, aqueous sodium hydroxide (15.779 g, 15.06 mmol) and seed crystals (57 mg, 1 wt%) were added, with the seed crystals remaining. In a separate vessel, aqueous sodium hydroxide (8.936 g, 8.528 mmol) was combined with water (25.019 g) and added to the slurry over 2 hours at 20.2°C. The slurry was stirred for 6 hours and filtered. The wet cake was rinsed sequentially with 1:1 ACN / water (10 mL) and water (25 mL). The wet cake was adjusted under vacuum and further dried in vacuo at 55°C for 12 hours with a N2 purge to give the title compound as a solid (4.759 g, 83%). Melting point 240.14°C - 241.26°C. FTIR (cm -1):3278.2,3135.5.3099.5,3057.9,3042.7,2969.7,2960.2,2941.1,2923.5,2862.7,1705.9,1667.5,1644.2,1624.2,1598.2,1584.2,1573.3,1528.2,1493.5,1466.1,1448.0,1430.2,1394.5,1369.6,1357.6,1329.9,1313.8,1257.0,1238.6,1226.6,1214.8,1189.2,1171.1,1126.5,1105.5,1075.8,1058.0,1044.5,1015.5,1006.1,982.6,965.4,940.7,916.7,884.6,874.0,834.8,803.8,798.4,774.5,760.0,751.9,743.4,722.5,710.0,687.5,668.7,641.2,624.9,602.1,591.6,555.1,510.5; 1 H NMR(CDCl3)δ 8.09(s,1H),7.42(t,J=6.8Hz,1H),7.22(d,J=8.8Hz,1H),7.10(d,J=6.0Hz,1H),6.53(m,1H),6.22(m,1H),4.13(q,J=6.8Hz,1H),4.08(s,3H),3.36(dt,J=4.4Hz,1H),3.05(dt,J=7.0Hz,1H),2.77(m,2H),2.24(d,J=1.6Hz,6H),1.29(d,J=6.8Hz,3H); 13 C NMR(CDCl3)δ 158.87( 1 J CF= 243Hz),151.29,149.63( 1 J CF= 257Hz),147.88,141.42( 3 J CF =8.7Hz),133.45( 3 J CF= 3.6Hz),129.70,129.68,128.57,125.86,125.37( 2 J CF =19.4Hz),123.98( 3 J CF =5.1Hz),118.27,114.77( 3J CF =10.1Hz), 114.52( 2 J CF =20.9Hz),114.14,112.16,105.43( 3 J CF =4.3Hz),47.03,42.45,35.88,24.92,20.29,14.57( 3 J CF= 3.6Hz); 19 F NMR (36 MHz, CDCl3) δ -122.24, -126.21 (J = 6.8 Hz); HRMS m / z calculated: 489.2089; found: 489.2069 (M+H). Chiral purity (by HPLC): >99.9%.

