Methods and intermediates for the synthesis of adagrasib

Abstract

The present invention relates to novel synthetic routes for synthesizing adagrasib. The present invention also provides intermediates used in the provided synthetic routes.

Description

[Technical Field]

[0001] The present invention relates to a new and improved synthetic route for the synthesis of adagrasib. [Background technology]

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRas) is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch, cycling between an inactive (GDP-bound) and an active (GTP-bound) state and transmitting upstream cellular signals from multiple tyrosine kinases to downstream effectors that control a wide variety of processes, including cell proliferation (see, e.g., Alamgeer et al. (2013) Current Opin Pharmacol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed over 30 years ago (e.g., Der et al. (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding, leading to constitutive stabilization of KRas and downstream signaling, have been reported in 25-30% of lung adenocarcinomas (e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single-base substitutions resulting in missense mutations at codons 12 and 13 of the primary amino acid sequence of KRas constitute approximately 40% of these KRas driver mutations in lung adenocarcinoma, where the G12C translocation is the most common activating mutation (e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online September 26, 2012. doi:10.1158 / 1078-0432.CCR-11-3265).

[0004] The well-known role of KRas in malignancies, and the discovery of these frequent mutations in KRas in various types of tumors, have made KRas an extremely attractive target for cancer therapy in the pharmaceutical industry. Despite 30 years of extensive research efforts to develop KRas inhibitors to treat cancer, KRas inhibitors have not demonstrated sufficient safety and / or efficacy to gain regulatory approval (e.g., McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] The KRasG12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849 and adagrasib) has the following structural formula: [ka] It is shown as follows.

[0006] Adaglasib is described, for example, in Example 478 of PCT application WO2019 / 099524.

[0007] While WO2019 / 099524 describes methods for making adagrasib, there is a need in the art for new and improved synthetic routes to make adagrasib. Summary of the Invention

[0008] In one embodiment, the present invention provides a new and improved method for preparing adagrasib.

[0009] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: a) The following structural formula: [ka] is reacted with a 4-halobutyric acid ester, an aprotic solvent, iodide, and a base to give a compound of the following structure: [ka] to produce the final compound of step (a) represented by The present invention provides a method for synthesizing adagrasib, comprising:

[0010] In one embodiment, step (a) is carried out at a temperature of about 20°C to about 120°C.

[0011] In one embodiment, the 4-halobutyric acid ester is 4-X(CH)COR, where R is any alkyl or (hetero)aryl group selected from the group consisting of methyl, ethyl, propyl, and trifluoroethyl, and X is any leaving group. In one embodiment, X is selected from the group consisting of Cl, Br, I, MsO, TsO, and TfO.

[0012] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl cyclopentyl methyl ether, methyl tert-butyl ether, and diethylene glycol dimethyl.

[0013] In one embodiment, the iodide is selected from the group consisting of sodium iodide, potassium iodide, and alkylated ammonium iodides.

[0014] In one embodiment, the base is an organic base.

[0015] In one embodiment, the organic base is selected from the group consisting of diisopropylethylamine (DIPEA), triethylamine (Et3N), triethylenediamine (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0016] In another embodiment, the base is an inorganic base.

[0017] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates. The inorganic base can be any alkali, such as lithium, sodium, and potassium.

[0018] In one embodiment, the method comprises step (b): b) reacting the final compound of step (a) with 2-halo-N-methoxy-N-methylacetamide, an aprotic solvent and a base to form a compound of the following structural formula: [ka] and producing the final compound of step (b) represented by Further includes:

[0019] In one embodiment, step (b) is carried out at a temperature of from about 20°C to about 150°C.

[0020] In one embodiment, the 2-halo-N-methoxy-N-methylacetamide is XCH2C(O)NMeOMe, where X is selected from the group consisting of Cl, Br, I, MsO, TsO, and TfO.

[0021] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0022] In one embodiment, step (b) further comprises iodide.

[0023] In one embodiment, the iodide is selected from the group consisting of sodium iodide, potassium iodide, and alkylated ammonium iodides.

[0024] In one embodiment, the base is an organic base.

[0025] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0026] In another embodiment, the base is an inorganic base.

[0027] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates. The inorganic base can be any alkali, such as lithium, sodium, and potassium.

[0028] In one embodiment, the method includes step (c): c) reacting the final compound of step (b) with a base and an aprotic solvent to form a compound of the following structural formula: [ka] and producing a final compound of step (c) represented by Further includes:

[0029] In one embodiment, step (c) is carried out at a temperature of about -80°C to about 25°C.

[0030] In one embodiment, the base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).

[0031] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0032] In one embodiment, the method includes step (d): d) reacting the final compound of step (c) with an S-alkylated isothiourea salt, a solvent, and a base to produce a compound of the following structural formula: [ka] and producing the final compound of step (d) represented by Further includes:

[0033] In one embodiment, step (d) is carried out at a temperature of about -20°C to about 50°C.

[0034] In one embodiment, the alkyl group in the S-alkylated isothiourea salt is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl, t-hexyl, cyclohexyl, and benzyl, and further wherein the counterion is Cl. - , Br - , I - , MsO - , TsO - , TfO - , BF4 - , SbF6 - , CF3COO - , NO3 - , and SO4 2- is selected from the group consisting of:

[0035] In one embodiment, the solvent is an alcoholic solvent.

[0036] In one embodiment, the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[0037] In one embodiment, the base is an organic base.

[0038] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0039] In another embodiment, the base is an inorganic base.

[0040] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0041] In one embodiment, the method includes step (e): e) reacting the final compound of step (d) with an acid, a triflating / mesylating agent, and an aprotic solvent to produce a compound of the following structural formula: [ka] and producing the final compound of step (e) represented by Further includes:

[0042] In one embodiment, step (e) is carried out at a temperature of from about 0°C to about 80°C.

[0043] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0044] In one embodiment, the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, and HCl. In one embodiment, the triflating agent is selected from the group consisting of Tf2O, CF3SO2Cl, and CF3SO2Br. The mesylating agent can include, but is not limited to, MsCl or (MeSO2)2O.

[0045] In one embodiment, the method includes step (f): f) reacting the final compound of step (e) with an oxidizing agent, a base and / or an alkoxide, a polar solvent, and optionally a catalyst to produce a compound of the following structural formula: [ka] and producing the final compound of step (f) represented by Further includes:

[0046] In one embodiment, step (f) is carried out at about -15°C to about 60°C.

[0047] In one embodiment, the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide, NaIO4, perborate, percarbonate, and urea hydrogen peroxide.

[0048] In one embodiment, the oxidizing agent is hydrogen peroxide.

[0049] In one embodiment, the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

[0050] In one embodiment, the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amylate, or ammonium or alkali salts thereof.

[0051] In one embodiment, the base is an inorganic base.

[0052] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0053] In one embodiment, the polar solvent is selected from the group consisting of acetonitrile and ROH, where R is methyl, ethyl, or 2-propyl.

[0054] In one embodiment, the invention further comprises step (g): g) reacting the final compound of step (f) with an alkoxide and a polar aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (g) represented by Further includes:

[0055] In one embodiment, step (g) is carried out at about -20°C to about 100°C.

[0056] In one embodiment, the alkoxide is a bulky alkoxide. As used herein, the term "bulky alkoxide" refers to a poorly nucleophilic, sterically hindered alkoxide.

[0057] In one embodiment, the alkoxide is selected from the group consisting of isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

[0058] In one embodiment, the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0059] In one embodiment, the invention provides a method comprising the steps of: h) reacting the final compound of step (g) with an activating agent, a base, a polar aprotic solvent, and an additive to obtain a compound of the following structural formula: [ka] wherein R is selected from the group consisting of substituted phenyl, methyl, ethyl, propyl, C4F9, and toluene. and producing the final compound of step (h) represented by Further includes:

[0060] In one embodiment, step (h) is carried out at a temperature of about -80°C to about 120°C.

[0061] In one embodiment, the activating agent is a sulfonyl halide R-SO2X (where R is tosyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, Br, Oms, or OTs), an anhydride, and an organic triflating reagent R 1 -N-Tf2 (where R 1 is phenyl, 5-chloro-2-pyridine, or 2-pyridine).

[0062] In one embodiment, the base is an organic base.

[0063] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0064] In another embodiment, the base is an inorganic base.

[0065] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0066] In one embodiment, the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0067] In one embodiment, the additive is selected from the group consisting of pyridine and substituted pyridines.

[0068] In one embodiment, the invention provides a method for producing a pharmaceutical composition comprising the steps of: i) combining the final compound of step (h) with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (i) represented by Further includes:

[0069] In one embodiment, step (i) is carried out at a temperature of from about 0°C to about 100°C.

[0070] In one embodiment, the salt is selected from the group consisting of HCl, TFA and HBr.

[0071] In one embodiment, the base is an organic base.

[0072] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0073] In another embodiment, the base is an inorganic base.

