Preparation method of GLP1 RA and intermediate thereof

Abstract

The invention relates to a preparation method of 3-[(1S, 2S)-1-[5-[(4S)-2, 2-dimethyl oxacyclohexane-4-yl]-2-[(4S)-2-(4-fluoro-3, 5-dimethyl phenyl)-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, 3-triazolo [4, 3-c] pyridine-5-carbonyl] indol-1-yl]-2-methylcyclopropyl]-1, 2, 4-triazolo [4, 3-c] pyridine-5- The invention relates to synthesis of 1, 2, 4-oxadiazole-5-one or a salt thereof, and related synthesis intermediate compounds.

Description

Technical Field

[0001] Disclosed herein is a method for synthesizing 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 or a salt thereof (referred to herein as GLP1RA) or a hydrate of the salt. Background Art

[0002] GLP1RAs are described and claimed in US 10,858,356.

[0003] US 10,858,356 describes a synthetic method for preparing GLP1RA. However, an alternative method for preparing the compound is needed. The method described herein provides one or more benefits compared to known methods because it passes through different intermediates. In one embodiment, the instant method is more robust and efficient. In one embodiment, the instant method is more scalable. In one embodiment, the instant method provides a higher yield. Summary of the Invention

[0004] GLP1RA can be prepared as a pharmaceutically acceptable salt. One salt of GLP1RA is the hemi-calcium 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 / 2Ca 2+ ”), which has the following structure:

[0005]

[0006] GLP1RA can be prepared as a hydrate of a pharmaceutically acceptable salt. One hydrate of GLP1RA is 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 hemi-calcium hydrate ("GLP1RA"). 1 / 2Ca 2+ hydrate”).

[0007]

[0008] In one embodiment, disclosed herein is a method for preparing compound 6 of the following structure:

[0009]

[0010] It involves a multi-step chemical reaction starting from compound 1 having the following structure:

[0011]

[0012] In one embodiment, the above method comprises a multi-step chemical reaction starting from the following compounds:

[0013]

[0014] After compound 5:

[0015]

[0016] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl; and compound 6 is obtained:

[0017]

[0018] In one embodiment, R is phenyl or benzyl. In another embodiment, R is phenyl. In another embodiment, R is benzyl.

[0019] In one embodiment, the above method includes the reaction step of converting compound 1 into compound 2 as shown below:

[0020]

[0021] In one embodiment, the above method further comprises a reaction step of converting compound 2 into compound 3, as shown below:

[0022]

[0023] In one embodiment, the above method further comprises the step of converting compound 3 into compound 4, as shown below:

[0024]

[0025] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl or heteroarylalkynyl phenyl or benzyl. In one embodiment, R is phenyl or benzyl.

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

[0027] In one embodiment of the reaction of compound 3 to compound 4, the method comprises reacting compound 3 with CDI in a solvent, followed by coupling with (R)-4-benyl-2-oxazolidinone in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent.

[0028] In one embodiment of the reaction of compound 3 to compound 4, the method comprises reacting compound 3 with CDI in a solvent, followed by coupling with (R)-4-phenyl-2-oxazolidinone in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent.

[0029] In one embodiment, the above method further comprises the step of converting compound 4 into compound 5, as shown below:

[0030]

[0031] wherein R is phenyl or benzyl. In one embodiment, R is phenyl. In another embodiment, R is benzyl.

[0032] In one embodiment of the reaction of compound 4 to compound 5, the process comprises copper-mediated addition of 2-methylallylmagnesium chloride to compound 4 in the presence of lithium chloride to provide compound 5.

[0033] In one embodiment, the above method further comprises the step of converting compound 5 into compound 6, as shown below:

[0034]

[0035] 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.

[0036] In one embodiment of the above step of converting compound 5 to compound 6, the reaction step comprises reducing compound 5 with lithium borohydride to obtain compound 6.

[0037] In one embodiment, the above method comprises the following multi-step reaction starting from compound 1 to obtain compound 6:

[0038]

[0039] as well as

[0040]

[0041] 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.

[0042] In one embodiment, disclosed herein is a method for preparing compound 12 of the following structure:

[0043]

[0044] It involves a multi-step chemical reaction starting from compound 6 having the following structure:

[0045]

[0046] In one embodiment, the above method comprises a multi-step chemical reaction starting from the following compounds:

[0047]

[0048] After compound 7:

[0049]

[0050] After compound 10:

[0051]

[0052] After compound 11:

[0053]

[0054] And obtain compound 12:

[0055]

[0056] In one embodiment, the above method includes the reaction step of converting compound 6 into compound 7 as shown below:

[0057]

[0058] In one embodiment, the above method further comprises the step of converting compound 10 into compound 11, as shown below:

[0059]

[0060] In one embodiment, the above multi-step process from compound 6 to compound 12 comprises the following reactions for converting compound 6 to compound 7 and converting compound 10 to compound 11:

[0061] as well as

[0062]

[0063] In one embodiment, disclosed herein is a method for preparing compound 20 of the following structure:

[0064]

[0065] This involves a multi-step chemical reaction starting from compound 19 having the following structure:

[0066]

[0067] In one embodiment, the above method comprises a multi-step chemical reaction starting from the following compounds:

[0068]

[0069] And obtain compound 20:

[0070]

[0071] In one embodiment, the above method includes the reaction step of compound 19 to compound 20, as shown below:

[0072]

[0073] The reaction step comprises a coupling reaction of compound 19 with (diphenylmethylene)hydrazine using a catalyst selected from Pd(OAc)2 and Xantphos to obtain compound 20.

[0074] In one embodiment, the above method further comprises the step of converting compound 20 into compound 21, as shown below:

[0075]

[0076] In one embodiment, the above method comprises a multi-step reaction for preparing compound 24 starting from compound 21, as shown below:

[0077]

[0078] In one embodiment, disclosed herein is compound 3 having the following structure:

[0079]

[0080] In one embodiment, disclosed herein is compound 4 having the following structure:

[0081]

[0082] wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.

[0083] In one embodiment, disclosed herein is compound 5 having the following structure:

[0084]

[0085] 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.

[0086] In one embodiment, disclosed herein is compound 6 having the following structure:

[0087]

[0088] In one embodiment, disclosed herein is compound 20 having the following structure:

[0089]

[0090] In one embodiment, disclosed herein is a compound having the structure:

[0091]

[0092] Unless otherwise defined in this specification, certain abbreviations are defined as follows:

[0093] ACN-acetonitrile;

[0094] aq.-watery;

[0095] Bn-benzyl;

[0096] CDI-1,1'-carbonyldiimidazole;

[0097] COMU-1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate;

[0098] CSTR-continuous stirred tank reactor;

[0099] DBU-1,8-diazabicyclo[5.4.0]undec-7-ene;

[0100] DCM - dichloromethane;

[0101] DEA-diethylamine;

[0102] DIPEA-N,N-diisopropylethylamine;

[0103] DMAc-dimethylacetamide;

[0104] DMF-dimethylformamide;

[0105] DMI-1,3-dimethyl-2-imidazolidinone;

[0106] DMSO-dimethyl sulfoxide;

[0107] DSC-Differential Scanning Calorimetry;

[0108] ESI - electrospray ionization;

[0109] EtOAc-ethyl acetate;

[0110] EtOH - ethanol and ethyl alcohol;

[0111] h-hour

[0112] HATU-1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate;

[0113] HPLC-high performance liquid chromatography;

[0114] HRMS-high resolution mass spectrometry;

[0115] IPA - isopropyl alcohol and isopropyl alcohol;

[0116] IPAc-isopropyl acetate;

[0117] KF-Karl Fischer titration;

[0118] MeOH - methanol and methyl alcohol;

[0119] 2-MeTHF-2-methyltetrahydrofuran;

[0120] min-minutes

[0121] mp-melting point

[0122] MTBE-methyl tert-butyl ether;

[0123] NMM-N-methylmorpholine;

[0124] NMP-1-methyl-2-pyrrolidone;

[0125] NMR-nuclear magnetic resonance;

[0126] NMT-not more than;

[0127] Ph-phenyl;

[0128] Pd(OAc)2-palladium(II) acetate;

[0129] QNMR - quantitative nuclear magnetic resonance;

[0130] TBAB-tetrabutylammonium bromide;

[0131] TEA-triethylamine;

[0132] THF - tetrahydrofuran;

[0133] TOF-MS - Time of Flight Mass Spectrometer.

[0134] Solution 1

[0135]

[0136] 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.

[0137] In Scheme 1, Step A shows the use of oxalyl chloride in a solvent such as ACN to generate the acid chloride of compound 1, which is then reacted with N-methylaniline to generate compound 2. There are many methods for amide coupling, whether by generating an acid chloride or by using an amide coupling reagent, such as SOCl2, Ac2O, 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. Various solvents such as toluene, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO or CPME can also be used. The reaction can be carried out at a temperature ranging from -10 to 100°C. In one embodiment, the reaction temperature is in the range of 0 to 40°C.

[0138] Step B shows that compound 2 undergoes Heck coupling with acrylic acid to generate compound 3. There are many methods to perform 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 a temperature ranging from -10 to 150°C. In one embodiment, the reaction temperature is 40 to 100°C.

[0139] Step C shows the reaction of compound 3 with CDI in a solvent such as ACN, followed by coupling with an 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. There are many other methods for amide coupling, whether by generating an acid chloride or by using an amide coupling reagent such as SOCl2, Ac2O, PivCl, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), Boc anhydride, T3P, DCC, DIC, EDC, HATU, HBTU, TBTU, TPTU, TBTU, TPTU, cyanuric chloride, CDMT or DMTMM. Various solvents such as toluene, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO or CPME can also be used. The reaction can be carried out at a temperature ranging from -10 to 100°C. In one embodiment, the reaction temperature is from 0 to 40°C.

[0140] Step D describes the copper-mediated addition of 2-methylallylmagnesium chloride to compound 4 in the presence of lithium chloride to provide compound 5. Other Grignard reagents such as 2-methylallylmagnesium bromide and 2-methylallylmagnesium iodide can be used in combination with salts such as LiBr or LiI and Cu reagents such as CuBr or CuI and carried out in solvents such as Et2O, MTBE, THF, 2-MeTHF, or CPME. The reaction of Step D can be carried out at a temperature range of -80 to 20°C. In one embodiment, the reaction temperature is -60 to -10°C.

[0141] Step E shows the reduction of compound 5 with lithium borohydride to give compound 6. There are many reducing agents, such as NaBH4, BH3, LAH, H2, 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 range of -80 to 80°C. In one embodiment, the temperature is -40 to 80°C.

[0142] Step F shows 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 performed using other acid / solvent combinations such as MsOH, TsOH, H2SO4, HCl or TFA in combination with toluene, MeCN, MTBE, THF, 2-MeTHF, DCM or dioxane. The reaction of step E can be carried out at a temperature ranging from -10 to 100°C. In one embodiment, the temperature is from 20 to 80°C.

[0143] Step G shows the alkylation of compound 7 with chloroacetonitrile to give compound 8 using a suitable base such as potassium hydroxide and catalytic tetrabutylammonium chloride hydrate in a solvent such as toluene.

[0144] Step H shows the reaction of compound 8 with (R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide using a suitable base such as potassium bis(trimethylsilyl)amide or lithium tert-butoxide in a suitable solvent such as THF to give compound 9.

[0145] Step I shows the addition of hydroxylamine to compound 9 in a suitable solvent such as IPA or THF to give compound 10.