[0181] Alternative preparation 27 A vessel containing the ACN solution of tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate from Alternative Preparation 26 was equipped with a mechanical stirrer, heating mantle, thermocouple, and N inlet. Methanesulfonic acid (2.107 g, 21.92 mmol) was added at 21.5 °C. After the addition, the reaction mixture was heated to 75 °C and held at 75 °C for an additional 0.5 h. After that, an assay by HPLC showed complete consumption of the intermediate tert-butyl (S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate. After cooling to 21° C., aqueous sodium hydroxide (15.068 g, 15.06 mmol) and seed crystals (55 mg, 1 wt%) were added, with the seed crystals remaining. In a separate vessel, aqueous sodium hydroxide (9.887 g, 9.635 mmol) was combined with water (25.267 g) and added to the slurry over 2 hours at 22.3° C. The slurry was stirred for 16 hours and filtered. The wet cake was rinsed sequentially with 1:1 ACN / water (10 mL) and water (25 mL). The wet cake was adjusted under vacuum and further dried in vacuo at 55°C for 12 hours while purging with N2 to give the title compound as a solid (5.206 g, 91.3%). Melting point 240.14°C - 241.26°C. FTIR (cm -1):3278.2,3135.5.3099.5,3057.9,3042.7,2969.7,2960.2,2941.1,2923.5,2862.7,1705.9,1667.5,1644.2,1624.2,1598.2,1584.2,1573.3,1528.2,1493.5,1466.1,1448.0,1430.2,1394.5,1369.6,1357.6,1329.9,1313.8,1257.0,1238.6,1226.6,1214.8,1189.2,1171.1,1126.5,1105.5,1075.8,1058.0,1044.5,1015.5,1006.1,982.6,965.4,940.7,916.7,884.6,874.0,834.8,803.8,798.4,774.5,760.0,751.9,743.4,722.5,710.0,687.5,668.7,641.2,624.9,602.1,591.6,555.1,510.5; 1 H NMR(CDCl3)δ 8.09(s,1H),7.42(t,J=6.8Hz,1H),7.22(d,J=8.8Hz,1H),7.10(d,J=6.0Hz,1H),6.53(m,1H),6.22(m,1H),4.13(q,J=6.8Hz,1H),4.08(s,3H),3.36(dt,J=4.4Hz,1H),3.05(dt,J=7.0Hz,1H),2.77(m,2H),2.24(d,J=1.6Hz,6H),1.29(d,J=6.8Hz,3H); 13 C NMR(CDCl3)δ 158.87( 1 J CF= 243Hz),151.29,149.63( 1 J CF= 257Hz),147.88,141.42( 3 J CF =8.7Hz),133.45( 3 J CF= 3.6Hz),129.70,129.68,128.57,125.86,125.37( 2 J CF =19.4Hz),123.98( 3 J CF =5.1Hz),118.27,114.77( 3J CF =10.1Hz), 114.52( 2 J CF =20.9Hz),114.14,112.16,105.43( 3 J CF =4.3Hz),47.03,42.45,35.88,24.92,20.29,14.57( 3 J CF= 3.6Hz); 19 F NMR (36 MHz, CDCl3) δ -122.24, -126.21 (J = 6.8 Hz); HRMS m / z calculated: 489.2089; found: 489.2069 (M+H). Chiral purity (by HPLC): >99.9%.

[0182] Preparation 28 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-((Z)-N'-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0183] [ka] A vessel was charged with 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (100 g, 0.23 mol) and IPA (900 mL). The mixture was heated to 65° C. over 30 minutes, after which 50 wt % aqueous hydroxylamine (45 g; 0.68 mol) was added over 3 hours. The charge vessel and lines were rinsed with IPA (10 mL), and the reaction was stirred at 65° C. for 16 hours. The reaction was cooled to 40° C. and analyzed by HPLC, which showed the reaction was complete, after which the resulting suspension was cooled to 5° C. over 3 hours. The slurry was stirred at 5° C. for 5 hours and filtered. The filter cake was rinsed with water (400 mL) and dried at 50° C. for 20 hours until the KF was ≦0.5% and the residual IPA was ≦1.5% to give the title compound as a solid (102 g, 95%). Melting point (DSC): 229.4° C.; 1 H NMR(CDCl3)δ 7.70(d,J=8.5Hz,1 H),7.39-7.30(m,2 H),7.27-7.09(m,5 H),6.40(s,2 H),6.00(s,1 H),3.88-3.72(m,2 H),3.67(s,3 H),2.99-2.84(m,1 H),1.78-1.51(m,6 H),1.36-1.32(m,3 H),1.30(s,3 H),1.25(s,3 H),1.15-1.07(m,1 H); 13 C NMR(CDCl3)δ 164.09,152.20,144.38,138.60,137.02,131.04,129.60,127.36,126.42,126.24,124.02,118.8 3,112.46,110.37,71.95,61.89,44.79,41.00,37.37,33.89,31.74,22.40,21.78,17.73,13.54. TOF-MS (ESI) m / z calculated: 475.2704, found: 475.2756 (M+H); chiral purity (by HPLC): >99%.

[0184] Alternative preparation28 A vessel was charged with 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (50 g, 0.11 mol) and THF (400 mL). The mixture was heated to 30-40°C over 30 minutes to obtain a clear solution, after which 50 wt% aqueous hydroxylamine (15 g; 0.23 mol) was added dropwise. The reaction was stirred at 30-40°C for 6-10 hours. The resulting suspension was stirred at 20-30°C for 15 hours. Water (500 mL) was added dropwise while maintaining the temperature at 20-30°C. The slurry was stirred at 20-30°C for 6 hours and filtered. The filter cake was rinsed with water (250 mL) and dried at 50° C. for 37 hours until the KF was 0.5% or less to give the title compound as a solid (52.2 g, 94.1%). Analytical data were consistent with those collected from Preparation 28.