[0074] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0075] In one embodiment, the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0076] In one embodiment, the invention provides a method for producing a pharmaceutical composition comprising the steps of: j) reacting the final compound of step (i) with a salt of 2-fluoroacrylic acid, a solvent and optionally a base to produce adagrasib. Further includes:

[0077] In one embodiment, step (j) is carried out at a temperature of about -10°C to about 50°C.

[0078] In one embodiment, the salt is a lithium, sodium, potassium, or ammonium salt.

[0079] In one embodiment, the base is an organic base.

[0080] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0081] In another embodiment, the base is an inorganic base.

[0082] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0083] In one embodiment, the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula R-OH, where R is alkyl, allyl, or aryl.

[0084] In one embodiment, the above steps (d), (e) and (f) are replaced by the following steps (d'), (e') and (f'): d') reacting the final compound of step (c) with an alkoxide and a polar solvent to form a compound of the following structural formula: [ka] and forming a final compound of step (d') represented by: e') reacting the final compound of step (d') with an alkylating agent, an inorganic base and / or an alkoxide, and a polar solvent to obtain a compound of the formula: [ka] and forming the final compound of step (e') represented by: f') reacting the final compound of step (e') with an oxidizing agent, a base and / or an alkoxide, a polar solvent, and optionally a catalyst to form a compound of the formula: [ka] and producing the final compound of step (f') shown below: to provide an alternative route to synthesize the final compound of step (f).

[0085] In one embodiment, step (d') is carried out at a temperature of about 20°C to about 120°C.

[0086] In one embodiment, in step (d'), the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula: R-OH, where R is alkyl, allyl, or aryl.

[0087] In one embodiment, in step (d'), the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide and tert-amylate, or ammonium or alkali salts thereof.

[0088] In one embodiment, step (e') is carried out at a temperature of about 20°C to about 120°C.

[0089] In one embodiment, in step (e'), the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula: R-OH, where R is alkyl, allyl, or aryl.

[0090] In one embodiment, in step (e'), the alkylating agent is selected from the group consisting of alkyl halides RX (where R is methyl, ethyl, isopropyl, or benzyl, and X is Cl, Br, I, alkyl, sulfonate, arylsulfonate, triflate, or nonaflate), dialkyl sulfates, and carbonates.

[0091] In one embodiment, in step (e'), the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

[0092] In one embodiment, in step (e'), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, hydroxides, and alkali salts thereof.

[0093] In one embodiment, step (f') is carried out at about -15°C to about 60°C.

[0094] In one embodiment, in step (f'), the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide, NaIO4, perborate, percarbonate, and urea hydrogen peroxide.

[0095] In one embodiment, in step (f'), the oxidizing agent is hydrogen peroxide.

[0096] In one embodiment, the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

[0097] In one embodiment, in step (f'), the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amylate, or ammonium or alkali salts thereof.

[0098] In one embodiment, in step (f'), the base is an inorganic base.

[0099] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0100] In one embodiment, in step (f'), the polar solvent is selected from the group consisting of acetonitrile and ROH (wherein R is methyl, ethyl, or 2-propyl).

[0101] In yet another embodiment, steps (d) and (e) described above are replaced by the following steps (d''') and (e'''): d''') Reacting the final compound of step (c) with an S-alkylated isothiourea salt, a solvent, and a base to obtain a compound of the following structural formula: [ka] producing the final compound of step (d''') shown below; to provide an alternative route to synthesize the final compound of step (e).

[0102] In one embodiment, step (d''') is carried out at a temperature of about -20°C to about 50°C.

[0103] In one embodiment, the alkyl group in the S-alkylated isothiourea salt is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl, t-hexyl, cyclohexyl, and benzyl; and further wherein the counterion is Cl. - , Br - , I - , MsO - , TsO - , TfO - , BF4 - , SbF6 - , CF3COO - , NO3- , and SO4 2- is selected from the group consisting of:

[0104] In one embodiment, the solvent is an alcoholic solvent.

[0105] In one embodiment, the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[0106] In one embodiment, the base is an organic base.

[0107] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0108] In another embodiment, the base is an inorganic base.

[0109] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0110] In one embodiment, the method comprises step (e'''): e''') reacting the final compound of step (d'') with a water miscible solvent and a base to form a compound of the following structural formula: [ka] and producing the final compound of step (e''') represented by Further includes:

[0111] In one embodiment, step (e''') is carried out at a temperature of about 0°C to about 25°C.

[0112] In one embodiment, the water-miscible solvent is selected from the group consisting of 2-propanol, tert-butanol, and acetonitrile.

[0113] In one embodiment, the base is an organic base.

[0114] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0115] In another embodiment, the base is an inorganic base.

[0116] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0117] In yet another embodiment, steps (e') and (f') comprise the following steps (e'') and (f'''): (e″) reacting the final compound of step (d′) with phosgene or a phosgene derivative, a polar aprotic solvent, and optionally a mineral acid to form a compound of the following structural formula: [ka] and forming the final compound of step (e'') represented by (f″) reacting the final compound of step (e″) with an alkoxide and a polar aprotic solvent to form a compound of the following structural formula: [ka] producing the final compound of step (f'') shown below; to provide an alternative route to synthesize the compound of step (g).

[0118] In one embodiment, step (e'') is carried out at a temperature of from about 0°C to about 120°C.

[0119] In one embodiment, in step (e''), the phosgene derivative is selected from the group consisting of diphosgene, triphosgene, thiophosgene and 1,1'-carbonyldiimidazole.

[0120] In one embodiment, in step (e''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0121] In one embodiment, in step (e''), the mineral acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

[0122] In one embodiment, step (f'') is carried out at a temperature of from about 0°C to about 120°C.

[0123] In one embodiment, in step (f''), the alkoxide is selected from the group consisting of isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

[0124] In one embodiment, in step (f''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0125] In yet another embodiment, steps (h) and (i) may be replaced with steps (h') and (i'); steps (h'') and (i''); or steps (h''') and (i''') shown below to provide alternative routes to synthesize the compound of step (i) as follows: h') reacting the final compound of step (g) with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base to form a compound of the following structural formula: [ka] and producing the final compound of step (h') represented by: i') combining the final compound of step (h') with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i') is obtained.

[0126] In one embodiment, step (h') is carried out at a temperature of about -80°C to about 50°C.

[0127] In one embodiment, in step (h'), the triflating agent is selected from the group consisting of Tf2O, CF3SO2Cl, and CF3SO2Br.

[0128] In one embodiment, in step (h'), the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, and HCl.

[0129] In one embodiment, in step (h'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0130] In one embodiment, in step (h'), the base is an organic base.

[0131] In one embodiment, in step (h'), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0132] In one embodiment, in step (h'), the base is an inorganic base.

[0133] In one embodiment, in step (h'), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0134] In one embodiment, in step (h'), the additive is selected from the group consisting of pyridine and a substituted pyridine, such as N,N-dimethylaminopyridine or lutidine.

[0135] In one embodiment, step (i') is carried out at a temperature of about 0°C to about 100°C.

[0136] In one embodiment, in step (i'), the salt is selected from the group consisting of HCl, TFA and HBr.

[0137] In one embodiment, in step (i'), the base is an organic base.

[0138] In one embodiment, in step (i'), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0139] In one embodiment, in step (i'), the base is an inorganic base.

[0140] In one embodiment, in step (i'), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0141] In one embodiment, in step (i'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0142] h″) Reacting the final compound of step (g) with a triflating agent, an acid, a base, and a polar aprotic solvent to obtain a compound of the following structural formula: [ka] and producing the final compound of step (h'') represented by: i″) combining the final compound of step (h″) with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i'') is obtained.

[0143] In one embodiment, step (h'') is carried out at a temperature of about -80°C to about 50°C.

[0144] In one embodiment, in step (h″), the triflating agent is selected from the group consisting of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine, 1-(trifluoromethanesulfonyl)imidazole, 1-(trifluoromethanesulfonyl)-1H-benzotriazole, N-(2-pyridyl)bis(trifluoromethanesulfonimide), and N-phenylbis(trifluoromethanesulfonimide).

[0145] In one embodiment, in step (h''), the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, and HCl.

[0146] In one embodiment, in step (h''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0147] In one embodiment, in step (h''), the base is an organic base.

[0148] In one embodiment, in step (h''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0149] In one embodiment, in step (h''), the base is an inorganic base.

[0150] In one embodiment, in step (h''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0151] In one embodiment, in step (h''), the additive is selected from the group consisting of pyridine and substituted pyridines such as N,N-dimethylaminopyridine or lutidine.

[0152] In one embodiment, step (i'') is carried out at a temperature of about 0°C to about 100°C.

[0153] In one embodiment, in step (i''), the salt is selected from the group consisting of HCl, TFA and HBr.

[0154] In one embodiment, in step (i''), the base is an organic base.

[0155] In one embodiment, in step (i''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0156] In one embodiment, in step (i''), the base is an inorganic base.

[0157] In one embodiment, in step (i''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0158] In one embodiment, in step (i''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0159] h''') reacting the final compound of step (g) with an aryl- or heteroaryl-sulfonyl, a base, a polar aprotic solvent, and an additive to obtain a compound of the following structural formula: [ka] and producing the final compound of step (h''') represented by: i''') combining the final compound of step (h'') with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i''') is obtained.