[0146] Step J describes the intramolecular cyclization of compound 10 using CDI and an appropriate base such as DBU in a solvent such as THF to provide compound 11. 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, and 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, at temperatures ranging from 0 to 150°C. In one embodiment, the temperature is from 5 to 40°C.

[0147] Step K shows the hydrolysis of compound 11 using a base such as sodium tert-butoxide in the presence of water in a solvent such as DMI, followed by acidification with aqueous H2SO4 to provide compound 12.

[0148] Option 2

[0149]

[0150] In Scheme 2, step A shows the reaction of compound (13) with methanesulfonic anhydride using a suitable base such as TEA in a suitable solvent such as DCM to provide compound 14. Step B shows the nucleophilic substitution of compound 14 using sodium cyanide and a phase transfer catalyst such as TBAB in a solvent such as DMF to provide compound 15. Step C shows the acidic deprotection of compound 15 using HCl in a solvent such as DCM to provide compound 16. Step D shows 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 provide compound 17. Step E shows the cyclization of compound 17 using a base such as potassium tert-butoxide in a solvent such as THF to provide compound 18.

[0151] Option 3

[0152]

[0153] Step A in Scheme 3 shows the coupling of compound 19 with (diphenylmethylene)hydrazine using an appropriate 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 provide compound 20. Step B shows the acidic deprotection of compound 20 with HCl in a solvent such as dioxane to provide compound 21. Alternatively, deprotection can be performed using acetic acid and water.

[0154] Option 4

[0155]

[0156] In Scheme 4, step A shows the coupling of compounds 18 and 21 using a suitable base such as NMM in a solvent such as NMP, followed by cyclization to provide compound 22. Step B shows the addition of (N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide) to compound 22 using a base such as potassium tert-butoxide in a solvent such as DMAc to provide compound 23. Step C shows the intramolecular cyclization of compound 23 using methanesulfonic acid in a solvent such as THF to provide compound 24.

[0157] Option 5

[0158]

[0159] In Scheme 5, step A shows the lithiation of compound 25 in a solvent such as 2-MeTHF, followed by reaction with DMF to give compound 26. Step B shows the addition of methylhydrazine to compound 27 in a solvent such as EtOH to give compound 27. Step C shows the intramolecular cyclization of compound 27 using CuCl and a base such as DBU in a solvent such as DMI to give compound 28.

[0160] An alternative route to compound 28 begins with step A1, where compound 29 is treated with acetic anhydride in a solvent such as toluene to provide compound 30. Step B1 shows the cyclization of compound 30 using isoamyl nitrite in a solvent such as toluene to provide compound 31. Step C1 shows the methylation of compound 31 using iodomethane, a base such as potassium carbonate, and a solvent such as DMF to provide compound 28.

[0161] Option 6

[0162]

[0163] In Scheme 6, step A shows 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 provide compound 32. Step B shows the deprotection of compound 32 using methanesulfonic acid in a solvent such as ACN to provide compound 33.

[0164] Option 7

[0165]

[0166] Steps A and B in Scheme 7 show treatment of compound 12 with a coupling agent such as HATU or COMU and a base such as DIPEA in solvents such as THF, DMI, and DMAc to form compound 34, followed by amide coupling of compound 34 and 33 to provide compound 35. Step C shows treatment of compound 35 with NaOH and calcium acetate dihydrate in a solvent system such as water and EtOH to provide compounds of Formula I.

[0167] There are many possible solvents, bases and calcium salt combinations that can be used to carry out the reaction. In one embodiment, a suitable solvent is selected from methanol, isopropanol, tetrahydrofuran, acetonitrile, dimethylformamide, ethyl acetate, toluene, dichloromethane, dimethyl sulfoxide, tert-butyl methyl ether, dimethylacetamide and 1,4-dioxane. A suitable base is selected from sodium ethoxide, sodium tert-butoxide, potassium hydroxide, potassium ethoxide, potassium tert-butoxide, sodium tert-amyl alcohol, sodium hydride and sodium bis(trimethylsilyl)amide. A suitable calcium salt is selected from calcium acetate, calcium citrate, calcium lactate, calcium gluconate, calcium chloride, calcium sulfate, calcium nitrate, calcium iodide and tricalcium phosphate. This step can be carried out in a temperature range of 0 to 150°C. In one embodiment, the temperature is 0 to 50°C.

[0168] Preparation Example 1

[0169] 5-Bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0170]

[0171] ACN (7951 kg), 5-bromo-1H-indole-2-carboxylic acid (991 kg, 4.13 kmol) and oxalyl chloride (654 kg, 5.15 kmol) were charged into a reactor. A solution of DMF (151 kg, 2.07 kmol) in ACN (958 kg) was added dropwise at 20-30° C., and the mixture was stirred at 20-30° C. for 45 minutes. N-methylaniline (550 kg, 5.13 kmol) was added at 0-20° C. and stirred for 2 hours. TEA (1080 kg, 10.67 kmol) was added at 0-20° C. and stirred for 2 hours. Water (1456 kg) was added, and the mixture was stirred at 20-30° 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 afford the title compound as a solid (1288.4 kg, 92%). mp (DSC): 259.2°C. 1 HNMR(DMSO-d6)δ3.39(br s,3H),5.27(s,1H),7.23(dd,J=8.78Hz,1.76Hz,1H),7.34-7.52(m,7H),11.81(s,1H). 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 calcd: 328.0211, found: 329.0308 (M+H).

[0172] Alternative Preparation Example 1

[0173] 5-Bromo-1H-indole-2-carboxylic acid (4.96 g, 20.66 mmol), DMF (0.81 mL, 10.5 mmol) and ACN (50 mL) were added to the reactor. A solution of oxalyl chloride (2.38 mL, 27.46 mmol) in ACN (10 mL) was added at a rate such that the temperature was maintained at <30°C. After the addition was complete, the reactants were stirred vigorously at ambient temperature for 60 min. The reaction temperature was then adjusted to 5°C, and N-methylaniline (2.75 mL, 25.4 mmol) was slowly added while maintaining the internal temperature at <10°C. After stirring for 10 min, TEA (7.0 mL, 50 mmol) was slowly added to the mixture while maintaining the internal temperature at <30°C. The mixture was stirred at ambient temperature for 2 h and quenched with water (5 mL). The resulting slurry was stirred at ambient temperature for 1 h, filtered, and the resulting wet cake was washed with ACN (15 mL) and water (25 mL) in sequence. The wet cake was dried at 70°C under vacuum for 24 h to afford the title compound as a solid (6.50 g, 96%). The analytical data were consistent with those collected in Preparation 1.

[0174] Preparation Example 2

[0175] (E)-3-(2-(Methyl(phenyl)carbamoyl)-1H-indol-5-yl)acrylic acid

[0176]

[0177] 5-Bromo-N-methyl-N-phenyl-1H-indole-2-carboxamide (60 kg, 182.3 mol) and N,N-dimethylacetamide (329 kg) were added to the reactor. The mixture was heated to 50-60 ° C and purged with nitrogen. Under a nitrogen atmosphere, tri-tert-butylphosphonium tetrafluoroborate (0.64 kg, 2.2 mol) and allylpalladium chloride (II) dimer (0.17 kg, 0.46 mol) were added, 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 reactants were purged with nitrogen and stirred at 50-70 ° C for 18 h. 1M aqueous sulfuric acid solution (410 kg) was added at 50-70 ° C to reach a pH of 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 yield the title compound as a solid (52.7 kg, 87%). mp (DSC): 293.2°C. 1H NMR (DMSO-d6) δ3.39 (s, 3H), 5.31 (s, 1H), 6.36 (d, J = 15.81Hz, 1H), 7.38-7.62 (m, 9H). 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 calcd: 320.1161, found: 321.1260 (M+H).

[0178] Preparation Example 3

[0179] (R,E)-5-(3-(4-benzyl-2-oxooxazolidin-3-yl)-3-oxoprop-1-en-1-yl)-N-methyl-N-phenyl-1H-

[0180] Indole-2-carboxamide

[0181]

[0182] (E)-3-(2-(methyl(phenyl)carbamoyl)-1H-indol-5-yl)acrylic acid (585 kg, 1.83 kmol) and ACN (5646 kg) were added to the reactor. CDI (360 kg, 2.22 kmol) was added, followed by a rinse with ACN (342 kg). The reaction was stirred at 5-10°C for 2 h, 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 to the reactor in sequence. The reaction was stirred at 10-25°C for 1 h, then quenched with 5N HCl (867.5 kg) to pH 4. The resulting suspension was stirred for 6-12 h and filtered. The wet cake was rinsed with water (2925 kg) and dried under vacuum at 50-80°C to constant weight to afford the title compound as a solid (742 kg, 75%). mp (DSC): 236.6°C. 1H NMR(DMSO-d6)δ2.95-3.12(m,2H),3.39(s,3H),4.20(dd,J=8.78Hz,2.76Hz,1H),4.36(t,J=8.41Hz,1H),4.72-4. 79(m,1H),5.35(s,1H),7.18-7.33(m,5H),7.38-7.52(m,7H),7.62-7.72(m,2H),7.79-7.88(m,1H),11.93(s,1H). 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 calcd: 479.1845, found: 480.1945 (M+H).

[0183] Preparation Example 4

[0184] 5-((R)-1-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-5-methyl-1-oxohex-5-en-3-yl)-N-methyl-N-

[0185] Phenyl-1H-indole-2-carboxamide

[0186]

[0187] A 0.5 M solution of 2-methylallylmagnesium chloride in THF (1250 kg, 683 mol) and lithium chloride (30 kg, 707.6 mol) were added to the reactor. The mixture was stirred at 10-25°C for 30-90 min and cooled to between -80 and -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 between -50 and -30°C for 10 min, 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 at <-30°C, followed by a THF rinse (143 kg). The reactants were stirred between -40 and -20°C for 4h and then quenched with 10% aqueous ammonium chloride solution (500kg) at <0°C. MTBE (232kg) was added and the layers were separated. Ethylenediamine (31kg) was added to the organic layer and the mixture was stirred at 20-30°C for 1-3h. 10% aqueous ammonium chloride solution (398kg) was added and the mixture was stirred at 20-30°C for 30-60min. The layers were separated and the organic phase was filtered through a celite pad. The celite pad was rinsed with THF (95kg) and the combined filtrate was washed with 1% aqueous acetic acid solution (315kg) and 10% aqueous ammonium chloride solution (408kg) in sequence. The organic matter was concentrated to 3-5vol and the solvent was exchanged for ~39vol of ethanol at <50°C under reduced pressure. The resulting mixture was heated to ~80°C until a clear solution was formed, and the mixture was then cooled to 5-10°C at a rate of 10°C / h. The resulting suspension was stirred at 5-10°C for 1-3 hours and filtered. The filter cake was returned to the reactor along with EtOH (2634 kg). The mixture was heated at 78°C until a clear solution formed, then cooled to 5-10°C at a rate of 10°C / h. 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 yield the title compound as a solid (81.54 kg, 77%). mp (DSC): 158.3°C. 1 H NMR(DMSO-d6)δ1.61(s,3H),2.25-2.42(m,2H),2.74-2.89(m,2H),2.99-3. 19(m,2H),3.35-3.45(m,4H),4.05-4.14(m,2H),4.42-4.48(m,1H),4.58(br d,J=16.56Hz,2H),5.17(s,1H),7.05(d,J=8.53Hz,1H),7.10-7.15(m,3H),7.22-7.48(m,9H),11.46(s,1H).13 C NMR(DMSO-d6)δ22.45,37.07,38.89,40.62,42.30,45.07,54.65,66.42,105.88,112.31,112.87,120.23,124.23,127.17,1 27.28,128.25,128.43,128.97,129.81,130.15,130.57,134.92,135.70,136.14,143.81,144.74,153.67,161.86,171.69. TOF-MS (ESI) m / z calculated value: 535.2471, found: 536.2572 (M+H).