[0185] Alternative preparation28 A reactor was charged with 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (5.0 g, 11.32 mmol) and THF (35.4 g). The mixture was heated to 30-40°C to give a light yellow solution. 50 wt% aqueous hydroxylamine solution (1.50 g, 22.64 mmol) was added dropwise over 3 hours, and the reaction was further stirred at 30-40°C for 6 hours. Seed crystals (0.05 g, 1 wt%) were added to the reaction mixture, and the resulting suspension was stirred at 30-40°C for 6 hours. Water (50 g) was added steadily over 8 hours at 30-40°C. The resulting slurry was cooled to 20-30°C over 1 hour and stirred for 1 hour. The resulting suspension was filtered, and the filter cake was rinsed with water (4 x 25 mL). The wet cake was dried under vacuum at 50°C for approximately 40 hours until the KF was less than 0.5% to afford the title compound as a solid (5.24 g, 94.2%). Analytical data were consistent with those collected from Preparation 28.

[0186] Preparation 29 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide

[0187] [ka] A vessel was charged with 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-((Z)-N'-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (100 g, 0.21 mol) and THF (400 mL). The temperature of the resulting mixture was adjusted to 20-30°C over 10 minutes. CDI (68 g, 0.42 mol) was added over 10 minutes, followed by DBU (80 g, 0.53 mol) over 30 minutes. The reaction was stirred at 20-30°C for 3-7 hours. THF (400 mL) was added with stirring at 20-30°C, and the resulting mixture was cooled to 10-20°C over 30 minutes. Water (500 mL) was added over 30 minutes while maintaining the internal temperature at 15°C. 2N HCl solution (220 mL) was added over 1 hour at 15°C. Seed crystals (1 g, 1 wt%) were added at 15°C, and the resulting suspension was stirred for 30 minutes. 2N HCl solution (680 mL) was added over 4 hours at 15°C, and the resulting slurry was stirred for 12 to 20 hours. The suspension was filtered, and the filter cake was rinsed with water (500 mL). The wet cake was stirred in water (1200 mL) at 25°C for 15 minutes, after which the suspension was cooled to 15°C and stirred for 4 to 8 hours. The suspension was filtered, and the filter cake was rinsed with water (500 mL). The solid was dried at 50-60°C for 16-24 hours until KF was 1% or less and residual THF was 720 ppm or less to give the title compound (102 g, 95%). Melting point (DSC): 218.28°C; 1H NMR(CDCl3)δ 11.40-11.16(m,1 H),7.56(d,J=8.5Hz,1 H)7.45-7.30(m,3 H),7.27-7.11(m,4 H),5.97(s,1 H),3.90-3.74(m,2 H),3.60(s,3 H),3.03-2.89(m,1 H),1.96-1.48(m,8 H),1.35-1.22(m,9 H). 13 C NMR(CDCl3)δ 163.80,158.88,157.34,144.18,139.61,136.60,130.78,129.82,127.96,126.51,126.34,124.83,119.56,1 11.41,110.69,71.89,61.79,44.80,37.40,35.62,33.82,31.75,23.54,21.78,18.15,13.77.TOF-MS(ESI)m / z Calculated value: 501.2496, measured value: 501.2541 (M+H), purity of キラル (HPLC による): 99% exceeding