[0160] In one embodiment, step (h''') is carried out at a temperature of about -30°C to about 100°C.

[0161] In one embodiment, in step (h'''), the aryl- or heteroaryl-sulfonyl is ArSO2X, where Ar is a substituted aromatic or heteroaromatic group and X is selected from the group consisting of F, Cl, Br, OMs, and OTs.

[0162] In one embodiment, Ar is selected from the group consisting of tolyl, mesityl and nosyl.

[0163] In one embodiment, in step (h'''), the base is an organic base.

[0164] In one embodiment, in step (h'''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0165] In one embodiment, in step (h'''), the base is an inorganic base.

[0166] In one embodiment, in step (h'''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0167] In one embodiment, in step (h'''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0168] In one embodiment, in step (h'''), the additive is selected from the group consisting of pyridine and substituted pyridines.

[0169] In one embodiment, step (i''') is carried out at a temperature of about 0°C to about 100°C.

[0170] In one embodiment, in step (i'''), the salt is selected from the group consisting of HCl, TFA and HBr.

[0171] In one embodiment, in step (i'''), the base is an organic base.

[0172] In one embodiment, in step (i'''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0173] In one embodiment, in step (i'''), the base is an inorganic base.

[0174] In one embodiment, in step (i'''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0175] In one embodiment, in step (i'''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0176] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] with a salt of 2-fluoroacrylic acid, a base, and a solvent to produce adagrasib.

[0177] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] a first reaction, reacting the compound with a 4-halobutyric acid ester, a non-polar solvent, iodide, and a base in a vessel; a second reaction in which 2-halo-N-methoxy-N-methylacetamide, an aprotic solvent, and a base are added to the vessel; A base and an aprotic solvent are added to the vessel to form a compound having the following structural formula: [ka] and a third reaction to produce a compound of the formula:

[0178] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] a first reaction in which the compound is reacted with an S-alkylated isothiourea salt, a solvent, and a base in a vessel; An acid, a triflating / mesylating agent, and an aprotic solvent are added to the solution to produce a compound of the following structural formula: [ka] and a second reaction to produce a compound of formula (I):

[0179] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] a first reaction in which the reaction product is reacted with an activator, a base, a polar aprotic solvent, and an additive in a vessel; [ka] A salt of the formula: [ka] and a second reaction to produce a compound of formula A method is provided.

[0180] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] a first reaction in which the compound (I) is reacted in a vessel with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base; [ka] A salt of the formula: [ka] and a second reaction to produce a compound of formula A method is provided.

[0181] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] a first reaction in which the compound is reacted with an aryl- or heteroaryl-sulfonyl, a base, a polar aprotic solvent, and an additive in a vessel; [ka] A salt of the formula: [ka] and a second reaction to produce a compound of formula A method is provided.

[0182] The present invention also encompasses each of the above steps alone (i.e., an embodiment relating to step (j); an embodiment relating to step (i); an embodiment relating to step (h), etc.), as well as combinations of steps (i.e., an embodiment relating to step (i) and step (j); an embodiment relating to step (h), step (i), and step (j), etc.).

[0183] Furthermore, it may not be necessary to isolate and / or purify the final compound of any of the above steps, for example, it is possible to arrive at the compound of step (c) without isolating and / or purifying the final compound of step (a) or (b).

[0184] The present invention also provides a compound having the following structural formula: [ka] The present invention provides a novel compound having the formula: DETAILED DESCRIPTION OF THE INVENTION

[0185] The present invention relates to a novel synthetic route for the synthesis of adagrasib, as well as novel intermediates used in the provided route.

[0186] While methods for synthesizing adagrasib are known (see WO 2019 / 099524), the synthesis provided by the present invention represents a significant improvement in that it provides higher isolated yields and higher or equivalent overall purity.

[0187] The new and improved synthesis of MRTX849, adagrasib, features five high-yielding steps and introduces expensive building blocks late in the process.

[0188] In the conventional synthesis of adagrasib, two expensive chiral pieces were introduced sequentially in steps 1 and 2. Using the novel solution, these two pieces are introduced late in the synthesis, thus significantly improving the cost-effectiveness of the production.

[0189] The new route also avoids the use of protection steps and eliminates both Boc and Cbz protecting groups, saving the time and resources required for their introduction and removal, making the route more environmentally friendly.

[0190] The new route avoids the use of palladium catalysts, a major cost factor. In conventional syntheses, increasingly expensive palladium is used in two of the six steps, dramatically increasing costs. The new procedure disclosed does not involve any transition metals.

[0191] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0192] As used herein, "KRas G12C" refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution with cysteine ​​instead of glycine at amino acid position 12. The amino acid codon and residue position assignment for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot PO116: Variant p.Gly12Cys.

[0193] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or harboring a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0194] As used herein, the term "adagrasib" refers to the compound having the name 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849), and having the following structural formula: [ka] The compound is represented by the formula:

[0195] Adaglasib is described, for example, in Example 478 of PCT application WO2019 / 099524.

[0196] The term "adagrasib" encompasses all chiral forms (enantiomers and diastereomers) and racemic forms of the compound.

[0197] In one embodiment, the term "adagrasib" refers to salts of the compounds described above, for example, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; and salts of the formula: --NRZ--, where R is hydrogen, alkyl, or benzyl. and Z is a counterion comprising chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, benzylloate, and diphenylacetate).

[0198] When this application refers to a compound, unless otherwise specified, it includes all chiral forms (enantiomers and diastereomers) and racemic forms of the compound, as well as tautomers thereof and any mixtures thereof.

[0199] "LG" refers to a leaving group and has the meaning conventionally associated with the term "leaving group" in synthetic organic chemistry; i.e., an atom or group displaceable under alkylation or nucleophilic aromatic substitution conditions. The term "leaving group" includes, but is not limited to, halogen (e.g., chlorine and bromine); alkanesulfonyloxy (e.g., methanesulfonyloxy and ethanesulfonyloxy); arenesulfonyloxy (e.g., benzylsulfonyloxy and tosyloxy); thienyloxy; dihalophosphinoyloxy; tetrahalophosphaoxy; perfluoroalkanesulfonyloxy (e.g., trifluoromethanesulfonyloxy), and the like. The leaving group should be selected to be chemically less reactive than the reactive group, bromine, to ensure proper reaction (except, of course, where the leaving group is bromine, in which case the reactivity would be equivalent).

[0200] In this application, unless otherwise specified, "R" refers to a group such as alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, carbocycle, cycloalkyl, heteroalkyl, heterocycle, aryl, aralkyl, or arylalkyl.

[0201] The term "alkyl" is intended to mean a straight or branched chain aliphatic group having from 1 to 12 carbon atoms, alternatively 1-8 carbon atoms, alternatively 1-6 carbon atoms. Other examples of alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, alternatively 2-6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like. A "C0" alkyl (as in "C0-C3 alkyl") is a covalent bond.

[0202] The term "alkenyl" is intended to mean an unsaturated, straight-chain or branched aliphatic group containing one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, alternatively 2-6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0203] The term "alkynyl" is intended to mean an unsaturated, straight-chain or branched aliphatic group containing one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, alternatively 2-6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0204] As used herein, the terms "alkylene," "alkenylene," or "alkynylene" refer to an alkyl, alkenyl, or alkynyl group, respectively, as defined above, positioned between and serving to connect two other chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0205] As used herein, the term "carbocycle" is intended to mean a cycloalkyl or aryl moiety.

[0206] The term "cycloalkyl" is intended to mean a saturated or unsaturated monocyclic, bicyclic, tricyclic, or polycyclic hydrocarbon group having about 3 to 15 carbons, alternatively 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, alternatively 5 or 6 carbons. In certain embodiments, a cycloalkyl group is fused to an aryl, heteroaryl, or heterocyclic group. Examples of cycloalkyl groups include, but are not limited to, cyclopenten-2-enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and the like.

[0207] The term "heteroalkyl" is intended to mean a saturated or unsaturated, straight-chain or branched aliphatic group, in which one or more carbon atoms may be independently replaced with a heteroatom selected from the group consisting of O, S, and N.

[0208] The term "aryl" is intended to mean, for example, a monocyclic, bicyclic, tricyclic, or polycyclic aromatic moiety containing one to three aromatic rings, e.g., a C6-C14 aromatic moiety. Alternatively, an aryl group is a C6-C10 aryl group, or alternatively, a C6 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0209] The terms "aralkyl" or "arylalkyl" are intended to mean a group comprising an aryl group covalently bonded to an alkyl group. When an aralkyl group is described as "optionally substituted," it is intended that one or both of the aryl and alkyl portions are independently optionally substituted or unsubstituted. Alternatively, the aralkyl group is (C1-C6) alkyl(C6-C10) aryl, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. For brevity, when written as "arylalkyl," this term and related terms are intended to indicate the order of groups in a compound as "aryl-alkyl." Similarly, "alkyl-aryl" is intended to indicate the order of groups in a compound as "alkyl-aryl."