[0188] Alternative Preparation Example 4

[0189] A 0.5M THF solution of 2-methylallylmagnesium chloride (1320 kg, 721 mol) and lithium chloride (31 kg, 731.3 mol) were added to the reactor. The mixture was cooled to -42 ° C, and then copper (I) iodide (140 kg, 735.1 mol) and (R, E) -5- (3- (4-benzyl-2-oxooxazolidin-3-yl) -3-oxoprop-1-ene-1-yl) -N-methyl-N-phenyl-1H-indole-2-carboxamide (100 kg, 208.5 mol) were added at <-30 ° C. The reactants were stirred between -40 and -20 ° C for 8 h, then quenched with 10% aqueous ammonium chloride solution (480 kg). MTBE (220 kg) was added, the contents were stirred for 1 h, and the layers were separated. Ethylenediamine (63 kg) was added to the organic layer, and the mixture was stirred at 20-30 ° C for 2 h. 10% aqueous ammonium chloride solution (400kg) was added, and the mixture was stirred at 20-30°C for 30-60min. The layers were separated, and the organic phase was filtered through a diatomaceous earth pad. The diatomaceous earth pad was rinsed with THF (89kg), and the combined filtrate was washed with 10% aqueous ammonium chloride solution (300kg). The organic phase was concentrated in vacuo, and the solvent was exchanged to 5vol with EtOH (948kg) at <50°C under reduced pressure. EtOH (2370kg) was added, and the resulting mixture was heated to 80°C until a clear solution was formed, and the mixture was then cooled to 5-10°C for 3h. The resulting suspension was filtered, and the filter cake was rinsed with EtOH (100kg). The solid was dried to constant weight at 50-80°C under vacuum to obtain the title compound as a solid (85.8kg, 76%). The analytical data were consistent with the data collected in Preparation Example 4.

[0190] Alternative Preparation Example 4-CSTR Method

[0191] Feed Preparations

[0192] Pump A feed: In a dry 3000-L glass-lined reactor (FLR1), 0.5 M 2-methylallylmagnesium chloride THF solution (1381.3 kg, 750.7 mol) and LiCl (31.8 kg, 750.7 mol) were added at 10-30°C and stirred for 0.5-1 h as feed A.

[0193] Pump B feed: In a 50 L stirred tank (FLR5), a THF solution of CuI (3 kg, 15.75 mol) (6 L) was used as feed B (prepared every ~40 min, total CuI: 143.0 kg, 750.1 mol).

[0194] Starting material mixture: (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) were added to a dry 5000 L stainless steel reactor (FLR4) at -45°C to -35°C. The reaction mixture was stirred and used as Feed C.

[0195] Quench the solution: Add citric acid monohydrate (79.5 kg, 378.3 mol) and water (750 kg, 5.0 vol) to a dry 5000 L stainless steel reactor (FLR6) at 15-30° C. Stir the solution for 0.5-1 h.

[0196] 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), which was then connected to CSTR1 (FLR2, 100 L, Cu complex), CSTR2 (FLR3, 100 L, Cu complex), the reaction reactor (FLR4), and the quenching reactor (FLR6). The flow rate of Pump 1 was set to 800 mL / min by the automatic control system. (FLR2 residence time: 87.5 min, FLR3 residence time: 37.5 min).

[0197] CSTR System Preparation: Start agitation in FLR2 and FLR3. Pump THF (150 kg) through all CSTR stages, then stop pumping. Analyze THF residual moisture in CSTR4 by KF until KF ≤ 500 ppm. Cool both CSTRs (FLR2 and FLR3) to -45°C to -20°C.

[0198] CSTR system startup and shutdown: Start Pump 1 and pump Feed A solution into CSTR1 (FLR2). After ~40 minutes, feed B is pumped into CSTR1, and then feed B is pumped approximately every 40 minutes. The copper complex mixture from CSTR2 is transferred to a 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 and stirred at -45°C to -35°C. The reaction was monitored in reactor (FLR4) by HPLC analysis for 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 specification: ≤1.0% 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 and quenched at -10 to 25°C.

[0199] Post-treatment and separation: The quenched mixture was diluted with MTBE (600 L, 4 vol). The layers were separated and the organic layer was washed with a 10% NH4Cl aqueous solution (750 L, 5 vol). Ethylenediamine (94.5 kg, 1.57 kmol) was added to the mixture and stirred at ambient temperature for 1 h. The mixture was washed 3 times with a 10% NH4Cl aqueous solution (750 L, 5 vol) and then washed with a 5% Na2SO4 aqueous solution (750 L, 5 vol). The solvent of the mixture was exchanged with 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, lasted for 3 h, and further stirred for 3 h. The resulting suspension was filtered, and the filter cake was rinsed with EtOH (600 L, 4 vol). The solid was dried under vacuum at 70 ° C to obtain the title product as a solid (130 kg, 80%). The analytical data were consistent with the data collected in Preparation Example 4.

[0200] Preparation Example 5

[0201] (R,E)-N-methyl-5-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-N-phenyl-1H-

[0202] Indole-2-carboxamide

[0203]

[0204] (E)-3-(2-(Methyl(phenyl)carbamoyl)-1H-indol-5-yl)acrylic acid (20 g, 62.4 mmol) and DMAc (140 mL) were added to a reactor and the contents were stirred for 20 min 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 h before (R)-4-phenyloxazolidin-2-one (17.7 g, 109.4) and DBU (27.5 g, 180.6 mmol) were added, followed by rinsing with DMAc (20 mL). The reaction was stirred at 20°C for 4 h and quenched with 5N HCl (70 mL) at ≤40°C to adjust the pH to 3-5. The resulting suspension was cooled to 0°C and stirred for a further 12 h. 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 h to constant weight to give the title compound as a solid (25 g, 80%). 1 H NMR(DMSO-d6)δ11.94(s,1H),7.79–7.65(m,2H),7.62(s,1H),7.51-7.24(m,12H),7.58(dd,J=8 .5,3.75Hz,1H),5.35(s,1H),4.79(t,J=8.63Hz,1H),4.19(dd,J=8.5,3.75Hz,1H),3.4(s,3H). 13 C 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 calcd: 466.1761, found: 466.1774 (M+H).

[0205] Preparation Example 6

[0206] (R)-5-(1-Hydroxy-5-methylhex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0207]

[0208] 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) were added to the reactor. 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 2M solution of lithium borohydride in THF (450 kg, 1 kmol) was added at <-5 ° C, and then stirred at 0-10 ° C for 15 h. At <10 ° C, the reactants were quenched with 10% aqueous ammonium chloride solution (2603 L). 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) to ~10 vol at <50°C under reduced pressure. The resulting mixture was heated to 65°C until a clear solution was obtained, then cooled to 5-10°C for 5 h and filtered. The filter cake was rinsed with water (525 L) and dried under vacuum at 50-80°C to constant weight to provide the title compound as a solid (279 kg, 74%). mp (DSC): 180.5°C. 1 H NMR(DMSO-d6)δ1.40-1.62(m,4H),1.64-1.82(m,1H),2.14-2.33,(m,2H),2.75 -2.95(m,1H),3.04-3.22(m,2H),3.38(s,3H),4.25(t,J=5.14Hz,1H),4.53(br d,J=12.30Hz,2H),5.15-5.20(m,1H),7.00(d,J=8.54Hz,1H),7.05(s,1H),7.27-7.34(m,1H),7.36-7.52(m,5H),11.46(s,1H). 13 C 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 calcd: 362.1994, found: 363.2091 (M+H).

[0209] Alternative Preparation Example 6

[0210] To a 12500-L reactor was added 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 (5500 L). The internal temperature was adjusted to -15°C, and MgCl (100 kg, 1.05 kmol) was added to the reactor at -15°C. A solution of lithium borohydride in THF (636 kg, 1.41 kmol) was added at -15°C, and the reaction was stirred at -15°C for 20 h, at which time HPLC analysis indicated consumption of the 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 added. The contents were concentrated to 1.5 vol at <65°C under reduced pressure (-0.09-0.1 MPa) and MeOH (2763 L, 5 vol) was added. The contents were concentrated to 1.5 vol at <65°C under reduced pressure (-0.09-0.1 MPa), and MeOH (4408 L, 8 vol) and water (1728 L, 3 vol) were added sequentially, and the mixture was heated to 65°C. The mixture was stirred for 2 h and cooled to 55°C for 1 h. Seed crystals (2.76 kg, 0.5 wt%) were added, and the resulting suspension was cooled to 5°C for 5 h, stirred for 8 h, and filtered. The resulting wet cake was rinsed with water (1650 L, 3 vol) and dried under vacuum at 65°C for 16 h to constant weight to give the title compound as a solid (297 kg, 77%). The analytical data were consistent with those collected in Preparation Example 6.

[0211] Preparation Example 7

[0212] N-methyl-5-((R)-5-methyl-1-oxo-1-((R)-2-oxo-4-phenyloxazolidin-3-yl)hex-5-en-3-yl)-N-

[0213] Phenyl-1H-indole-2-carboxamide

[0214]

[0215] (2-Methylallyl) magnesium chloride (0.5M in THF, 1381 g, 754.6 mmol) and LiCl (31.8 g, 750.1 mmol) were added to the reactor. The mixture was adjusted to 25 ° C and stirred for 30 min. The mixture was cooled to -45 ° C and CuI (143.2 g, 751.9) was added while maintaining the temperature at <-40 ° C. The reactants were further stirred at -45 ° C for 30 min, and then (R, E) -N-methyl-5- (3-oxo-3- (2-oxo-4-phenyloxazolidin-3-yl) prop-1-ene-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 h. Aqueous citric acid solution (0.5 N, 500 mL) was added at <0 ° C for 1 h. 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% NH4Cl aqueous solution (500 mL). The organics were treated with ethane-1,2-diamine (65 g, 1.08 mol) for 2 h at 25 ° C and washed with 10% NH4Cl aqueous solution (500 mL × 2). The organics were concentrated to 1-2 vol and the solvent was exchanged with methyl ethyl ketone (600 mL). The resulting mixture was heated to 75 ° C to obtain a clear solution, which was cooled to 65 ° C and seeded. The resulting suspension was stirred at 65 ° C for another 2 h, and then n-heptane (600 mL) was added at 65 ° C for 1.5 h. The slurry was cooled to 25 ° C for 2.5 h and further stirred for 8 h. The suspension was filtered, and the filter cake was rinsed with n-heptane (200 mL) and dried under vacuum at 60 °C for 16 h to constant weight to afford the title compound as a solid (84 g, 80%). 1 H NMR(CDCl3)δ9.40(s,1H),7.44–7.42(m,3H),7.28-7.24(m,2H),7.21-7.19(m,4H) ,7.10-7.07(m,3H),7.02(dd,J=8.5,1.63Hz,1H),5.10-5.06(m,2H),4.52(d,J=11 .6Hz,2H),4.29(t,J=8.7Hz,1H),4.05(dd,J=8.8,3.4Hz,1H),3.43(s,3H),3.35-3 .31(m,1H),3.03-3.00(d,J=12.3Hz,1H),2.23-2.21(d,J=7.0Hz,2H),1.51(s,3H). 13C NMR (CDCl3) 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 calcd: 522.2415, found: 522.2387 (M+H).