[0188] Alternative modulation 29 A reactor was charged with 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (25.0 g, 56.61 mmol) and THF (375 mL). The mixture was heated to 30°C to 40°C to give a solution. 50 wt% aqueous hydroxylamine (7.50 g, 114 mmol) was added dropwise over 2 hours, and the reaction was further stirred at 30°C to 40°C for 18 hours. The temperature of the resulting reaction mixture was adjusted to 45°C to 55°C and concentrated under reduced pressure to 9 volumes. THF (225 mL, 9 volumes) was charged, and the contents were concentrated under reduced pressure to 6 volumes. Additional THF (225 mL, 9 volumes) was charged, and the contents were concentrated under reduced pressure to 6 volumes. THF (225 mL, 9 vol) was charged and the contents were concentrated under reduced pressure to 6 vol. Additional THF (225 mL, 9 vol) was charged and the contents were concentrated under reduced pressure to 6 vol. THF (50 mL, 2 vol) was charged and the mixture was heated to 65-75°C and stirred for 30 minutes. Mixture 2 was cooled to 20-30°C and CDI (18.4 g, 113.5 mmol) and DBU (21.55 g, 141.6 mmol) were charged sequentially. The reaction was stirred at 20-30°C for 21 hours. Water (125 mL) was added while maintaining the internal temperature at 10-20°C. 2N HCl solution (58 g) was added at 10-20°C. Seed crystals (0.3 g) were added at 10-20°C, and the resulting suspension was stirred for 1 hour. A 2N HCl solution (175 g) was added at 10°C-20°C, and the resulting slurry was stirred for 15.5 hours. The suspension was filtered, and the filter cake was rinsed with water (250 mL). The wet cake was stirred in water (600 mL) at 10°C-20°C for 5 hours and filtered. The filter cake was rinsed with water (250 mL) and dried to constant weight at 55°C-65°C for 72 hours to give the title compound (27.87 g, 94.4%). Analytical data were consistent with those collected from Preparation 29.

[0189] Preparation 30 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0190] [ka] A vessel was charged with 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (100 g, 0.2 mol), water (4.5 mL, 0.25 mol), and DMI (350 mL) at 25°C. The temperature was adjusted to 25°C and sodium t-butoxide (58 g, 0.6 mol) was added. The reaction was heated to 75°C-85°C over 120 minutes and maintained at this temperature for 10 hours. The reaction mixture was cooled to 20°C-30°C. An 18 wt% aqueous solution of H2SO4 (435 g, 0.8 mol) was added below 30°C, and the mixture was further diluted with IPA (200 mL). The resulting mixture was heated to 45°C and stirred for 0.5 to 1 hour. Water (1000 mL) was added over 2 hours while maintaining the temperature at 45°C. Seed crystals (1 g, 1 wt%) were added, followed by water (910 mL) over 2 hours while maintaining the temperature at 45°C. The resulting slurry was cooled to 25°C over 2 hours and stirred for 10 hours. The suspension was filtered, and the filter cake was rinsed with water (500 mL). The suspension was slurried in IPA (300 mL) and water (600 mL). The suspension was filtered, and the wet cake was dissolved in THF (660 mL) with stirring at 35 to 45°C. The resulting solution was concentrated to 280 to 380 mL. Additional THF was added, and the mixture was concentrated to 330 mL of THF until the KF was 0.5% or less. The resulting THF solution was adjusted to 45-50°C and diluted with n-heptane (160 mL). Seed crystals (1 g, 1 wt%) were added, and the contents were stirred for 1-2 hours to obtain a slurry. n-heptane (1490 mL) was added over 2 hours, maintaining the internal temperature at 45-50°C. The resulting suspension was stirred for 1-2 hours, cooled to 15°C over 2 hours, and further stirred at this temperature for 12-16 hours. The suspension was filtered, and the filter cake was rinsed with n-heptane (450 mL). The solid was dried at 55-65°C for 16-18 hours until the residual solvent levels met the specifications (THF: NMT 720 ppm, n-heptane: NMT 0.2%, IPA: 0.5% IPA) to give the title compound as a solid (75 g, 92%).Melting point (DSC): 219.77℃;. 1 H NMR(CDCl3)δ 7.53(d,J=5.0Hz,1 H),7.39-7.25(m,2 H),7.19(d,J=4.3Hz,1 H),3.75-3.66(m,2 H),3.09-2.96(m,1 H),2.05-1.86(m,1 H),1.83-1.73(m,1 H),1.72-1.45(m,5 H),1.43-1.36(m,1 H),1.31-1.23(m,5 H),1.21-1.14(m,3 H); 13 C NMR(CDCl3)δ 165.93,161.62,157.26,140.12,138.60,128.22,126.38,126.28,120.40,113.50,112.01,72.01,61.79,44.75,37.48,34.6 7,33.86,31.74,23.20,21.81,19.50,14.57;TOF-MS(ESI)m / z Calculated value: 412.1867, measured value: 412.1900 (M+H), purity of キラル (HPLC による): 99.5% super.