[0210] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound and exhibits minimal or no undesired toxic effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, specifically including quaternary ammonium salts of the formula: --NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion comprising chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, benzyl, and diphenylacetate).

[0211] As used herein, the term "mineral acid" (or "inorganic acid") refers to any acid derived from an inorganic compound that dissociates in water to produce hydrogen ions (H+). Non-limiting examples of mineral acids include hydrogen halides of the general formula: HX (where X is F, Cl, Br, or I), nitric acid, phosphoric acid, sulfuric acid, boric acid, and perchloric acid.

[0212] As used herein, the term "organic acid" refers to any organic compound having acidic properties. Non-limiting examples of organic acids include sulfonic acids of the general formula: RSO3H, where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, or aryl, as defined above, and carboxylic acids (having one or more carboxylic acid moieties) of the general formula: RCOH, where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, or aryl, as defined above. Non-limiting examples of organic acids include lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

[0213] Synthesis scheme In one embodiment, the present invention provides a new and improved method for preparing adagrasib.

[0214] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising the steps of: a) The following structural formula: [ka] is reacted with a 4-halobutyric acid ester, an aprotic solvent, iodide, and a base to give a compound of the following structure: [ka] and producing the final compound of step (a) represented by The present invention provides a method comprising:

[0215] In one embodiment, step (a) is carried out at a temperature of about 20°C to about 120°C.

[0216] In one embodiment, the 4-halobutyric acid ester is 4-X(CH)COR, where R is any alkyl or (hetero)aryl group selected from the group consisting of methyl, ethyl, propyl, and trifluoroethyl, and X is any leaving group. In one embodiment, X is selected from the group consisting of Cl, Br, I, MsO, TsO, and TfO.

[0217] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and diethylene glycol dimethyl.

[0218] In one embodiment, the iodide is selected from the group consisting of sodium iodide, potassium iodide, and alkylated ammonium iodides.

[0219] In one embodiment, the base is an organic base.

[0220] In one embodiment, the organic base is selected from the group consisting of diisopropylethylamine (DIPEA), triethylamine (Et3N), triethylenediamine (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0221] In another embodiment, the base is an inorganic base.

[0222] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates. The inorganic base can be used with any alkali, such as lithium, sodium, and potassium.

[0223] In one embodiment, the method comprises step (b): b) reacting the final compound of step (a) with 2-halo-N-methoxy-N-methylacetamide, an aprotic solvent and a base to produce a compound of the following structural formula: [ka] and producing the final compound of step (b) represented by Further includes:

[0224] In one embodiment, step (b) is carried out at a temperature of from about 20°C to about 150°C.

[0225] In one embodiment, the 2-halo-N-methoxy-N-methylacetamide is XCH2C(O)NMeOMe, where X is selected from the group consisting of Cl, Br, I, MsO, TsO, and TfO.

[0226] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0227] In one embodiment, step (b) further comprises iodide.

[0228] In one embodiment, the iodide is selected from the group consisting of sodium iodide, potassium iodide, and alkylated ammonium iodides.

[0229] In one embodiment, the base is an organic base.

[0230] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0231] In another embodiment, the base is an inorganic base.

[0232] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates. The inorganic base can be used with any alkali, such as lithium, sodium, and potassium.

[0233] In one embodiment, the method includes step (c): c) reacting the final compound of step (b) with a base and an aprotic solvent to form a compound of the following structural formula: [ka] and producing a final compound of step (c) represented by Further includes:

[0234] In one embodiment, step (c) is carried out at a temperature of about -80°C to about 25°C.

[0235] In one embodiment, the base is a bulky base. As used herein, the term "bulky base" refers to a poorly nucleophilic, sterically hindered base.

[0236] In one embodiment, the base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).

[0237] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0238] In one embodiment, the method includes step (d): d) reacting the final compound of step (c) with an S-alkylated isothiourea salt, a solvent and a base to obtain a compound of the following structure: [ka] and producing the final compound of step (d) represented by Further includes:

[0239] In one embodiment, step (d) is carried out at a temperature of about -20°C to about 50°C.

[0240] In one embodiment, the alkyl group in the S-alkylated isothiourea salt is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl, t-hexyl, cyclohexyl, and benzyl, and the counterion is Cl. - , Br - , I - , MsO - , TsO - , TfO - , BF4 - , SbF6 - , CF3COO - , NO3 - , and SO4 2- is selected from the group consisting of:

[0241] In one embodiment, the solvent is an alcoholic solvent.

[0242] In one embodiment, the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[0243] In one embodiment, the base is an organic base.

[0244] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0245] In another embodiment, the base is an inorganic base.

[0246] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0247] In one embodiment, the method includes step (e): e) reacting the final compound of step (d) with an acid, a triflating agent and an aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (e) represented by Further includes:

[0248] In one embodiment, step (e) is carried out at a temperature of about 0°C to about 50°C.

[0249] In one embodiment, the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, and HCl. In one embodiment, the triflating agent is selected from the group consisting of TfO, CFSOCl, and CFSOBr. The mesylating agent may include, but is not limited to, MsCl or (MeSO)O.

[0250] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0251] In one embodiment, the method includes step (f): f) reacting the final compound of step (e) with an oxidizing agent, a base and / or alkoxide, a polar solvent, and optionally a catalyst to obtain a compound of the following structural formula: [ka] and producing the final compound of step (f) represented by Further includes:

[0252] In one embodiment, step (f) is carried out at about -15°C to about 60°C.

[0253] In one embodiment, the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide, NaIO4, perborates, percarbonates, and urea hydrogen peroxide.

[0254] In one embodiment, the oxidizing agent is hydrogen peroxide.

[0255] In one embodiment, the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

[0256] In one embodiment, the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amylate, or ammonium or alkali salts thereof.

[0257] In one embodiment, the base is an inorganic base.

[0258] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0259] In one embodiment, the polar solvent is selected from the group consisting of acetonitrile and ROH (where R is methyl, ethyl, or 2-propyl).

[0260] In one embodiment, the invention provides a method for producing a pharmaceutical composition comprising the steps of: g) reacting the final compound of step (f) with an alkoxide and a polar aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (g) represented by Further includes:

[0261] In one embodiment, step (g) is carried out at about -20°C to about 100°C.

[0262] In one embodiment, the alkoxide is selected from the group consisting of isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

[0263] In one embodiment, the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0264] In one embodiment, the invention provides a method comprising the steps of: h) reacting the final compound of step (g) with an activating agent, a base, a polar aprotic solvent, and an additive to obtain a compound of the following structural formula: [ka] wherein R is selected from the group consisting of substituted phenyl, methyl, ethyl, propyl, C4F9, and toluene. and producing the final compound of step (h) represented by Further includes:

[0265] In one embodiment, step (h) is carried out at a temperature of about -80°C to about 120°C.

[0266] In one embodiment, the activating agent is a sulfonyl halide R-SO2X (where R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, Br, Oms, or OTs), an anhydride, and an organic triflate reagent R 1 -N-Tf2 (where R 1 is phenyl, 5-chloro-2-pyridine, or 2-pyridine).

[0267] In one embodiment, the base is an organic base.

[0268] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0269] In another embodiment, the base is an inorganic base.

[0270] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0271] In one embodiment, the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0272] In one embodiment, the additive is selected from the group consisting of pyridine and substituted pyridines.

[0273] In one embodiment, the invention provides a method for producing a pharmaceutical composition comprising the steps of: i) combining the final compound of step (h) with [ka] , a base and a polar aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (i) represented by Further includes:

[0274] In one embodiment, step (i) is carried out at a temperature of from about 0°C to about 100°C.

[0275] In one embodiment, the salt is selected from the group consisting of HCl, TFA and HBr.

[0276] In one embodiment, the base is an organic base.

[0277] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0278] In another embodiment, the base is an inorganic base.

[0279] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0280] In one embodiment, the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0281] In one embodiment, the invention provides a method for producing a pharmaceutical composition comprising the steps of: j) reacting the final compound of step (i) with a salt of 2-fluoroacrylic acid, a solvent, and optionally a base to produce adagrasib. Further includes:

[0282] In one embodiment, step (j) is carried out at a temperature of about -10°C to about 50°C.

[0283] In one embodiment, the salt is a lithium, sodium, potassium, or ammonium salt.

[0284] In one embodiment, the base is an organic base.

[0285] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0286] In another embodiment, the base is an inorganic base.

[0287] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0288] In one embodiment, the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula R-OH, where R is alkyl, allyl, or aryl.

[0289] In one embodiment, the above steps (d), (e) and (f) are replaced by the following steps (d'), (e') and (f'): d') reacting the final compound of step (c) with an alkoxide and a polar solvent to form a compound of the following structural formula: [ka] and forming a final compound of step (d') represented by: e') reacting the final compound of step (d') with an alkylating agent, an inorganic base and / or an alkoxide, and a polar solvent to produce a compound of the following structural formula: [ka] and forming the final compound of step (e') represented by: f') reacting the final compound of step (e') with an oxidizing agent, an alkoxide and / or an inorganic base, and a polar solvent to produce a compound of the following structural formula: [ka] and producing the final compound of step (f') represented by to provide an alternative route to synthesize the final compound of step (f).