[0216] Preparation Example 8

[0217] (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0218]

[0219] (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) were added to the reactor. The reactants were heated at 60-70 ° C for 12 h 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 / h. The resulting suspension was filtered and the filter cake was rinsed with IPA (147 kg). The wet filter cake was slurried at 60-70 ° C for 1 h in a mixture of water (1892 kg) and IPA (218 kg) and cooled to 20-30 ° C. The resulting suspension was stirred at 20-30°C for 2 h and filtered. The filter cake was dried under vacuum at 50-80°C to constant weight to afford the title compound as a solid (128.4 kg, 87%). mp (DSC): 220.1°C. 1 H NMR(DMSO-d6)δ0.75-1.75(m,12H),2.72-2.99(m,1H),3.54-3.70(m,3H),5.21(br s,1H),7.04(s,1H),7.09(s,1H),7.21-7.41(m,3H),7.46(br s,3H)11.48(br s,1H). 13C 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 calcd: 362.1994, found: 363.2098 (M+H).

[0220] Alternative Preparation Example 8

[0221] (R)-5-(1-Hydroxy-5-methylhex-5-en-3-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0222]

[0223] 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 MgCl2 (1.85 g, 19.4 mmol) were added to the reactor. The mixture was cooled to -15 ° C and a solution of 2N LiBH4 in THF (19 mL, 38.0 mmol) was added at -15 ° C. The reactants were stirred for 16 h and then quenched with 10% NH4Cl aqueous solution (100 mL) at <0 ° C. The mixture was warmed to 10-20 ° C and concentrated to 5-7 vol. The remaining mixture was extracted with 2-MeTHF (200 mL×2). The organic layers were combined and washed with water (100 mL). The solvent of the organic matter was exchanged with MeOH (800mL) and diluted with water (200mL). The mixture was heated to 60°C to obtain a clear solution, which was cooled to 20°C for 2h. The resulting suspension was further stirred for 16h and filtered. The filter cake was rinsed with water (100mL) and dried under vacuum at 60°C for 16h to constant weight to obtain the title compound as a solid (10g, 70%). The analytical data were consistent with the data collected in Preparation Example 8.

[0224] Preparation Example 9

[0225] (S)-1-(Cyanomethyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

[0226]

[0227] (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) were added to a reactor. The mixture was heated at 50°C for 2 h and cooled to ambient temperature. Potassium hydroxide (50 wt%, 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 slowly added with vigorous stirring. After the addition was complete, the reaction was stirred for a further 2 h. 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 constant weight to give the title compound (100 g, 90%). mp (DSC): 84.3°C. 1 H NMR(CDCl3)δ1.28(d,J=19.6Hz,6H),1.54-1.72(m,4H),2.91-2.95(m,1H),3 .53(s,2H),3.75-3.86(m,2H),5.55(s,2H),5.91(s,1H),7.17-7.47(m,8H). 13 C NMR (CDCl3) 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 calcd: 402.2176, found: 402.2249 (M+H).

[0228] Preparation Example 10

[0229] 1-((1S,2S)-1-cyano-2-methylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl

[0230] -N-phenyl-1H-indole-2-carboxamide

[0231]

[0232] (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.

[0233] A CSTR containing four reactors (reactor A, reactor B, reactor C, and reactor D) was constructed. 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 specified flow rate while maintaining the internal temperature at -10°C. The reaction mixture in reactor A (residence time: 2 min) was continuously pumped into reactor B. The reaction mixture in reactor B (residence time: 2 min) was then pumped into reactor C at the same flow rate, and the reaction mixture in reactor C (residence time: 2 min) was then pumped into reactor D at the same flow rate. After the reaction was completed, the mixture was pumped into a container and quenched with 50% aqueous acetic acid to pH 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, and the viscous material was filtered off, 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 constant weight to give the title compound (71 g, 65%). mp (DSC): 180.9°C. 1 H NMR(CDCl3)δ1.29(d,J=19.6Hz,6H),1.76-1.53(m,10H),1.94-1.80(m,2H),3.0 1-2.89(m,1H),3.54(s,3H),3.88-3.75(m,2H),5.89(s,1H),7.45-7.10(m,8H). 13C NMR (CDCl3) 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 calcd: 442.2489, found: 442.2526 (M+H).

[0234] Alternative Preparation Example 10

[0235] At 0°C, (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) were added to a reactor. A 2N solution of lithium tert-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 x 500 mL). The organic layer was solvent-exchanged with 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 at 50° C. in vacuo to afford the title compound as a solid (78 g, 71%). The analytical data were consistent with those collected in Preparation 10.

[0236] Alternative Preparation Example 10

[0237] (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) were added to a reactor. 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 slowly added, and the reaction was stirred for a further hour after the addition was complete. 5 wt% aqueous sodium bicarbonate solution (300 mL) was added 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 x 5). Toluene (500 mL) was added to the organic layer, and the resulting organics were filtered through a pad of celite. The celite pad was rinsed with toluene (300 mL), the filtrate was allowed to stand and separated to remove any aqueous layer. The organic layer was circulated through CUNO and the CUNO pad was rinsed with toluene (300 mL). The combined filtrate was azeotropically distilled with toluene to 2 vol until KF ≤ 0.1%. THF (800 mL) was added and the mixture was cooled to 0 ° C. At 0 ° C, (R) -4-methyl-1,3,2-dioxathiolane 2,2-dioxide (68.81 g, 498 mmol) was added and the resulting mixture was stirred at 0 ° C for 20 min. Lithium tert-butoxide (152.39 g, 1.9 mol) was slowly added and the mixture was stirred for 19 h. The mixture was quenched with 50% acetic acid aqueous solution (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 200 mL and the solvent was exchanged with acetonitrile 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 h, cooled to 20 ° C, lasted for 4 h, and stirred at 20 ° C for 13 h. Water (280 mL) was added, lasted for 3 h, and the suspension was stirred at 20 ° C for 16 h. The suspension was filtered and the solid was recrystallized from a mixture of ACN (500 mL) and water (340 mL) and dried under vacuum at 55 ° C to constant weight to obtain the title compound as a solid (75.65 g, 62%). The analytical data were consistent with the data collected in Preparation Example 10.

[0238] Preparation Example 11

[0239] (S)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

[0240]

[0241] (S)-(1-hydroxypropyl-2-yl) tert-butyl carbamate (200g, 1.14mol) and DCM (400mL) are added to the container. The mixture is cooled to 0-5 ℃. TEA (173.24g, 1.71mol) is added and lasts for 20min while keeping the internal temperature below 10 ℃. A solution of methanesulfonic anhydride (218.71g, 1.26mol) dissolved in DCM (600mL) is added to the reactant and lasts for 4 hours while keeping the internal temperature below 5 ℃. The reaction contents are stirred at this temperature for another 30min. After the reaction is complete (about 30min), water (400mL) is added and lasts for 30min while keeping the internal temperature below 8 ℃. The aqueous phase is separated and further extracted with DCM (800mL). The organic phases were combined and washed sequentially with 10% aqueous citric acid solution (800 mL), 8% NaHCO (800 mL) and 10% aqueous NaCl solution (800 mL). The organic layer was concentrated to 400 mL in vacuo and n-heptane (400 mL) was added. The suspension was cooled to 0-10° C. and stirred for 2 h. The resulting mixture was filtered and dried to give the title compound as a solid (290 g, 99+%). 1 H NMR(CDCl3)δ4.74-4.62(m,1H),4.25(d,J=9.9Hz,1H),4.16(ddd,J=10.1,4.2,2. 0Hz, 1H), 3.99 (s, 1H), 3.05 (q, J = 1.8Hz, 3H), 1.46 (s, 9H), 1.25 (d, J = 7.1Hz, 3H).

[0242] Preparation Example 12

[0243] (S)-tert-Butyl(1-cyanopropyl-2-yl)carbamate

[0244]

[0245] DMF (1.2 L), NaCN (75.45 g, 1.54 mol) and TBAB (38.178 g, 0.118 mol) were added to a container. The mixture was heated to 35-45 ° C, and (S)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (300 g, 1.184 mol) dissolved in DMF (300 mL) was then added, followed by stirring for 18 h. The mixture was cooled to 15-25 ° 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 × 3), and then washed once with a saturated sodium chloride solution (1.8 L). The organic layer was concentrated to about 300 mL in a vacuum, and MTBE (900 mL) was added. The organic layer was concentrated to about 300 mL in a vacuum, 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) δ4.65 (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).

[0246] Preparation Example 13

[0247] (S)-3-Aminobutyronitrile hydrochloride

[0248]

[0249] (S)-(1-cyanopropyl-2-yl) tert-butyl carbamate (235g, 1.276mol) and DCM (1.88L) are added in a container. HCl gas (139.67g, 3.827mol) is added while keeping the reaction temperature at 15-25 ℃. Content is stirred for 6h, then the mixture is cooled to 0-5 ℃, and stirred for 2 hours. The gained mixture is filtered and dried to obtain the title compound as a white solid (150g, 97.5%). 1 H NMR(D2O) δ3.79-3.72(m,1H),2.93(dq,J=5.8,2.8Hz,2H),1.44-1.40(m,3H).

[0250] Preparation Example 14

[0251] (S)-Ethyl 3-((tert-Butoxycarbonyl)(1-cyanoprop-2-yl)amino)propanoate

[0252]

[0253] EtOH (4.4 L) and (S)-3-aminobutyronitrile hydrochloride (879 g, 7.3 mol) are added to a container. TEA (999 g, 9.9 mol) is added dropwise, followed by ethyl acrylate (918 g, 9.5 mol) while maintaining the temperature at 15-25 ° C. The mixture is then heated to 70-85 ° C and stirred for 24 h. Thereafter, the mixture is cooled to 15-25 ° C, and TEA (852.6 g, 8.4 mol) is added dropwise, followed by di-tert-butyl dicarbonate (2160.7 g, 9.9 mol) at 15-25 ° C. The mixture is stirred at 15-25 ° C for 10 h, then quenched with N-methylpiperazine (73.1 g, 0.8 mol) at 15-25 ° C and stirred for 2 hours. The mixture is concentrated to 2.64 L in vacuo, followed by the addition of EtOAc (4.4 L) and H2O (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 obtain a solution of the title compound (4101 g, 82%). 1 H NMR (CDCl3) δ4.02-4.18 (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).

[0254] Preparation Example 15

[0255] (S)-tert-Butyl 5-cyano-4-hydroxy-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate

[0256]

[0257] THF (12L) and potassium tert-butoxide (1042g, 9.3mol) are added to a container and cooled to 0-5°C. A THF solution (1200g, 4.2mol) of (S)-3-((tert-butoxycarbonyl) (1-cyanopropyl-2-yl) amino) ethyl propionate is added dropwise while maintaining the temperature at 0-5°C. The mixture is stirred at 0-5°C for 4h, then quenched with 2N HCl until pH is 2-3. IPAc (6L) is added. The organic phase is separated and then washed with a 15% NaCl aqueous solution (3.6L). The mixture is concentrated to 2-3L in a vacuum, then IPAc (3.6L) is added, and the organic phase is washed with a 15% NaCl aqueous solution (3.6L). The mixture is processed with 5% activated carbon (60g), filtered, and concentrated to 2-3L in a vacuum. Heptane (7.2L) is added, and once again the mixture is concentrated to 2-3L in a vacuum. 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 cooled to 15-25°C. Heptane (6.0 L) was added over 1 h, and the mixture was 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)δ10.88(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).