[0191] Replace modulation 30 A reactor was charged with 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-1H-indole-2-carboxamide (4.0 g, 7.99 mmol), water (0.18 mL, 9.99 mmol), and DMI (16 mL). NaOt-Bu (2.35 g, 24.0 mmol) was added portionwise while maintaining the internal temperature at 26 °C. The mixture was then stirred at 80 °C for 10 h, after which it was cooled to 25 °C and slowly quenched with 18 wt% aqueous HSO (15.8 mL, 32.0 mmol). The resulting solution was diluted with IPA (6.40 g, 106.0 mmol) and then warmed to 45° C. Water (18.0 mL) was added over 60 minutes, followed by product seeds (40.0 mg, 0.097 mmol), and the resulting mixture was stirred for 45 minutes to form a suspension. Water (58.4 mL) was added over 2 hours, and the resulting suspension was stirred for 2 hours. The slurry was cooled to 25° C., stirred for an additional 10 hours, and filtered. The wet cake was rinsed with water (20.0 mL) and dissolved in THF (26.4 mL). The resulting solution was concentrated to approximately 3.3 volumes, and then THF (26.4 mL) was added. The resulting solution was concentrated to approximately 3.3 volumes, and then THF (26.4 mL) was added. The resulting solution was concentrated to approximately 3.3 volumes. The concentrated solution was filtered, and THF (26.4 mL) was added to the filtrate. The resulting solution was concentrated to approximately 3.3 volumes and heated to 45°C. Heptane (6.40 mL) was added, and product seeds (40.0 mg, 0.097 mmol) were added to the solution. The resulting suspension was stirred for 90 minutes. Heptane (59.6 mL) was added over 120 minutes, and the resulting slurry was stirred at 45°C for an additional 90 minutes. The temperature was adjusted to 15°C, stirred for an additional 4 hours, and filtered. The filter cake was rinsed with heptane (26.3 mL) and dried under vacuum at 60°C for 18 hours to give the title compound as a solid (3.04 g, 91.1%). Analytical data were consistent with those collected from Preparation 30.

[0192] Preparation 31 (1S,2S)-8'-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-methyl-3'H,5'H-spiro[cyclopropane-1,12'-[1,2,4]oxadiazolo[4',3':4,5]pyrazino[1,2-a]indole]-3',5'-dione

[0193] [ka] 5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (15.0 g, 36.5 mmol) was suspended in EtOAc (225 mL) in a three-neck round-bottom flask under a nitrogen atmosphere and cooled to 0 °C. N,N-Diisopropylethylamine (9.54 mL, 54.7 mmol) was added dropwise to the mixture to give a solution. Acetyl chloride (5.19 mL, 72.9 mmol) was added dropwise over approximately 2 minutes. The mixture was stirred at ambient temperature for 1 hour and then concentrated in vacuo to approximately 100 mL. The resulting slurry was diluted with a saturated aqueous solution of NH4Cl (100 mL) and stirred for 10 minutes. The slurry was filtered, and the collected solid was slurried in aqueous NH4Cl (50 mL x 2) and water (50 mL x 2) and filtered. The resulting solid was dried under vacuum at 55°C. The solid was further slurried in water and filtered to remove residual ammonium salts. The wet solid was then dried under full vacuum at 55°C to give the title compound as a powder (4.83 g, 31%). 1 H NMR(DMSO-d6):δ 7.65(s,1 H),7.62(s,1 H),7.55(d,J=8.8Hz,1 H),7.32(d,J=9.2Hz,1 H),3.72(d,J=8.0Hz,2 H),3.16(dd,J=7.6Hz,10Hz,1 H),3.05(m,1 H),2.69(m,1 H),1.70(m,2 H),1.64-1.44(m,3 H),1.28(d,J=6.0Hz,3 H),1.31(s,3 H),1.19(s,3 H). 13C NMR (DMSO-d6): δ 155.9, 152.5, 151.4, 140.1, 134.2, 128.3, 128.0, 127.7, 121.1, 113.2, 110.9, 71.7, 61.1, 44.5, 42.1, 36.7, 33.8, 32.0, 25.3, 22.2, 21.3, 11.7. TOF-MS (ESI) m / z calculated: 411.2027; found: 411.2062 (M+NH4 + ).