[0290] In one embodiment, step (d') is carried out at a temperature of about 20°C to about 120°C.

[0291] In one embodiment, in step (d'), the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula: R-OH, where R is alkyl, allyl, or aryl.

[0292] In one embodiment, in step (d'), the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide and tert-amylate, or ammonium or alkali salts thereof.

[0293] In one embodiment, step (e') is carried out at a temperature of about 20°C to about 120°C.

[0294] In one embodiment, in step (e'), the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula: R-OH, where R is alkyl, allyl, or aryl.

[0295] In one embodiment, in step (e′), the alkylating agent is selected from the group consisting of alkyl halides RX (where R is methyl, ethyl, isopropyl, or benzyl, and X is Cl, Br, I, alkyl, sulfonate, arylsulfonate, triflate, or nonaflate), dialkyl sulfates, and carbonates.

[0296] In one embodiment, in step (e'), the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

[0297] In one embodiment, in step (e'), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, hydroxides, and alkali salts thereof.

[0298] In one embodiment, step (f') is carried out at about -15°C to about 60°C.

[0299] In one embodiment, in step (f'), the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide, NaIO4, perborate, percarbonate, and urea hydrogen peroxide.

[0300] In one embodiment, in step (f'), the oxidizing agent is hydrogen peroxide.

[0301] In one embodiment, the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

[0302] In one embodiment, in step (f'), the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amylate, or ammonium or alkali salts thereof.

[0303] In one embodiment, in step (f'), the base is an inorganic base.

[0304] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0305] In one embodiment, in step (f'), the polar solvent is selected from the group consisting of acetonitrile and ROH (wherein R is methyl, ethyl, or 2-propyl).

[0306] In yet another embodiment, steps (d) and (e) described above may be replaced with the following steps (d''') and (e'''), providing an alternative route for synthesizing the final compound of step (e). d''') Reacting the final compound of step (c) with an S-alkylated isothiourea salt, a solvent and a base to obtain a compound of the following structure: [ka] The final compound of step (d''') is obtained.

[0307] In one embodiment, step (d''') is carried out at a temperature of about -20°C to about 50°C.

[0308] In one embodiment, the alkyl group in the S-alkylated isothiourea salt is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl, t-hexyl, cyclohexyl, and benzyl, and the counterion is Cl. - , Br - , I - , MsO - , TsO - , TfO - , BF4 - , SbF6 - , CF3COO - , NO3 - , and SO4 2- is selected from the group consisting of:

[0309] In one embodiment, the solvent is an alcoholic solvent.

[0310] In one embodiment, the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[0311] In one embodiment, the base is an organic base.

[0312] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0313] In another embodiment, the base is an inorganic base.

[0314] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0315] In one embodiment, the invention provides a method for producing a pharmaceutical composition comprising the steps of: e''') reacting the final compound of step (d''') with a water miscible solvent and a base to form a compound of the following structural formula: [ka] and producing the final compound of step (e''') represented by Further includes:

[0316] In one embodiment, step (e''') is carried out at a temperature of about 0°C to about 25°C.

[0317] In one embodiment, the water-miscible solvent is selected from the group consisting of 2-propanol, tert-butanol, and acetonitrile.

[0318] In one embodiment, the base is an organic base.

[0319] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0320] In another embodiment, the base is an inorganic base.

[0321] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0322] In yet another embodiment, steps (e') and (f') may be replaced by the following steps (e'') and (f''') to provide an alternative route to synthesize the compound of step (g) as follows: (e″) reacting the final compound of step (d′) with phosgene or a phosgene derivative, a polar aprotic solvent and a mineral acid to form a compound of the following structural formula: [ka] and producing the final compound of step (e'') represented by: (f″) reacting the final compound of step (e″) with an alkoxide and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (f'') is obtained.

[0323] In one embodiment, step (e'') is carried out at a temperature of from about 0°C to about 120°C.

[0324] In one embodiment, in step (e''), the phosgene derivative is selected from the group consisting of diphosgene, triphosgene, thiophosgene and 1,1'-carbonyldiimidazole.

[0325] In one embodiment, in step (e''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0326] In one embodiment, in step (e''), the mineral acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

[0327] In one embodiment, step (f'') is carried out at a temperature of from about 0°C to about 120°C.

[0328] In one embodiment, in step (f''), the alkoxide is selected from the group consisting of isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

[0329] In one embodiment, in step (f''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0330] In yet another embodiment, steps (h) and (i) can be replaced with the following steps: steps (h') and (i'); steps (h'') and (i''); or steps (h''') and (i'''), providing an alternative route to synthesize the compound of step (i) as follows: h') reacting the final compound of step (g) with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base to form a compound of the following structural formula: [ka] to produce a final compound represented by the formula: i') combining the final compound of step (h') with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i') is obtained.

[0331] In one embodiment, step (h') is carried out at a temperature of about -80°C to about 50°C.

[0332] In one embodiment, in step (h'), the triflating agent is selected from the group consisting of Tf2O, CF3SO2Cl, and CF3SO2Br.

[0333] In one embodiment, in step (h'), the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, and HCl.

[0334] In one embodiment, in step (h'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0335] In one embodiment, in step (h'), the base is an organic base.

[0336] In one embodiment, in step (h'), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0337] In one embodiment, in step (h'), the base is an inorganic base.

[0338] In one embodiment, in step (h'), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0339] In one embodiment, in step (h'), the additive is selected from the group consisting of pyridine and substituted pyridines such as N,N-dimethylaminopyridine or lutidine.

[0340] In one embodiment, step (i') is carried out at a temperature of about 0°C to about 100°C.

[0341] In one embodiment, in step (i'), the salt is selected from the group consisting of HCl, TFA and HBr.

[0342] In one embodiment, in step (i'), the base is an organic base.

[0343] In one embodiment, in step (i'), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0344] In one embodiment, in step (i'), the base is an inorganic base.

[0345] In one embodiment, in step (i'), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0346] In one embodiment, in step (i'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP. h″) reacting the final compound of step (g) with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base to form a compound of the following structural formula: [ka] and producing the final compound of step (h'') represented by: i″) combining the final compound of step (h″) with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i'') is obtained.

[0347] In one embodiment, step (h'') is carried out at a temperature of about -80°C to about 50°C.

[0348] In one embodiment, in step (h″), the triflating agent is selected from the group consisting of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine, 1-(trifluoromethanesulfonyl)imidazole, 1-(trifluoromethanesulfonyl)-1H-benzotriazole, N-(2-pyridyl)bis(trifluoromethanesulfonimide), and N-phenylbis(trifluoromethanesulfonimide).

[0349] In one embodiment, in step (h''), the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, and HCl.

[0350] In one embodiment, in step (h''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0351] In one embodiment, in step (h''), the base is an organic base.

[0352] In one embodiment, in step (h''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0353] In one embodiment, in step (h''), the base is an inorganic base.

[0354] In one embodiment, in step (h''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0355] In one embodiment, in step (h''), the additive is selected from the group consisting of pyridine and substituted pyridines such as N,N-dimethylaminopyridine or lutidine.

[0356] In one embodiment, step (i'') is carried out at a temperature of about 0°C to about 100°C.

[0357] In one embodiment, in step (i''), the salt is selected from the group consisting of HCl, TFA and HBr.

[0358] In one embodiment, in step (i''), the base is an organic base.

[0359] In one embodiment, in step (i''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0360] In one embodiment, in step (i''), the base is an inorganic base.

[0361] In one embodiment, in step (i''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0362] In one embodiment, in step (i''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP. h''') reacting the final compound of step (g) with an aryl- or heteroarylsulfonyl, a base and a polar aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (h''') represented by: i''') combining the final compound of step (h'') with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i''') is obtained.

[0363] In one embodiment, step (h''') is carried out at a temperature of about -30°C to about 100°C.

[0364] In one embodiment, in step (h'''), the aryl- or heteroarylsulfonyl is ArSO2X, where Ar is a substituted aromatic or heteroaromatic group and X is selected from the group consisting of F, Cl, Br, OMs, and OTs.

[0365] In one embodiment, Ar is selected from the group consisting of tolyl, mesityl, and nosyl.

[0366] In one embodiment, in step (h'''), the base is an organic base.

[0367] In one embodiment, in step (h'''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0368] In one embodiment, in step (h'''), the base is an inorganic base.

[0369] In one embodiment, in step (h'''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0370] In one embodiment, in step (h'''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0371] In one embodiment, in step (h'''), the additive is selected from the group consisting of pyridine and substituted pyridines.

[0372] In one embodiment, step (i''') is carried out at a temperature of about 0°C to about 100°C.

[0373] In one embodiment, in step (i'''), the salt is selected from the group consisting of HCl, TFA and HBr.

[0374] In one embodiment, in step (i'''), the base is an organic base.

[0375] In one embodiment, in step (i'''), the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0376] In one embodiment, in step (i'''), the base is an inorganic base.