[0258] Preparation Example 16

[0259] 1-(Diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl)hydrazine

[0260]

[0261] 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) were added to a container. The mixture was degassed with nitrogen for 30 min, and then Pd(OAc)2 (0.55 g, 24.62 mmol) and Xantphos (1.4 g, 24.62 mmol) were added. The mixture was degassed with nitrogen for 30 min, then heated to 100-106 ° C for 1 h. After the reaction was complete, the mixture was cooled to 85-95 ° C, and water (500 mL) was added dropwise over 1 h. The mixture was stirred at 85-95 ° C for 1-2 h, cooled to 65-75 ° C, and stirred for 1-2 h, then continued to cool to 15-25 ° C, and stirred for 2-4 h. The resulting filter cake was filtered and washed with tert-amyl alcohol (500 mL) and water (1 L). Water (2.5 L) and the wet filter cake were added to a container and slurried at 15-30° C. The contents were stirred at 15-30° C. for 2-4 h, then filtered and washed with water (1 L). The resulting solid was dried under a nitrogen stream at <60° C. until the water content was ≤5.0% 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) δ7.59-7.44(m,5H),7.29(d,J=7.1Hz,6H),6.69(d,J=6.1Hz,2H),2.20(s,6H). 13 C NMR(DMSO-d6)δ143.16,139.16,133.52,129.94,129.49,129.42,128.72 ,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 calcd: 319.2, found: 318.9 (M+H).

[0262] Preparation Example 17

[0263] (4-Fluoro-3,5-dimethylphenyl)hydrazine hydrochloride hydrate

[0264]

[0265] At 0-30 ° C, dioxane (1.05 L) was added to the container and HCl gas was introduced until ≥20.0%. At 0-30 ° C, water (98.9 g, 5.50 mol) was added to the reaction solution and then heated to 35-45 ° C. 1-(diphenylmethylene)-2-(4-fluoro-3,5-dimethylphenyl)hydrazine (700 g, 2.20 mol) was added in batches over 2 h. After completion, the mixture was cooled to 15-25 ° C and stirred for 2-4 h. The filter cake was filtered and washed with dioxane (1.4 L) and then dried at ≤30 ° C to dioxane ≤1.0% to give the title compound (403 g, 87%). IR (cm -1 ):3224(width),2855(width),2684(width),1574(pointy). 1 H NMR (DMSO-d6) δ10.22(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)δ156.19,153.84,141.62,141.59,124.59,124.40,115.79,115.75,66.81,15.00,14.97. 19 F NMR (DMSO-d6) δ -127.90. Thermogravimetric analysis (TGA) showed a weight loss of 8.759% from 50°C to 160°C. TOF-MS (ESI) m / z calculated: 155.1, found: 155.0 (M+H).

[0266] Preparation Example 18

[0267] (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-

[0268] tert-Butyl formate

[0269]

[0270] NMP (1350mL) is added to the container and then degassed with nitrogen for 0.5h, followed by the addition of (4-fluoro-3,5-dimethylphenyl) hydrazine hydrochloride hydrate (274g, 1.31mol) and NMM (279g, 2.77mol). The mixture is stirred at 15-25°C for 1h. (S)-5-cyano-4-hydroxy-6-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (300g, 1.26mol) is added and the mixture is heated to 70-80°C for 30min. After completion, the mixture is cooled to 15-25°C and MTBE (3L) and 20% NH4Cl (330g NH4Cl in 1.2L water) are added. The mixture is stirred for 0.5h and the layers are separated. The aqueous layer is extracted with MTBE (1.5L). The combined layers were washed twice with 15% NaCl aqueous solution (247.5 g NaCl in 1.275 L water). The organic matter was concentrated to 600 mL in vacuo at ≤ 40 ° C. Heptane (2.4 L) was added dropwise to the mixture, then heated to 50-60 ° C and stirred for 6 h. The mixture was then cooled to 0-5 ° C for 6 h and then kept at 0-5 ° C for 16 h. The mixture was filtered and the resulting filter cake was washed with MTBE / n-heptane: 0.5 V / 3.8 V. The product was dried at 25 ° C with a stream of nitrogen 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)δ7.21(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)δ158.93,156.53,154.22,141.97,135.16,135.13,124.98, 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 calcd: 375.2, found 375.1 (M+H). HPLC chiral purity = 100% area.

[0271] Preparation Example 19

[0272] N-(2,2-Dimethoxyethyl)-1H-imidazole-1-carboxamide

[0273]

[0274] DMAc (750 mL) and CDI (181.8 g, 1.12 mol) were added to a vessel and then cooled to 0-5°C. 2,2-Dimethoxyethylamine (109.5 g, 1.04 mol) was added dropwise at 0-5°C over 2 hours, followed by stirring at this temperature for 3 hours. The reaction was monitored by NMR until no starting material remained. This solution was used in the subsequent step. 1 H NMR(CDCl3)δ8.46(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).

[0275] Preparation Example 20

[0276] (S)-3-(3-(2,2-dimethoxyethyl)ureido)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro

[0277] -tert-Butyl 5H-pyrazolo[4,3-c]pyridine-5-carboxylate

[0278]

[0279] A solution of (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (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 -5-5°C. Potassium tert-butoxide (449.4 g, 4.0 mol) was added in 3 equal portions, followed by stirring at -5-10°C for 18 h. Water (2400 mL) was added to the mixture at -5-10°C for 2 h. ( 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-carboxylic acid tert-butyl ester (3 g) was used as seed material and stirred at -5-10°C for 18 h. Water (1.2 L) was added to the reaction mixture at -5-10°C for 2 h, and the slurry was then stirred at -5-10°C for 4 h. The mixture was filtered and the resulting wet cake was washed with water (1.8 L). The product was dried at ≤50°C to give the title compound (321.0 g, 84%). IR (cm -1 ):3283,3103,2977,2938,2872,2841,~1700,1680,1626. 1 H NMR(DMSO-d6)δ8.10(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)δ155.69,155.63,146.29,134.74,132.64,124.95,124.76,1 24.61,124.56,114.69,102.85,79.39,53.70,41.41,28.58,14.79,14.75. 19 F NMR (DMSO-d6) δ -123.68. TOF-MS (ESI) m / z calculated: 506.3, found: 505.9 (M+H). Chiral purity = 100% (HPLC).

[0280] Preparation Example 21

[0281] (S)-tert-Butyl 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

[0282]

[0283] THF (3.5 L) and (S) -3- (3- (2,2- dimethoxyethyl) urea) -2- (4- fluoro-3,5- dimethylphenyl) -4- methyl -2,4,6,7- tetrahydro -5H- pyrazolo [4,3-c] pyridine -5- tert-butyl carboxylate (350 g, 0.69 mol) were added to a container. At 15-25 ° C, methanesulfonic acid (73.2 g, 0.76 mol) was added dropwise to the mixture. The mixture was heated to 40-50 ° C and stirred for 18 h. HPLC showed a mixture of the title compound and the deprotected title compound. The mixture was cooled to 15-25 ° C, quenched with K 3 PO 4 (147 g, dissolved in 1.4 L water), and di-tert-butyl dicarbonate (51 g, based on the amount of the deprotected intermediate according to HPLC results) was added at 15-25 ° C, and then stirred for 18 h. The aqueous phase was separated and the organic phase was concentrated to 1-1.4 L in vacuo. IPAc (1.4 L) and 15% NaCl aqueous solution (1.05 L) were added. The organic phase was separated and concentrated to 0.7-1 L in vacuo. 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 = 0.2V / 1.8V. The resulting material was dried at ≤ 50 ° C to give the title compound (240 g, 78.5%).

[0284] For further purification, (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-carboxylic acid tert-butyl ester (160 g) was dissolved in EtOH (800 mL). The mixture was stirred at 20-25 ° C for 2 h to obtain a solution. At 20-25 ° C, water (800 mL) was added dropwise, and then 1% seed crystals were added to the solution. The suspension was stirred for 16 h, and then water (800 mL) was added at 20-25 ° C for 4-10 h. The suspension was stirred for another 2-4 h, filtered, and the resulting solid was washed with water (800 mL). The substance was dried at ≤50 ° C to give the title compound as a solid (150 g, 94%). IR (cm -1):3220,3107,2982,2933,2858,1699,1670,1602. 1 HNMR(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)δ159.76,157.34,154.00,153.18,146.92,134.14,134.11,130.27,125.2 6,125.07,124.30,124.25,112.83,111.31,111.17,79.68,28.54,24.15,14.81,14.77. 19 F NMR (DMSO-d6) δ-122.60 enantiomer <0.10%; chiral purity: >99.9% (HPLC).

[0285] Preparation Example 22

[0286] 3,6-Dibromo-2-fluorobenzaldehyde

[0287]

[0288] Under nitrogen, a solution of 1,4-dibromo-2-fluorobenzene (249 kg, 981 mol) was prepared in 2-MeTHF (1749 L), and the solution was polish filtered to remove any insoluble material and transferred to a holding vessel.

[0289] The n-butyllithium solution (697 L, 1.6 M in THF) was polish filtered to remove insoluble material and transferred to a storage container.

[0290] A solution of diisopropylamine in 2-MeTHF was prepared by adding diisopropylamine (135 kg, 1334 mol) and 2-MeTHF (300 L). The mixture was controlled at 10-30°C and stirred. The solution was then finely filtered to remove insoluble matter and transferred to another storage container.

[0291] A solution of DMF in 2-MeTHF was prepared by dissolving DMF (156 kg, 2134 mol) in 2-MeTHF (499 L), polish filtering the solution, and transferring it to a storage container.

[0292] An aqueous citric acid solution was prepared by dissolving citric acid monohydrate (748 kg, 3560 mol) in water (1830 kg), and the solution was precision filtered to remove insoluble matter and transferred to a storage container.

[0293] Flow reaction: A plug flow reactor was constructed consisting of a pre-cooling loop for 1,4-dibromo-2-fluorobenzene, diisopropylamine, and DMF solutions, as well as main reactor tubing for lithiation and addition to DMF, placed in a cooling tank controlled at -45 to -40°C. After leaving the cooling zone, the reaction feed was quenched with aqueous citric acid in another plug flow reactor and collected for batch processing. (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).

[0294] Heptane (124kg) is added to the quenched reaction mixture (4244kg), and the mixture is stirred and then allowed to stand. The water layer is removed, and the organic layer is washed with water (530kg). The mixture is allowed to stand, and the water layer is removed. The organic layer is recycled for 8h by the CUNO cartridge (cartridge) containing activated carbon. The organic layer is then concentrated to 340L in a vacuum and heated to 55-65°C. After stirring 4h at 55-65°C, heptane (736kg) is slowly added at 55-65°C, and after the heptane addition is completed, the mixture is stirred for 1.5h at this temperature. The slurry is then gradually cooled to 0-5°C, lasts 7h, and is stirred for 3h at this temperature. The solid is then separated by filtration, and the product filter cake is washed with heptane (120kg). The solid product is then dried under vacuum to obtain the title compound, which is a solid (160.85kg, 58%). 1 H NMR(DMSO-d6)δ10.15(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). 13C NMR (DMSO-d6) δ 188.41 (d, J = 1.7 Hz), 158.71 (d, J = 262.6 Hz), 138.98 (d, J = 2.1 Hz), 131.53 (d, J = 4.4 Hz), 123.89 (d, J = 11.0 Hz), 123.75 (d, J = 2.3 Hz), 109.73 (d, J = 21.2 Hz). HRMS m / z calcd: 279.8535; found: 279.8528 (M+H).