[0194] Preparation 32 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one

[0195] [ka] A vessel was charged with 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (15.08 g, 36.5 mmol) and suspended in THF (45 mL) and DMI (37.5 mL). To the flask under N2, HATU (15.30 g, 40.24 mmol) was added, followed by THF (15 mL), and the mixture was stirred using overhead stirring. DIPEA (14.14 g, 109.4 mmol) was added over at least 30 min while maintaining the internal temperature between 20 °C and 30 °C, followed by stirring for 1 h. To the mixture was added (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (17.6 g, 35.7 mmol) as a solid and rinsed forward with THF (15.0 mL). The reaction was stirred at ambient temperature for 42 hours. EtOAc (195 mL) was added to dilute the reaction mixture, followed by the sequential addition of water (45 mL) and a 5 wt% aqueous solution of NaSO (45 mL). The resulting biphasic mixture was stirred for at least 30 minutes, after which the layers were separated. The organic layer was returned to the reaction flask, and 15 wt% aqueous NaCO (150 mL) was added. The resulting biphasic mixture was stirred for at least 30 minutes, after which the layers were separated. The 5 wt% Na2SO4 aqueous solution (150 mL) washing process was repeated three times, and the organic layer was concentrated in vacuo below 40°C. THF (105 mL) was added, and the resulting mixture was again concentrated to dryness below 40°C. The THF solvent exchange process was repeated two more times, and the resulting solution was transferred to a reactor under temperature control. To this mixture, formic acid (150 mL) was added dropwise with stirring, maintaining the internal temperature between 20°C and 30°C. Water (195 mL) was added over 11 hours, and the resulting slurry was then stirred for 8 hours. The suspension was filtered, and the filter cake was rinsed with water (105 mL). The wet cake was suspended in water (300 mL) and stirred at 40°C for 4 hours.The suspension was filtered and the wet cake was rinsed with water (105 mL). The wet cake was dried in a vacuum oven under a N sweep at 65° C. for 23 hours to give the title compound as a powder (27.00 g, 84%). FTIR (cm. -1 ):3114.3,2971.1,2930.6,2874.7,1789.8,1748.1,1714.6,1704.1,1668.7,1651.6,1614.8,1587.3,1557.6,1530.8,1495.6,1474.4,1449.8,1431.4,1383.3,1337.4,1324.3,1305.4, 1253.5,1234.6,1201.0,118.4,1127.3,1106.9,1078.7,1058.4,983.4,967.6,958.3,931.3,913.4,902.4,880.3,859.0,847.8,810.7,796.5,771.8,742.1,721.8,692.8,681.3,659.2; 1 H NMR(DMSO-d6)δ 8.31(s,1H),7.63(d,J=8.9Hz,1H),7.57-7.23(m,4H),7.20(m,2H),7.09(m,1H),7.02-6.69(m,2H),5.89- 5.14(m,1H),4.94-4.31(m,1H),4.11(m,3H),3.80-2.70(m,7H),2.25(m,6H),1.85-1.34(m,10H),1.27(br s,3H),1.18(br s,6H); 19 F NMR (CDCl3) δ -122.2, -126.7.

[0196] Alternative preparation 32 A vessel was charged with 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (35.04 g, 85.08 mmol), HATU (35.58 g, 93.57 mmol), THF (141 mL), and DMAc (88 mL). DIPEA (44.5 mL) was added over 30 minutes while maintaining the internal temperature between 20° C. and 30° C. The resulting solution was stirred for 1.5 hours, after which time (S)-1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (37.14 g, 83.38 mmol) was added, followed by a THF (35 mL) rinse. The mixture was stirred at 20°C to 30°C for 45 to 55 hours. EtOAc (490 mL), water (105 mL), and 5 wt% aqueous NaSO (105 mL) were added sequentially. The resulting biphasic mixture was stirred for at least 30 minutes, after which the layers were separated. The organic layer was returned to the reaction flask, and 15 wt% aqueous NaCO (350 mL) was added. The resulting biphasic mixture was stirred for at least 30 minutes, after which the layers were separated. The 15 wt% Na2CO3 aqueous solution (350 mL) washing process was repeated three times, and the organic layer was concentrated in vacuo to approximately 122.5 mL below 40 °C. THF (142 g) was added, and the resulting mixture was concentrated to approximately 122.5 mL below 40 °C. The solvent exchange process was repeated two more times, and the resulting solution was transferred to a jacketed, temperature-controlled reactor. The original reactor and transfer line were rinsed with THF (52.5 mL), which was then combined with the contents of the reactor. The mixture was stirred at 25 °C, and formic acid (350 mL) was charged over 2 hours while maintaining the internal temperature between 20 °C and 30 °C. Water (455 mL) was added over 6 hours, and the resulting slurry was then stirred for at least 12 hours. The suspension was filtered, and the filter cake was rinsed with water (245 mL). The wet cake was suspended in water (700 mL) and stirred at 25° C. for 6 hours.The suspension was filtered and the wet cake was rinsed with water (245 mL). The wet cake was dried in a vacuum oven under a N sweep at 60° C. for at least 48 hours to give the title compound as a powder (56.96 g, 84%). Analytical data were consistent with that collected from Preparation 31.