[0377] In one embodiment, in step (i'''), the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

[0378] In one embodiment, in step (i'''), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

[0379] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: a) The following structural formula: [ka] is reacted with a 4-halobutyric acid ester, a non-polar solvent, iodide, and a base to produce a compound of the following structure: [ka] and producing the final compound of step (a) represented by The present invention provides a method comprising:

[0380] In one embodiment, step (a) is carried out at a temperature of about 20°C to about 120°C.

[0381] In one embodiment, the invention provides a method for producing a pharmaceutical composition comprising the steps of: b) reacting the final compound of step (a) with 2-halo-N-methoxy-N-methylacetamide, an aprotic solvent and a base to produce a compound of the following structural formula: [ka] and producing the final compound of step (b) represented by Further includes:

[0382] In one embodiment, step (b) is carried out at a temperature of from about 20°C to about 150°C.

[0383] In one embodiment, the method includes step (c): c) reacting the final compound of step (b) with a base and an aprotic solvent to form a compound of the following structural formula: [ka] and forming a final compound of step (c) represented by Further includes:

[0384] In one embodiment, step (c) is carried out at a temperature of about -80°C to about 25°C.

[0385] In one embodiment, the method further comprises step (d): d) reacting the final compound of step (c) with an S-alkylated isothiourea salt, a solvent and a base to obtain a compound of the following structural formula: [ka] and producing the final compound of step (d) represented by Includes.

[0386] In one embodiment, step (d) is carried out at a temperature of about -20°C to about 50°C.

[0387] In one embodiment, the method includes step (e): e) reacting the final compound of step (d) with an acid, a triflating / mesylating agent, and an aprotic solvent to obtain a compound of the following structural formula: [ka] and producing the final compound of step (e) represented by Further includes:

[0388] In one embodiment, step (e) is carried out at a temperature of about -20°C to about 80°C.

[0389] In one embodiment, the method includes step (f): f) reacting the final compound of step (e) with an oxidizing agent, a base and / or an alkoxide, a polar solvent, and optionally a catalyst to form a compound of the following structural formula: [ka] and producing the final compound of step (f) represented by Further includes:

[0390] In one embodiment, step (f) is carried out at about -15°C to about 60°C.

[0391] In one embodiment, the method includes step (g): g) reacting the final compound of step (f) with an alkoxide and a polar aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (g) represented by Further includes:

[0392] In one embodiment, the method comprises step (h): h) reacting the final compound of step (g) with an activating agent, a base, a polar aprotic solvent and an additive to form a compound of the following structural formula: [ka] wherein R is selected from the group consisting of substituted phenyl, methyl, ethyl, propyl, C4F9, and toluene. and producing the final compound of step (h) represented by Further includes:

[0393] In one embodiment, step (h) is carried out at a temperature of about -80°C to about 120°C.

[0394] In one embodiment, the method comprises step (i): i) combining the final compound of step (h) with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (i) represented by Further includes:

[0395] In one embodiment, step (i) is carried out at a temperature of from about 0°C to about 100°C.

[0396] In one embodiment, the method further comprises step (j): j) reacting the final compound of step (i) with a salt of 2-fluoroacrylic acid, a solvent, and optionally a base to produce adagrasib; Includes:

[0397] In one embodiment, step (j) is carried out at a temperature of about -10°C to about 50°C.

[0398] In one embodiment, steps (d), (e), and (f) described above may be replaced with the following steps (d'), (e'), and (f'), providing an alternative route for synthesizing the final compound of step (f). d') reacting the final compound of step (c) with an alkoxide and a polar solvent to form a compound of the following structural formula: [ka] and producing the final compound of step (d') represented by: e') reacting the final compound of step (d') with an alkylating agent, an inorganic base and / or an alkoxide, and a polar solvent to produce a compound of the following structural formula: [ka] The final compound of step (e') is obtained.

[0399] In one embodiment, step (d') is carried out at a temperature of about 20°C to about 120°C.

[0400] In one embodiment, step (e') is carried out at a temperature of about 20°C to about 120°C. f') reacting the final compound of step (e') with an oxidizing agent, an alkoxide and / or an inorganic base, and a polar solvent to produce a compound of the following structural formula: [ka] and producing the final compound of step (f') represented by Includes:

[0401] In one embodiment, step (f') is carried out at a temperature of about -15°C to about 60°C.

[0402] In yet another embodiment, steps (d) and (e) described above may be replaced with the following steps (d''') and (e'''), providing an alternative route for synthesizing the final compound of step (e). d''') Reacting the final compound of step (c) with an S-alkylated isothiourea salt, a solvent, and a base to obtain a compound of the following structural formula: [ka] and producing the final compound of step (d''') represented by: e''') reacting the final compound of step (d'') with a water miscible solvent and a base to form a compound of the following structural formula: [ka] The final compound of step (e''') is obtained.

[0403] In one embodiment, step (e''') is carried out at a temperature of about 0°C to about 25°C.

[0404] In yet another embodiment, steps (e') and (f') can be replaced by the following steps (e'') and (f'''), providing an alternative route to synthesize the compound of step (g) as follows: (e″) reacting the final compound of step (d′) with phosgene or a phosgene derivative, a polar aprotic solvent and a mineral acid to form a compound of the following structural formula: [ka] and producing the final compound of step (e'') represented by: (f″) reacting the final compound of step (e″) with an alkoxide and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (f'') is obtained.

[0405] In one embodiment, step (e'') is carried out at a temperature of from about 0°C to about 120°C.

[0406] In one embodiment, step (f'') is carried out at a temperature of from about 0°C to about 120°C.

[0407] In yet another embodiment, steps (h) and (i) can be replaced with the following steps (h') and (i'); steps (h'') and (i''); or steps (h''') and (i'''), providing alternative routes to synthesize the compound of step (i) as follows: h') reacting the final compound of step (g) with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base to form a compound of the following structural formula: [ka] and producing the final compound of step (h') represented by: i') combining the final compound of step (h') with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i') is obtained.

[0408] In one embodiment, step (h') is carried out at a temperature of about -80°C to about 50°C.

[0409] In one embodiment, step (i') is carried out at a temperature of about 0°C to about 100°C. h″) Reacting the final compound of step (g) with a triflating agent, an acid, a base, and a polar aprotic solvent to obtain a compound of the following structural formula: [ka] and producing the final compound of step (h'') represented by: i″) combining the final compound of step (h″) with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i'') is obtained.

[0410] In one embodiment, step (h'') is carried out at a temperature of about -80°C to about 50°C.

[0411] In one embodiment, step (i'') is carried out at a temperature of about 0°C to about 100°C. h''') reacting the final compound of step (g) with an aryl- or heteroarylsulfonyl, a base and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (h''') is produced.

[0412] In one embodiment, step (h''') is carried out at a temperature of about -30°C to about 100°C. i''') combining the final compound of step (h'') with [ka] , a base, and a polar aprotic solvent to form a compound of the following structural formula: [ka] The final compound of step (i''') is obtained.

[0413] In one embodiment, step (i''') is carried out at a temperature of about 0°C to about 100°C.

[0414] In one embodiment, the method further comprises synthesizing adagrasib, comprising: [ka] with a salt of 2-fluoroacrylic acid, a base and a solvent to produce adagrasib.

[0415] The present invention also encompasses the above steps not only per se (i.e., embodiments relating to step (j); embodiments relating to step (i); embodiments directed to step (h), etc.), but also combinations of steps (i.e., embodiments relating to step (i) and step (j); embodiments relating to step (h), step (i), and step (j), etc.).

[0416] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] reacting the compound with an activating agent, a base, a polar aprotic solvent, and an additive; [ka] wherein R is selected from the group consisting of substituted phenyl, methyl, ethyl, propyl, C4F9, and toluene. Generate; [ka] of, [ka] a salt of, a base and a polar aprotic solvent, [ka] a process for producing; [ka] with a salt of 2-fluoroacrylic acid, a base, and a solvent to produce adagrasib. The present invention provides a method comprising:

[0417] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] reacting with an S-alkylated isothiourea salt, a solvent and a base; [ka] a process for producing; [ka] reacting with an acid, a triflating / mesylating agent, and an aprotic solvent; [ka] a process for producing; [ka] reacting with an oxidizing agent, a base and / or an alkoxide, a polar solvent, and optionally a catalyst; [ka] a process for producing; [ka] reacting with an alkoxide and a polar aprotic solvent; [ka] a process for producing; [ka] reacting with an activator, a base, a polar aprotic solvent, and an additive; [ka] wherein R is selected from the group consisting of substituted phenyl, methyl, ethyl, propyl, C4F9, and toluene. a process for producing; [ka] of, [ka] a salt of, a base and a polar aprotic solvent, [ka] producing; and [ka] with a salt of 2-fluoroacrylic acid, a base, and a solvent to produce adagrasib. The present invention provides a method comprising:

[0418] In one embodiment, the present invention provides a method for synthesizing adagrasib, comprising: [ka] reacting with an alkoxide and a polar solvent; [ka] a process for producing; [ka] with an alkylating agent, an inorganic base and / or an alkoxide, and a polar solvent; [ka] producing; and [ka] reacting with an oxidizing agent, a base and / or an alkoxide, a polar solvent, and optionally a catalyst; [ka] A process for producing The present invention provides a method comprising:

[0419] The present invention also provides a compound having the following structural formula: [ka] The present invention provides a novel compound represented by the formula:

[0420] The following examples illustrate further specific embodiments of the present invention and are not intended to limit the scope of the invention. Example 1 [ka]

[0421] Phase 1: In a 100 L glass reactor, amine 19 (2 kg), KI (20 g), PhMe (7 kg), methyl 4-bromobutyrate (5.68 kg), and TEA (5.8 kg) were charged sequentially. The reaction was heated to 90° C. and stirred for 17 hours. The reaction mixture was cooled to room temperature, followed by the addition of toluene (7 kg) and HO (8 kg). After stirring for 1 hour, the stirring was stopped, the phases were allowed to separate, the bottom aqueous layer was drained, and the organic layer was concentrated to give the crude product. 21 obtained.