[0295] Preparation Example 23

[0296] (E)-1-(3,6-Dibromo-2-fluorobenzylidene)-2-methylhydrazine

[0297]

[0298] Anhydrous EtOH (2298L) was added to the reactor, followed by 3,6-dibromo-2-fluorobenzaldehyde (574kg, 2036mol), and the mixture was controlled to 15-25°C. An aqueous solution of methylhydrazine (40% w / w, 258kg, 2240mol) was slowly added over a period of 4h, and the mixture was then stirred at 15-25°C for another 9h. Heptane (1172kg) was then added over a period of 4h, after which the mixture was cooled to between -5 and 5°C for 6h and then maintained at this temperature for 3h. The solid was separated by filtration, and the filter cake was washed with heptane (576L). The solid was dried under vacuum at 25-35°C for 8h to give the title compound as a solid (443.5kg, 70%).

[0299] 1 H NMR(CD3CN)δ7.49-7.30(m,3H),6.72(s,1H),2.95(dd,J=4.5,1.0Hz,3H).19FNMR(CD3CN)δ-106.22(d,J=4.9Hz). 13 C NMR (CD3CN) δ 156.13 (d, J = 254.6 Hz), 131.52, 129.61 (d, J = 4.4 Hz), 126.05 (d, J = 14.1 Hz), 125.74 (d, J = 4.7 Hz), 121.76 (d, J = 3.4 Hz), 108.98 (d, J = 22.4 Hz), 32.75. HRMS m / z calcd: 308.9033; found: 308.9036 (M+H).

[0300] Preparation Example 24

[0301] 5-Bromo-4-fluoro-1H-indazole

[0302]

[0303] To a solution of 4-bromo-3-fluoro-2-methylaniline (50 g, 0.245 mol) in anhydrous toluene (435 g) was added acetic anhydride (75 g, 0.735 mol) dropwise at 0-15°C. After stirring at 15-30°C for 2-4 hours, a solution of N-(4-bromo-3-fluoro-2-methylphenyl)acetamide was generated. The temperature was adjusted to 35-40°C, and isoamyl nitrite (57.4 g, 0.490 mol) was added dropwise below 40°C. The reaction temperature was then adjusted to 75-80°C, and the contents were stirred for 16-20 hours to obtain a solution of 1-(5-bromo-4-fluoro-1H-indazol-1-yl)ethan-1-one. The mixture was cooled to 0-10°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. Filtered and the resulting wet cake was rinsed with toluene (87 g). The wet cake was then added to a container containing water (250 g). The contents were stirred and 10% NaOH solution was added to adjust the pH to 11-13 while keeping the temperature below 30°C. The slurry was cooled to 0-5°C and 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%). mp (DSC) 161.04°C; 1 H NMR (DMSO-d6) δ7.37-7.39 (dd, J=8.8, 1.0Hz, 1H), 7.50-7.54 (dd, J=8.8, 6.4Hz, 1H), 8.22 (d, J=0.8Hz, 1H). 13 C NMR(DMSO-d6)δ152.13,149.65,142.01,141.93,130.06,129.40,113.75,113.51,108.48,108.44,96.69,96.50. 19 F NMR (DMSO-d6) δ-121.04.

[0304] Preparation Example 25

[0305] 5-Bromo-4-fluoro-1-methyl-1H-indazole

[0306]

[0307] DMI (63 kg) was added to the reactor, degassed by sparging with nitrogen, and then transferred to a holding drum. (E)-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), then transferred to a holding drum.

[0308] Fresh DMI (30 kg) was added to the vessel and the DMI was degassed by bubbling with nitrogen. CuCl (1.3 kg, 13.1 mol) was added, followed by DBU (11.1 kg, 72.9 mol), and the mixture was further degassed with vacuum / nitrogen cycles (3×). The mixture was heated to 70-80°C, and then (E)-1-(3,6-dibromo-2-fluorobenzylidene)-2-methylhydrazine solution was added for 4 h. The mixture was kept at 70-80°C for 11 h and then cooled to 40-50°C, at which point analysis showed that the reaction was not complete. The mixture was reheated to 70-80°C for 4 h and then cooled to 40-50°C, at which point analysis samples showed that the starting material had been consumed, and the mixture was cooled to 20-30°C. 2M HCl aqueous solution (124 kg, 248 mol) was added for 6 h, and then the mixture was stirred for 4 h to allow it to crystallize. The solid was isolated by filtration and the filter cake was washed with water (59.4 kg).The solid was dried under vacuum at 35-45°C for 25 h to give a crop of 5-bromo-4-fluoro-1-methyl-1H-indazole.

[0309] The crude product 5-bromo-4-fluoro-1-methyl-1H-indazole from multiple production batches was combined (471 kg, 2056 mol) and EtOAc (3296 L) was added. The reactor wall was rinsed with additional EtOAc (178 kg). An aqueous ammonium hydroxide solution (25% w / w, 850 kg) was added and rinsed with water (ca. 10 kg). The mixture was controlled at 20-30 ° C and stirred for 4 h, after which 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 solution (25% w / w, 850 kg) and water (938 L) were added. The mixture was maintained at 20-30 ° C and stirred for 1.5 h. After standing, the aqueous layer was removed. The organic phase was circulated through a CUNO filter equipped with activated carbon for 7 h, and then the CUNO was rinsed with EtOAc (140 kg). This batch was repeated three times for CUNO filtration. 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. At 45-55 ° C, water (1422 L) was added over a period of 5 h. The mixture was cooled to 15-25 ° C and stirred for 3 h. The solid product was separated by filtration, and the filter cake was washed with water (1421 kg). The product filter cake was dried at 30-40 ° C under vacuum for 8 h, then dried at 35-45 ° C for 16 h to obtain the title compound as a solid (234.1 kg, 50%). 1 H NMR(DMSO-d6)δ8.08(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 = 250.3 Hz), 141.73 (d, J = 9.0 Hz), 130.29, 128.65 (d, J = 2.6 Hz), 114.44 (d, J = 23.5 Hz), 108.14 (d, J = 4.4 Hz), 97.30 (d, J = 18.8 Hz), 36.23. HRMS m / z calcd: 228.9771; found: 228.9772 (M+H).

[0310] Alternative Preparation Example 25

[0311] At 25-30 ℃, 5-bromo-4-fluoro-1H-indazole (20 g, 0.093 mol) and K2CO3 (20 g, 0.145 mol) were added to a solution of DMF (435 g). Stirred at 25-30 ℃ for 30-60 min, the temperature was adjusted to 0-10 ℃, and then methyl iodide (17 g, 0.120 mol) was added dropwise while keeping the temperature below 10 ℃. After stirring at 25-30 ℃ for 4-6 h, water (320 g) was added while keeping the temperature below 30 ℃, and then stirred at 25-30 ℃ for 2-4 h. The resulting solid was filtered and washed with water (40 g). The wet cake was added to a container containing DMF (38 g), and the mixture was heated to 40-50 ℃ and then stirred for 1-2 h. Water (80 g) was added to the mixture while keeping the temperature below 50 ℃, and then cooled to 25-30 ℃ for 2-3 h. Stir at 25-30°C for 1-2 hours, filter, and wash the wet cake with water (60 g). Dry the solid at 35-45°C under vacuum for 12-16 hours to give the title compound as a solid (12.31 g, 57.8%). mp (DSC) 106.90°C; 1 H NMR (CDCl3) δppm 4.05 (s, 3H), 7.03-7.06 (dd, J=8.8, 0.8Hz, 1H), 7.40-7.44 (dd, J=8.8, 6.2Hz, 1H), 8.00 (d, J=0.6Hz, 1H). 13 C NMR(CDCl3)δppm 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) δppm-111.32.

[0312] Preparation Example 26

[0313] (S)-tert-Butyl 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

[0314]

[0315] (S)-tert-Butyl 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) were added to a vessel. In a separate vial, trans-N,N'-dimethylcyclohexane-1,2-diamine (0.758 g, 5.22 mmol) and copper (I) chloride (0.229 g, 2.31 mmol) or copper (I) iodide (0.446 g, 2.34 mmol) were added. The vessel was degassed and placed in a glove box. The container was equipped with a mechanical stirrer, a heating mantle, and a thermocouple. Degassed 1,3-dimethyl-2-imidazolidinone (20 mL) was added to the container along with trans-N,N'-dimethylcyclohexane-1,2-diamine and cuprous (I) chloride or cuprous (I) iodide. The mixture was heated to 100°C and maintained for 15 h. Thereafter, the mixture was removed from the glove box and analyzed, and the results showed that the reaction was complete. EtOAc (30 mL), 12% aqueous ammonium chloride solution (30 mL), and methylcyclohexane (10 mL) were added to the mixture. The mixture was stirred and allowed to stand, and the aqueous phase was separated from the organic phase. The organic phase was washed sequentially with another portion of 12% aqueous ammonium chloride solution (30 mL) and 0.5N aqueous hydrochloric acid solution (20 mL). The organic phase was stirred with activated carbon (345 mg, 7 wt%) and filtered. The flask was rinsed with EtOAc (10 mL), and the filter was then rinsed with EtOAc. The combined filtrate was washed with 5% aqueous sodium bicarbonate solution (30 mL) and water (20 mL) in sequence. The final organic phase was vacuum distilled to 15 mL at 40 ° C in a 250 mL three-necked flask. ACN (25 mL) was added, and the mixture was vacuum distilled to 15 mL again. ACN (25 mL) was added, and the mixture was vacuum distilled to 15 mL again. ACN (40 mL) was added, and the mixture was vacuum distilled to 15 mL. After distillation, ACN (30 mL) was added to the resulting mixture. The solution was used directly for 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)δ8.3(s,1H),7.65(d,1H,J=16.3Hz),7.4-7.5(m,1H),7.14(br d,J=6.1Hz,1H),7.05(d,J=2.9Hz,1H),6.9-7.0(m,1H),5.2(brs,1H),4.3(brs 1H),4.1(s,3H),2.2(s,6H),1.4(s,9H),1.23(d,J=5.6Hz,3H). 13 C NMR(DMSO-d6)δ158.5(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),113.2,1 07.2, 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; found value: 590.2791 (M+H).

[0316] Alternative Preparation Example 26

[0317] (S)-tert-Butyl 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) were added to a vessel. In a separate vial, trans-N,N'-dimethylcyclohexane-1,2-diamine (0.768 g, 5.29 mmol) and cuprous chloride (I) (0.226 g, 2.28 mmol) or cuprous iodide (I) (0.479 g, 2.52 mmol) were added. The vessel was degassed and placed in a glove box. The container was equipped with a mechanical stirrer, a heating mantle, and a thermocouple. Degassed N-methylpyrrolidone was added to the container 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 maintained for 15 hours. Thereafter, the mixture was removed from the glove box and analyzed, and the results showed that the reaction was complete. EtOAc (30 mL), 12% aqueous ammonium chloride solution (30 mL), and methylcyclohexane (10 mL) were added to the mixture. The mixture was stirred and allowed to stand, 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 a 0.5N aqueous hydrochloric acid solution (20 mL). The organic phase was washed with water (20 mL). The final organic phase was vacuum distilled to 15 mL at 40°C in a 250 mL three-necked flask. ACN (25 mL) was added, and the mixture was vacuum distilled again to 15 mL. Add ACN (25mL), and the mixture is vacuum distilled to 15mL again. Add ACN (40mL), and the mixture is vacuum distilled to 15mL. After distillation, ACN (40mL) is joined in the gained mixture. This solution is directly used for subsequent preparation. The analytical data are consistent with the data collected in Preparation Example 26.