[0197] Alternative preparation 32 A reactor was charged with 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (3.22 g, 7.32 mmol), THF (30 mL), DIPEA (2.84 g, 22.0 mmol), COMU (3.44 g, 8.03 mmol), and THF (3 mL). The temperature was adjusted to 20°C to 30°C, and the mixture was stirred for 1 hour. (S)-1-(4-Fluoro-1-methyl-1H-indazol-5-yl)-3-(2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-1,3-dihydro-2H-imidazol-2-one (3.71 g, 7.29 mmol) and THF (6 mL) were added to a reactor. The mixture was stirred at 20-30 °C for 17 h. EtOAc (40 mL) and 5% aqueous NaSO (24 mL) were added at 20-30 °C, followed by stirring for 15 min. The layers were separated. The organics were washed sequentially with 15% aqueous NaCO (40 mL) and 5% aqueous NaSO (3 × 40 mL). The organics were concentrated to dryness in vacuo below 40 °C. EtOAc (28 mL) was added to the mixture and concentrated to dryness in vacuo at below 40°C. The solvent exchange process was repeated two more times, followed by the addition of 28 mL of EtOAc. The temperature was adjusted to 45-55°C, followed by stirring for 0.5 h. A mixture of 8 mL of EtOAc and 24 mL of n-heptane was added dropwise to the vessel at 45-55°C. The mixture was cooled to 20-30°C over 3.5 h and then stirred for 16 h. After filtration, the cake was rinsed with 12 mL of n-heptane and dried under vacuum at 50-55°C for 20 h to give the title compound (7.03 g, 87%). Analytical data were consistent with those collected from Preparation 31.

[0198] Example 1 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-5-oxo-1,2,4-oxadiazol-4-ide hemicalcium

[0199] [ka] In a reactor, sodium hydroxide (0.55 g), water (6.6 mL), and 3A To a solution of EtOH (22.5 mL) was added 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((S)-3-(3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (7.02 g, 7.95 mmol) while maintaining the internal temperature between 20 °C and 30 °C. The addition funnel was rinsed with 3A EtOH (8.4 mL), and the mixture was stirred until a clear solution was obtained. A solution of calcium acetate dihydrate (0.73 g, 4.14 mmol) in water (5.3 mL) was added dropwise to give a cloudy mixture. Dry seeds (0.2 g) were added, and the resulting suspension was stirred for 10 hours. Water (56.8 mL) was added to the reaction over 6 hours, followed by stirring for at least 5 hours. The mixture was filtered, and the cake was washed with water (35 mL). The solid was dried in a vacuum oven at 55 °C with an N sweep for at least 48 hours to give the title compound as a free-flowing powder (6.89 g, 88.4%). TOF-MS (ESI) m / z 881.37 (MH-Ca)

Claims

1. Compound 6 of the following structure: 【Chemistry 1】 1. A method for producing The following structure: 【Chemistry 2】 The method comprises a multi-step chemical reaction starting from compound 1 of formula (I).

2. Starting from compound 1, compound 5: 【Transformation 3】 wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. via 10. The method of claim 1, comprising a multi-step chemical reaction to arrive at compound 6.

3. The reaction steps for converting compound 1 to compound 2 are as follows: 【Chemistry 4】 wherein the reaction is carried out in a solvent selected from toluene, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO and CPME.