[0422] Phase 2: In a 100 L reactor, the crude product from step 1 21 , NMP (5.2 kg), Weinreb fragment 22 (7.0 kg) and DIPEA (4.4 kg) were charged. The mixture was heated to 100-110°C and stirred for 19 hours. The mixture was then cooled to room temperature, and then 20% aqueous citric acid (8 kg) was added. After stirring at room temperature for 30 minutes, the stirring was stopped, the phases were allowed to separate, and the bottom aqueous layer was transferred to a 50 L reactor and washed with toluene (7 kg). The resulting organic layer was then transferred back to the 100 L reactor. The layers were combined and washed sequentially with 5% aqueous sodium bicarbonate (8.0 kg) and 10% brine (8.0 kg). The organic layer was then separated and concentrated to give the crude product. 23 obtained.

[0423] Phase 3: In a 50 L reactor, 23To the reactor, toluene (3.4 kg) was added. The mixture was cooled to -35°C, and KHMDS in toluene (15% w / w, 22.4 kg) was added over a 3-hour period, while maintaining the temperature at -33 to -28°C. Another portion of KHMDS in toluene (15% w / w, 3.3 kg) was added, and the resulting reaction mixture was stirred at -33°C for 14 hours. Another 100 L reactor, charged with 20% aqueous citric acid (8 kg), was cooled to 0-5°C, and the reaction solution was added. The temperature of the stirred mixture was then adjusted to 25°C, and the phases were allowed to settle. The bottom aqueous layer was decanted and further washed with toluene (3.4 kg). The two organic layers were combined, and 20% aqueous citric acid (4.0 kg) and water (4.0 kg) were added. The mixture was stirred for 30 minutes, and then the bottom aqueous layer was drained. The resulting organic layer was washed sequentially with 5% sodium bicarbonate (8.0 kg) and 10% brine (8.0 kg), and then polished by filtering through a charcoal / Celite bed. The filtrate was concentrated, and isopropanol (3.15 kg) / heptane (5.84 kg) was added. The resulting mixture was warmed to 60-65°C to dissolve the solids, then cooled to 44°C over 1 hour. 50 g of ketoester was added as seed crystals. 17 and heptane (2.74 kg) were added sequentially. The mixture was slowly cooled to -10°C over 15 hours. After filtration, the cake was washed with a mixture of heptane (2.75 kg) and isopropanol (0.40 kg). The product was dried at 60°C for 48 hours to give 2.56 kg of the ketoester. 17 was obtained as a light brown powder (60% overall yield over three steps).

[0424] [ka] 17 : Brown powder (2.56 kg, 89.2% assay) Yield 60%; R f =0.76 (heptane / ethyl acetate = 1 / 1)

[0425] 1H NMR (400MHz, CDCl3) δ 12.03(s,1H), 7.75(dd,J=8.1, 1.3Hz,1H), 7.61(dd,J=8.2, 1.2Hz,1H), 7.55(dd,J=7.5, 1.3Hz, 1H), 7.44(t,J=7.8Hz,1H), 7.34(t,J=7.8Hz,1H), 7.22(dd,J=7.6, 1.2Hz,1H), 3.92(dd,J=17.4, 1.5Hz,1H), 3.84(s,3H), 3.52(dt,J=17.4, 2.0Hz,1H), 3.44(dddd,J=11.9, 5.1, 3.3, 1.4Hz,1H), 3.07(ddd,J=11.9, 9.8, 4.1Hz,1H), 2.73(dddt,J=13.6, 9.6, 5.6, 1.9Hz,1H), 2.41-2.31(m,1H); 13 C NMR (100MHz, CDCl3) δ 172.5, 169.1, 148.2, 137.4, 130.1, 129.7, 128.2, 126.4, 126.0, 125.6, 125.0, 118.5, 96.4, 54.8, 51.6, 50.5, 22.4;HRMS:(ESI)m / z:[M+H] + :C 17 H 17 Calculated for O3ClN: 318.0892, Measured: 318.0884

[0426] Example 2 The following pre-alkylated isothioureas were prepared according to procedures reported in the literature: 16a 1 , 16b 1 , 16c 2 , 16e 3 , 16f 3 , 16g 4 was synthesized according to: 16d is commercially available. [ka]

[0427] [ka] 16a and 16b are described in Sanmartin, C.; Dominguez, MV; Cordeu, L.; Cubedo, E.; Garcia-Foncillas, J.; Font, M.; Palop, JA Synthesis and Biological Evaluation of 2,4,6-Functionalized Derivatives of Pyrido[2,3-d]pyrimidines as Cytotoxic Agents and Apoptosis Inducers. Arch. Pharm. 2008, 341, 28-41.

[0428] 16a was prepared as follows.

[0429] [ka]

[0430] A 200 L clean, glass-lined reactor was inerted with nitrogen. 75 L of isopropanol was charged, followed by 10.0 kg of thiourea (131 moles, 1 equiv.). The temperature was adjusted to 20°C, and the mixture was stirred at 100 rpm. 24.6 kg of 2-iodopropane (145 moles, 1.10 equiv.) was charged. 5 L of isopropanol was used to rinse the 2-iodopropane charge line, and the reaction mixture was heated to a temperature of 75-78°C over 2 hours. The temperature was adjusted to 80°C, and the reaction mixture was stirred for 20 hours, at which point the mixture was sampled for HPLC analysis to confirm complete conversion of starting material (thiourea not more than 0.5% a / a relative to product [NMT]). In-process control (IPC) indicated 0.34% a / a thiourea, and the reaction was carried forward to the next step. The temperature was adjusted to 85°C, the reactor was placed under a vacuum of 0.04 MPa, and isopropanol was distilled. Distillation was stopped when the remaining liquid volume in the reactor reached a volume of 40 L (4 v / w). 60 L of isopropyl acetate was loaded into the reactor, which was then heated to 98°C under a vacuum of 0.04 MPa to evaporate the isopropyl acetate. Distillation was stopped when the remaining mixture reached a volume of 40 L (4 v / w). 30 L of isopropyl acetate was charged to the reaction mixture. It was again heated to 100°C and evacuated at 0.04 MPa, allowing the isopropyl acetate mixture to distill down to a level of 40 L (4 v / w). The mixture was sampled to check the water content (IPC: NMT 3%, actual 0.02%) and isopropanol content (IPC: NMT 10%, actual 7%). The reactor contents were cooled to 20-25°C and charged with isothiourea seeds (12.5g, 0.125% w / w). The mixture was stirred for 2 hours, then 20L of n-heptane was charged over 2 hours. The slurry was stirred for an additional 2 hours before draining the reactor contents into a Nutsche Filter for isolation. 13L of isopropyl acetate and 13L of n-heptane were charged to the reactor, mixed, and then used to rinse the filter cake.This process of rinsing the reactor and the solids in the Nutsche filter was repeated three times, then the filter cake was checked to ensure it was white to yellow in colour (actually light yellow). The isolated solid was transferred to a dryer with a relative humidity of less than 40% and dried at 25-30°C for 12 hours at a reduced pressure of 0.8 bar. The solid was checked to ensure it had a moisture content of NMT 0.5% (actually 0.19%). 30.56 kg (51.9 wt% assay) of light yellow solid. 16a was collected in 99.4% a / a purity and 94.4% yield. Proton and carbon NMR spectra matched those reported in the literature. 1 H NMR (400MHz, CD3CN) δ 8.45(s,2H), 7.88(s,2H), 3.99(dt,J=13.4, 6.7Hz,1H), 1.39(d,J=6.8Hz,6H); 13 C NMR (101MHz, CD3CN) δ 171.53(s), 37.70(s), 22.13(s)

[0431] 16c is described in Brand, E.; Brand, FC Guanidoacetic Acid. Org. Synth. 1942, 22, 59.

[0432] Compounds 16e and 16f are described in Sprague, JM; Johnson, T.B. The Preparation of Alkyl Sulfonyl Chlorides from Isothioureas. II. J. Am. Chem. Soc. 1937, 59, 1837-1840.