[0318] Preparation Example 27

[0319] (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

[0320]

[0321] A vessel containing a solution of (S)-tert-butyl 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 in ACN from Preparation 26 was equipped with a mechanical stirrer, a heating mantle, a thermocouple, and an N2 inlet. Methanesulfonic acid (2.054 g, 21.37 mmol) was combined with ACN (10 mL), drawn up using a syringe, and added at 21°C over a period of 0.5 h. After the addition was complete, the reaction mixture was heated from 21°C to 55°C at 30°C / h. The reaction mixture reached 55°C over 1.5 h and was maintained at 55°C for an additional 0.5 h. After this time, HPLC analysis indicated complete consumption of the intermediate (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-carboxylic acid tert-butyl ester. Cooling to 22° C. was followed by addition of aqueous sodium hydroxide solution (15.779 g, 15.06 mmol) and seed crystals (57 mg, 1 wt %), resulting in the continued presence of seed crystals. In a separate container, aqueous sodium hydroxide solution (8.936 g, 8.528 mmol) was combined with water (25.019 g) and added to the slurry at 20.2° C. over a period of 2 h. The slurry was stirred for 6 h and filtered. The wet cake was rinsed with 1:1 ACN / water (10 mL) and water (25 mL) in sequence. The wet cake was treated under vacuum and further dried at 55°C in vacuum with N2 purge for 12 h to give the title compound as a solid (4.759 g, 83%). mp 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)δ8.09(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)δ158.87( 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 value: 489.2089; found value: 489.2069 (M+H). Chiral purity (HPLC): >99.9%.

[0322] Alternative Preparation Example 27

[0323] A vessel containing a solution of (S)-tert-butyl 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 in ACN from Alternative Preparation 26 was equipped with a mechanical stirrer, heating mantle, thermocouple, and N2 inlet. Methanesulfonic acid (2.107 g, 21.92 mmol) was added at 21.5°C. After the addition was complete, the reaction mixture was heated to 75°C and maintained at 75°C for an additional 0.5 h. After this time, HPLC analysis indicated complete consumption of the intermediate (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-carboxylic acid tert-butyl ester. Cooling to 21° C. was followed by addition of aqueous sodium hydroxide solution (15.068 g, 15.06 mmol) and seed crystals (55 mg, 1 wt %), resulting in the continued presence of seed crystals. In a separate container, aqueous sodium hydroxide solution (9.887 g, 9.635 mmol) was combined with water (25.267 g) and added to the slurry at 22.3° C. over a period of 2 h. The slurry was stirred for 16 h and filtered. The wet cake was rinsed with 1:1 ACN / water (10 mL) and water (25 mL) in sequence. The wet cake was treated under vacuum and further dried at 55°C in vacuum with N2 purge for 12 h to give the title compound as a solid (5.206 g, 91.3%). mp 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)δ8.09(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)δ158.87( 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 value: 489.2089; found value: 489.2069 (M+H). Chiral purity (HPLC): >99.9%.

[0324] Preparation Example 28

[0325] 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

[0326]

[0327] 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) were added to a vessel. The mixture was heated to 65°C for 30 min, after which 50 wt% aqueous hydroxylamine solution (45 g; 0.68 mol) was added over 3 h. The feed vessel and lines were rinsed with IPA (10 mL), and the reactants were stirred at 65°C for 16 h. The reaction was cooled to 40°C, and analysis by HPLC showed that the reaction was complete, after which the resulting suspension was cooled to 5°C for 3 h. The slurry was stirred at 5°C for 5 h and filtered. The filter cake was rinsed with water (400 mL) and stirred at 50 °C for 20 h until KF ≤ 0.5% and residual IPA ≤ 1.5% to afford the title compound as a solid (102 g, 95%). mp (DSC): 229.4 °C; 1H NMR(CDCl3)δ7.70(d,J=8.5Hz,1H),7.39-7.30(m,2H),7.27-7.09(m,5H),6.40(s,2H),6.00(s,1H),3.88-3.72(m,2H ),3.67(s,3H),2.99-2.84(m,1H),1.78-1.51(m,6H),1.36-1.32(m,3H),1.30(s,3H),1.25(s,3H),1.15-1.07(m,1H); 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, 118.83, 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 calcd: 475.2704, found: 475.2756 (M+H); chiral purity (HPLC): >99%.

[0328] Alternative Preparation Example 28

[0329] 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) were added to a vessel. The mixture was heated to 30-40 ° C for 30 min to obtain a clear solution, after which 50 wt% aqueous hydroxylamine solution (15 g; 0.23 mol) was added dropwise. The reactants were stirred at 30-40 ° C for 6-10 h. The resulting suspension was stirred at 20-30 ° C for 15 h. Water (500 mL) was added dropwise while maintaining the temperature at 20-30 ° C. The slurry was stirred at 20-30 ° C for 6 h and filtered. The filter cake was rinsed with water (250 mL) and dried at 50° C. for 37 h until KF ≤ 0.5% to afford the title compound as a solid (52.2 g, 94.1%). The analytical data were consistent with those collected in Preparation 28.

[0330] Alternative Preparation Example 28

[0331] 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) were added to the reactor. The mixture was heated to 30-40 ° C to give a light yellow solution. 50 wt% hydroxylamine aqueous solution (1.50 g, 22.64 mmol) was added dropwise over 3 h, and the reactants were further stirred at 30-40 ° C for 6 h. 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 h. Water (50 g) was added at a constant rate at 30-40 ° C for 8 h. The resulting slurry was cooled to 20-30 ° C for 1 h and stirred for 1 h. The resulting suspension was filtered and the filter cake was rinsed with water (4 x 25 mL). The wet cake was stirred at 50 ° C under vacuum for 40 h until KF < 0.5% to give the title compound as a solid (5.24 g, 94.2%). The analytical data were consistent with those collected in Preparation 28.

[0332] Preparation Example 29

[0333] 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

[0334]

[0335] 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) were added to a vessel. The temperature of the resulting mixture was adjusted to 20-30°C over 10 min. CDI (68 g, 0.42 mol) was added over 10 min, followed by DBU (80 g, 0.53 mol) over 30 min. The reaction was stirred at 20-30°C for 3-7 h. THF (400 mL) was added with stirring at 20-30°C, and the resulting mixture was cooled to 10-20°C over 30 min. Water (500 mL) was added over 30 min while maintaining the internal temperature at 15 ° C. 2N HCl solution (220 mL) was added at 15 ° C for 1 h. Seed crystals (1 g, 1 wt%) were added at 15 ° C, and the resulting suspension was stirred for 30 min. 2N HCl solution (680 mL) was added at 15 ° C for 4 h, and the resulting slurry was stirred for 12-20 h. The suspension was filtered and the filter cake was rinsed with water (500 mL). The wet cake was stirred with water (1200 mL) at 25 ° C for 15 min, after which the suspension was cooled to 15 ° C and stirred for 4-8 h. 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 h until KF ≤ 1% and residual THF ≤ 720 ppm to give the title compound (102 g, 95%). mp (DSC): 218.28 ° C; 1 H NMR(CDCl3)δ11.40-11.16(m,1H),7.56(d,J=8.5Hz,1H)7.45-7.30(m,3H),7.27-7.11(m,4H),5.9 7(s,1H),3.90-3.74(m,2H),3.60(s,3H),3.03-2.89(m,1H),1.96-1.48(m,8H),1.35-1.22(m,9H). 13C 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, 111.41, 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 calcd: 501.2496, found: 501.2541 (M+H); chiral purity (HPLC): >99%.

[0336] Alternative Preparation Example 29

[0337] 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) were added to the reactor. The mixture was heated to 30-40 ° C to obtain a solution. 50 wt% hydroxylamine aqueous solution (7.50 g, 114 mmol) was added dropwise over 2 h, and the reactants were further stirred at 30-40 ° C for 18 h. The temperature of the resulting reaction mixture was adjusted to 45-55 ° C and concentrated to 9 vol under reduced pressure. THF (225 mL, 9 vol) was added and the contents were concentrated to 6 vol under reduced pressure. Additional THF (225 mL, 9 vol) was added and the contents were concentrated to 6 vol under reduced pressure. THF (225 mL, 9 vol) was added and the contents were concentrated to 6 vol under reduced pressure. Additional THF (225 mL, 9 vol) was added and the contents were concentrated to 6 vol under reduced pressure. THF (50 mL, 2 vol) was added and the mixture was heated to 65-75 ° C and stirred for 30 min. The mixture was cooled to 20-30 ° C and CDI (18.4 g, 113.5 mmol) and DBU (21.55 g, 141.6 mmol) were added in sequence. The reactants were stirred at 20-30 ° C for 21 h. 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 h. 2N HCl solution (175 g) was added at 10-20 ° C and the resulting slurry was stirred for 15.5 h. The suspension was filtered and the filter cake was rinsed with water (250 mL). The wet filter cake was stirred with water (600 mL) at 10-20 ° C for 5 h and filtered. The filter cake was rinsed with water (250 mL) and dried at 55-65 ° C for 72 h to constant weight to obtain the title compound (27.87 g, 94.4%). The analytical data were consistent with the data collected in Preparation Example 29.

[0338] Preparation Example 30

[0339] 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-

[0340] (3-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid

[0341]

[0342] At 25 ° C, 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) were added to a container. The temperature was adjusted to 25 ° C, and sodium tert-butoxide (58 g, 0.6 mol) was added. The reaction was heated to 75-85 ° C for 120 min and maintained at this temperature for 10 h. The reaction mixture was cooled to 20-30 ° C. At <30 ° C, 18 wt% H2SO4 aqueous solution (435 g, 0.8 mol) was added, and the mixture was further diluted with IPA (200 mL). The obtained mixture is heated to 45 DEG C and stirred for 0.5-1h. Water (1000mL) is added and lasts for 2h while maintaining the temperature at 45 DEG C. Seed crystals (1g, 1wt%) are added, followed by water (910mL) and lasts for 2h while maintaining the temperature at 45 DEG C. The obtained slurries are cooled to 25 DEG C, last for 2h, and stirred for 10h. The suspension is filtered and the filter cake is rinsed with water (500mL). The solid is slurried in IPA (300mL) and water (600mL). The suspension is filtered and the wet filter cake is dissolved in THF (660mL) and stirred at 35-45 DEG C. The obtained solution is concentrated to 280-380mL. Additional THF is added and the mixture is concentrated to 330mL of THF, until KF≤0.5%. The obtained THF solution is adjusted to 45-50 DEG C and diluted with n-heptane (160mL). Seed crystals (1 g, 1 wt %) were added and the contents were stirred for 1-2 h to give a slurry. n-Heptane (1490 mL) was added over a period of 2 h while maintaining the internal temperature at 45-50 ° C. The resulting suspension was stirred for 1-2 h, cooled to 15 ° C, over a period of 2 h, and further stirred at this temperature for 12-16 h. 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 h until the residual solvent level 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%). mp (DSC): 219.77 ° C; 1H NMR(CDCl3)δ7.53(d,J=5.0Hz,1H),7.39-7.25(m,2H),7.19(d,J=4.3Hz,1H),3.75-3.66(m,2H),3.09-2.96(m,1H) ,2.05-1.86(m,1H),1.83-1.73(m,1H),1.72-1.45(m,5H),1.43-1.36(m,1H),1.31-1.23(m,5H),1.21-1.14(m,3H); 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, 34.67, 33.86, 31.74, 23.20, 21.81, 19.50, 14.57; TOF-MS (ESI) m / z calcd: 412.1867, found: 412.1900 (M+H); chiral purity (HPLC): >99.5%.