4. A reaction step of converting compound 2 to compound 3 in the presence of a catalyst in a solvent as shown below: 【Transformation 5】 Further comprising: The catalyst is tetrakis(triphenylphosphine) [Pd(PPh ３ ) ４ ], palladium(0), palladium chloride (PdCl ２ ), palladium(II) acetate [Pd(OAc)] ２ , allylpalladium(II) chloride dimer [PdCl(C ３ H ５ )] ２ , Pd(dppf)Cl ２ , Pd(dtbpf)Cl ２ and a combination of two or more of the listed catalysts; 4. The process of any one of claims 1 to 3, wherein the solvent is selected from toluene, MeCN, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO, and CPME.

5. The reaction steps for converting compound 3 to compound 4 are as follows: 【Transformation 6】 wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. The method of any one of claims 1 to 4, further comprising:

6. 6. The method of claim 5, wherein the reacting step comprises reacting compound 3 with CDI in a solvent, followed by coupling with (R)-4-phenyl-2-oxazolidone in the presence of 1,8-doazabicyclo[5.4.0]undec-7-ene in a solvent.

7. 6. The method of claim 5, wherein the reacting step comprises reacting compound 3 with CDI in an ACN solvent, followed by coupling with (R)-4-venyl-2-oxazolidone in the presence of 1,8-doazabicyclo[5.4.0]undec-7-ene in an N,N-dimethylacetamide solvent.

8. The reaction steps for converting compound 4 to compound 5 are as follows: 【Transformation 7】 wherein R is phenyl or benzyl. The method of any one of claims 1 to 7, further comprising:

9. 9. The method of claim 8, wherein the reacting step comprises copper-mediated addition of 2-methylallylmagnesium chloride, 2-methylallylmagnesium bromide, or 2-methylallylmagnesium iodide to compound 4 in the presence of lithium chloride to provide compound 5.

10. The reaction steps for converting compound 5 to compound 6 are as follows: 【Transformation 8】 wherein R is phenyl or benzyl. The method of any one of claims 1 to 9, further comprising:

11. the reacting step comprises reacting compound 5 with a reducing agent in a solvent to obtain compound 6; The reducing agent is lithium borohydride, NaBH ４ , B.H. ３ , L.A.H.,H. ２ , DIBAl, and Red-Al; 11. The method of claim 10, wherein the solvent is selected from toluene, THF, 2-MeTHF, DCM, MTBE, and CPME.

12. The reaction steps are as follows: 【Chemistry 9】 wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl. The method according to any one of claims 1 to 11, comprising:

13. Compound 6 has the following structure: 【Chemistry 10】 13. The method of any one of claims 1 to 12, further comprising a multi-step chemical reaction to convert 12 to compound 12 having the formula:

14. The reaction steps for converting compound 6 to compound 7 are as follows: 【Chemistry 11】 14. The method of claim 13, comprising:

15. The reaction steps for converting compound 10 to compound 11 are as follows: 【Chemistry 12】 15. The method of claim 13 or 14, further comprising:

16. Compound 24 of the following structure: 【Chemistry 13】 A multi-step process for preparing compound 20 from compound 19, comprising the chemical reaction: 【Chemistry 14】 A method comprising:

17. The reaction is carried out with Pd(OAc) ２ 17. The method of claim 16, which is a coupling reaction of compound 19 with (diphenylmethylene)hydrazine using a catalyst selected from the group consisting of and Xantphos.

18. The chemical reaction converting compound 20 to compound 21 is shown below: 【Chemistry 15】 18. The method of claim 16 or 17, further comprising:

19. A multi-step reaction to prepare compound 24 from compound 21 is shown below: 【Chemistry 16】 17. The method of claim 16, further comprising:

20. The following structure: 【Chemistry 17】 Compound.

21. The following structure: [Chemistry 18] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.

22. The following structure: 【Chemistry 19】 wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.

23. The following structure: 【Chemistry 20】 Compound.

24. The following structure: 【Chemistry 21】 Compound.

25. The following structure: 【Chemistry 22】 Compound.

26. The following structure: 【Chemistry 23】 26. The method or compound of any one of claims 1 to 25 for use in preparing a compound 35 having the formula:

27. Method for converting compound 35 to the hemicalcium salt of this compound: 【Chemistry 24】 27. The method of claim 26, further comprising: wherein compound 35 is treated with NaOH and a calcium salt selected from calcium acetate, calcium citrate, calcium lactate, calcium gluconate, calcium chloride, calcium sulfate, calcium nitrate, calcium iodide, and tricalcium phosphate.

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