[0343] Alternative Preparation Example 30

[0344] 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) were added to a reactor. 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 H2SO4 (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 min, and then product seed crystals (40.0 mg, 0.097 mmol) were added, and the resulting mixture was stirred for 45 min to obtain a suspension. Water (58.4 mL) was added over 2 h, and the resulting suspension was stirred for 2 h. The slurry was cooled to 25 ° C, further stirred for 10 h, 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 ~ 3.3 vol, and then THF (26.4 mL) was added, and the resulting solution was concentrated to ~ 3.3 vol, and then THF (26.4 mL) was added, and the resulting solution was concentrated to ~ 3.3 vol. The concentrated solution was filtered, and THF (26.4 mL) was added to the filtrate. The resulting solution was concentrated to ~ 3.3 vol and heated to 45 ° C. Heptane (6.40mL) was added, and product seed crystals (40.0mg, 0.097mmol) were added to the solution. The resulting suspension was stirred for 90min. Heptane (59.6mL) was added, lasted for 120min, and the resulting slurries were stirred for another 90min at 45°C. The suspension was cooled to 15°C, further stirred for 4h, and filtered. The filter cake was rinsed with heptane (26.3mL) and dried under vacuum at 60°C for 18h to obtain the title compound as a solid (3.04g, 91.1%). The analytical data were consistent with the data collected in Preparation Example 30.

[0345] Preparation Example 31

[0346] (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

[0347]

[0348] Under a nitrogen atmosphere, 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-necked round-bottom flask 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 min. The mixture was stirred at ambient temperature for 1 h and then concentrated under vacuum to approximately 100 mL. The resulting slurry was diluted with saturated aqueous NH4Cl solution (100 mL) and stirred for 10 min. The slurry was filtered and the collected solid was slurried in aqueous NH4Cl solution (50 mL x 2) and water (50 mL x 2) and filtered. The resulting solid was dried at 55°C under vacuum. The solid was further slurried in water and filtered to remove residual ammonium salts. The wet solid was then dried at 55°C under full vacuum to give the title compound as a powder (4.83 g, 31%). 1 H NMR (DMSO-d6): δ7.65(s,1H),7.62(s,1H),7.55(d,J=8.8Hz,1H),7.32(d,J=9.2Hz,1H),3.72(d,J=8.0Hz,2H),3.16(dd,J=7 .6Hz,10Hz,1H),3.05(m,1H),2.69(m,1H),1.70(m,2H),1.64-1.44(m,3H),1.28(d,J=6.0Hz,3H),1.31(s,3H),1.19(s,3H). 13 C 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 value: 411.2027; found value: 411.2062 (M+NH4 + ).

[0349] Preparation Example 32

[0350] 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

[0351]

[0352] 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) was added to a vessel and suspended in THF (45 mL) and DMI (37.5 mL). Under N2, HATU (15.30 g, 40.24 mmol) was added to the flask, followed by THF (15 mL), and the mixture was stirred using an overhead stirrer. DIPEA (14.14 g, 109.4 mmol) was added over at least 30 min while maintaining the internal temperature at 20-30°C, and then stirred for 1 h. To the mixture was added solid (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) and flushed forward with THF (15.0 mL). The reaction was stirred at ambient temperature for 42 h. EtOAc (195 mL) was added to dilute the reaction mixture followed by water (45 mL) and 5 wt% aqueous Na2SO4 solution (45 mL). The resulting biphasic mixture was stirred for at least 30 min after which the layers were separated. The organic layer was returned to the reaction flask and 15 wt% aqueous Na2CO3 solution (150 mL) was added. The resulting biphasic mixture was stirred for at least 30 min after which the layers were separated. The 5wt% Na2SO4 aqueous solution (150mL) washing process was repeated three times, and the organic layer was concentrated in vacuo at <40°C. THF (105mL) was added, and the resulting mixture was concentrated to dryness again at <40°C. The THF solvent exchange process was repeated twice more, and the resulting solution was transferred to a reactor with temperature control. Formic acid (150mL) was added dropwise to the mixture while stirring, while maintaining the internal temperature at 20-30°C. Water (195mL) was added for 11 hours, after which the resulting slurry was stirred for 8 hours. The suspension was filtered, and the filter cake was rinsed with water (105mL). The wet cake was suspended in water (300mL) and stirred at 40°C for 4 hours. The suspension was filtered, and the wet cake was rinsed with water (105mL). The wet cake was dried at 65°C in a vacuum drying oven under N2 purge for 23 hours to give the title compound as a powder (27.00g, 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)δ8.31(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.

[0353] Alternative Preparation Example 32

[0354] 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) were added to the vessel. DIPEA (44.5 mL) was added over 30 min while maintaining the internal temperature at 20-30° C. The resulting solution was stirred for 1.5 h, after which (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 rinse with THF (35 mL). The mixture was stirred at 20-30 °C for 45-55 h. EtOAc (490 mL), water (105 mL), and 5 wt% aqueous Na2SO4 (105 mL) were added sequentially. The resulting biphasic mixture was stirred for at least 30 min, after which the layers were separated. The organic layer was returned to the reaction flask, and 15 wt% aqueous Na2CO3 (350 mL) was added. The resulting biphasic mixture was stirred for at least 30 min, after which the layers were separated. The 15wt% Na2CO3 aqueous solution (350mL) washing process was repeated three times, and the organic layer was concentrated to ~122.5mL in a vacuum at <40°C. THF (142g) was added, and the resulting mixture was concentrated to ~122.5mL at <40°C. The solvent exchange process was repeated twice more, and the resulting solution was transferred to a reactor with jacket temperature control. The original reactor and transfer line were rinsed with THF (52.5mL) and combined with the contents in the reactor. The mixture was stirred at 25°C, and formic acid (350mL) was added for 2h while maintaining the internal temperature at 20-30°C. Water (455mL) was added for 6h, after which the resulting slurry was stirred for at least 12h. The suspension was filtered, and the filter cake was rinsed with water (245mL). The wet filter cake was suspended in water (700mL) and stirred at 25°C for 6h. The suspension was filtered, and the wet filter cake was rinsed with water (245mL). The wet cake was dried at 60° C. in a vacuum oven under N 2 purge for at least 48 h to afford the title compound as a powder (56.96 g, 84%). The analytical data were consistent with those collected in Preparation 31.

[0355] Alternative Preparation Example 32

[0356] 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) were added to a reactor. The temperature was adjusted to 20-30° C. and 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 Na2SO4 solution (24 mL) were added at 20-30°C, followed by stirring for 15 minutes. The layers were separated. The organics were washed sequentially with 15% aqueous Na2CO3 solution (40 mL) and 5% aqueous Na2SO4 solution (3×40 mL). The organic phase was concentrated to dryness in vacuo at below 40°C. EtOAc (28mL) is added to the mixture and concentrated to dryness in vacuo at below 40 ℃. The solvent exchange process is repeated twice more, and EtOAc (28mL) is then added. The temperature is adjusted to 45-55 ℃, followed by stirring for 0.5h. At 45-55 ℃, a mixture of EtOAc (8mL) and n-heptane (24mL) is added dropwise to the container. The mixture is cooled to 20-30 ℃, lasts for 3.5h, and then stirred for 16h. Filter, and rinse the filter cake with n-heptane (12mL), and dry 20h under vacuum at 50-55 ℃ to obtain the title compound (7.03g, 87%). The analytical data are consistent with the data collected in Preparation Example 31.

[0357] Example 1

[0358] 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-oxadiazole-4-ide hemi-calcium

[0359]

[0360] Sodium hydroxide (0.55 g), water (6.6 mL) and 3A were added to the reactor. 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 at 20-30°C. The feeding 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 obtain a turbid mixture. Dry seed crystals (0.2 g) were added, and the resulting suspension was stirred for 10 h. Water (56.8 mL) was added to the reactant over a period of 6 h, followed by stirring for at least 5 h. The mixture was filtered, and the filter cake was washed with water (35 mL). The solid was dried at 55 ° C in a vacuum drying oven under N2 purge for at least 48 h to obtain the title compound as a free-flowing powder (6.89 g, 88.4%). TOF-MS (ESI) m / z 881.37 (MH-Ca).

Claims

1. A method for preparing compound 6 having the following structure: It involves a multi-step chemical reaction starting from compound 1 having the following structure:

2. The method of claim 1, comprising a multi-step chemical reaction starting from compound 1 and proceeding through compound 5: wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl or heteroarylalkynyl; and compound 6 is obtained.

3. The method of claim 1 or 2, comprising the step of converting compound 1 into compound 2 as shown below: The reaction is carried out in a solvent selected from the group consisting of toluene, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO and CPME.

4. The method according to any one of claims 1 to 3, further comprising a reaction step of converting compound 2 into compound 3 in the presence of a solvent and a catalyst, as shown below: wherein the catalyst is selected from the group consisting of 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, Pd(dtbpf)Cl2, and combinations of two or more of the listed catalysts; and 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 method according to any one of claims 1 to 4, further comprising the step of converting compound 3 into compound 4, as shown below: wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.

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-oxazolidinone in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent.

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

8. The method of any one of claims 1 to 7, further comprising the step of converting compound 4 into compound 5, as shown below: wherein R is phenyl or benzyl.

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 method of any one of claims 1 to 9, further comprising the step of converting compound 5 into compound 6, as shown below: wherein R is phenyl or benzyl.

11. The method of claim 10, wherein the reacting step comprises reacting compound 5 with a reducing agent in a solvent to obtain compound 6; wherein the reducing agent is selected from lithium borohydride, NaBH4, BH3, LAH, H2, DIBAl and Red-Al; and The solvent is selected from toluene, THF, 2-MeTHF, DCM, MTBE and CPME.

12. The method of any one of claims 1 to 11, comprising the following reaction steps: wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.

13. The method of any one of claims 1 to 12, further comprising a multi-step chemical reaction to convert compound 6 into compound 12 having the following structure:

14. The method of claim 13, comprising the step of converting compound 6 into compound 7 as shown below:

15. The method of claim 13 or 14, further comprising the step of converting compound 10 into compound 11, as shown below:

16. A multi-step process for preparing compound 24 having the following structure: The chemical reaction from compound 19 to compound 20 is as follows:

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

18. The method of claim 16 or 17, further comprising a chemical reaction to convert compound 20 into compound 21 as shown below:

19. The method of claim 16, further comprising a multi-step reaction of preparing compound 24 from compound 21, as shown below:

20. Compounds having the following structure:

21. Compounds having the following structure: wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.

22. Compounds having the following structure: wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.

23. Compounds having the following structure:

24. Compounds having the following structure:

25. Compounds having the following structure:

26. The method or compound of any one of the preceding claims, wherein the method or compound is used to prepare compound 35 having the following structure:

27. The method of claim 26, further comprising converting compound 35 into a hemi-calcium salt of the compound: The 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.

Images