[0433] 16g is described in Yang, Z.; Xu, J. Preparation of Alkanesulfonyl Chlorides from S-Alkyl Isothiourea Salts via N-Chlorosuccinimide Mediated Oxidative Chlorosulfonation. Org. Synth. 2014, 91, 116-124.

[0434] 16a : yellow solid (89% yield); 1 H NMR (400MHz, DMSO-d6) δ=9.14-8.63(m,4H), 3.91(dt,J=13.1, 6.5Hz,1H), 1.32(d,J=6.5Hz,6H)

[0435] [ka] 16b : Orange solid (90% yield); 1 H NMR (400MHz, DMSO-d6) δ=8.92(s,4H), 3.5(q,J=8.0Hz,2H), 1.25(t,J=8.0Hz,3H)

[0436] [ka] 16c : Off-white solid (89% yield); 1 H NMR (400MHz, DMSO-d6) δ=8.92(s,4H), 3.13-3.18(m,2H), 1.23-1.27(m,3H)

[0437] [ka] 16e : Off-white solid (51% yield); 1 H NMR (400MHz, DMSO-d6) δ=9.19(s,4H), 1.50(s,9H)

[0438] [ka] 16f : Off-white solid (66.7% yield); 1 H NMR (400MHz, DMSO-d6) δ=8.98-9.14(m,4H), 1.92-1.98(m,2H), 1.64-1.72(m,2H), 1.53-1.59(m,1H), 1.34-1.45(m,4H), 1.20-1.28(m,1H)

[0439] [ka] 16g : White solid (94% yield); 1 H NMR (400MHz, DMSO-d6) δ=9.88(s,4H), 7.44-7.46(m,2H), 7.30-7.43(m,3H), 4.56(s,2H) 4.2 Screening of pre-alkylated isothioureas: 4.3 Reaction Procedure: [ka] Synthesis of Compound 8 (Final Compound of Step (e)) [ka]

[0440] Phase 1 ketoester in a 5 L reactor 6 (200 g, 613 mmol) and isopropylisothiouronium iodide 7 To a solution of (1.1 equiv., 168 g) in 2-MeTHF (2 L) at 0° C. was added DIPEA (1.1 equiv., 117 mL) dropwise over 30 min. The reaction was stirred at 0° C. for 18 h to reach a reaction temperature of 0° C., resulting in a white slurry.

[0441] Phase 2TfOH (1.0 equiv., 54 mL) was added dropwise to the slurry at 0°C over 10 min. The resulting mixture was then heated to 50°C over 0.5 h and then stirred for 5 h. After the intermediate was consumed, 1.2 L of Na2SO3 (aqueous solution, 7 wt%) was added and the reaction mixture was stirred at 50°C for 10 min. The layers were separated and the organic layer was concentrated at 35°C to give 1000 mL of slurry. To the slurry, 1500 mL of acetonitrile was added over 2 h and then cooled to 0°C over 2 h. The resulting slurry was filtered and the residue was washed with a mixed solvent of ACN / 2-MeTHF (v / v=3 / 1, 2 x 400 mL). The solid was dried under vacuum at 35°C for 18 h to give the product. 8 was obtained as a light yellow solid (223 g, 98.6 wt%, 94% yield, 99.9% purity). 1 H NMR (400MHz, DMSO-d6) δ 12.59(s,1H), 7.88(dd,J=8.2, 1.3Hz,1H), 7.70(dd,J=8.2, 1.1Hz,1H), 7.54(dd,J=7.4, 1.3H z,1H), 7.49(t,J=7.8Hz,1H), 7.40(t,J=7.8Hz,1H), 7.31(dd,J=7.6, 1.2Hz,1H), 3.94(d,J=1 7.1Hz,1H), 3.83(p,J=6.8Hz,1H), 3.69(dt,J=17.2, 2.2Hz,1H), 3.46-3.38(m,1H), 3.02(ddd ,J=11.9, 10.0, 4.1Hz,1H), 2.78-2.65(m,1H), 2.47-2.41(m,1H), 1.30(dd,J=6.9, 5.2Hz,6H); 13 C NMR (101MHz, DMSO-d6) δ 162.0, 157.8, 148.1, 137.0, 129.5, 128.9, 128.5, 126.8, 125.8, 124.9, 12 4.6, 118.7, 114.5, 56.9, 49.6, 35.6, 22.5(d,J=1.6Hz), 21.8;HRMS(ESI)C 20 H 21 Calculated for ClN3OS: 386.1089 [M+H] + , Measurement value: 386.1081

[0442] Weak acids such as acetic acid did not drive the reaction to completion, whereas strong acids such as HCl or MsOH substantially improved the conversion of the reaction. Synthesis of Compound 9 (Final Compound of Step (f)) [ka]

[0443] To a solution of K3PO4 (3.0 equiv., 358 g) in water (2.64 L) in a 5 L reactor was added acetonitrile (1.76 L) and sulfide. 8 To the resulting mixture was added 220 g (562 mmol). The resulting mixture was then heated to 55°C for 0.5 h and then stirred for 1 h. The mixture was then cooled to 20°C, yielding two layers. After discarding the lower layer, the remaining upper layer was cooled to 0°C, and 30% HO (2.5 equiv., 143 mL) was added over 60 min. After 4 h, the sulfide starting material was consumed, and 176 mL of NaSO (aqueous solution, 21 wt%) was added over 10 min. The resulting mixture was filtered, and the filtrate was cooled to 10°C. Aqueous HCl (320 mL, 1 M) was added over 20 min to adjust the pH of the mixture to approximately 5. 2 g of sulfone was seeded and stirred for 2 h, yielding a slurry. Aqueous HCl (270 mL, 1 M) was then added dropwise over 20 min to adjust the pH of the reaction mixture to approximately 3. Then, 1.6 L of water was added over 1 hour to obtain a yellow slurry, which was filtered and the cake was washed with a mixed solvent of ACN / HO (v / v=3 / 7) (2×440 mL). The product was dried under vacuum at 30° C. for 24 hours to obtain the sulfone. 9 was obtained as a light yellow solid (231 g, 95.2 wt%, 94% yield, 99.9% purity). 1H NMR (400MHz, DMSO-d6) δ 13.65(s,1H), 7.87(dd,J=8.3, 1.3Hz,1H), 7.71(dd,J=8.3, 1.1Hz,1H), 7.53(dd,J=7.5, 1.3Hz,1 H), 7.49(t,J=7.8Hz,1H), 7.40(t,J=7.8Hz,1H), 7.33(dd,J=7.6, 1.2Hz,1H), 4.18(d,J=17.2Hz,1 H), 3.95(dt,J=17.2, 1.8Hz,1H), 3.81(hept,J=6.9Hz,1H), 3.55-3.45(m,1H), 3.13(ddd,J=11.9 , 10.0, 4.1Hz,1H), 2.96(ddd,J=16.6, 10.1, 6.4Hz,1H), 2.72-2.62(m,1H), 1.25(d,J=6.9Hz,6H); 13 C NMR (101MHz, DMSO-d6) δ 168.0, 163.5, 159.9, 147.7, 137.0, 129.6, 128.8, 128.6, 126.8, 125.9, 125.0 , 124.9, 119.0, 117.3, 57.1, 50.7, 49.2, 22.3, 14.6(d,J=8.4Hz);HRMS(ESI)C 20 H 21 Calculated for ClN3O3S: 418.0992 [M+H] + , Measurement value: 418.0987 Synthesis of Compound 11 (Final Compound of Step (g)) [ka]

[0444] In a 2 L jacketed reactor, sulfone 9 (100 g, 95.2% assay, 0.228 moles) and prolinol 10 To a solution of (32.8 g, 0.284 mol) in 2-MeTHF (800 mL) cooled to 0° C., a solution of NaOtAm in 2-MeTHF (30 wt %, 0.23 L, 0.57 mol) was added slowly over 1 h, maintaining the reaction temperature below 5° C. The reaction mixture was allowed to warm to 20° C. over 10 h and stirred at this temperature for an additional 6 h. 9After the HCl distillate was consumed, the reaction mixture was cooled to 0°C, followed by the slow addition of water (0.5 L) and aqueous HCl (2 M, 0.5 L) over a period of 1 h, while maintaining the reaction temperature at NMT 5°C. The mixture was allowed to warm to 20°C and stirred for 30 min. The layers were separated, and the aqueous layer was washed with 2-MeTHF (0.4 L). To the aqueous layer, 2-MeTHF (1.0 L) and 10 M NaOH (120 mL) were added sequentially to adjust the pH to 9. The mixture was heated at NMT 45°C for 1 h. The layers were separated, and the aqueous layer was discarded. The organic layer was washed with brine solution (0.5 L) and polish filtered while maintaining the reaction temperature at NMT 40°C. Acetonitrile (1.0 L) and 1 wt% seed crystals were added. After stirring at 45°C for 3 h, the mixture was concentrated to 1.0 L. Additional acetonitrile (1.0 L) was charged and concentrated back to 1.0 L (twice) to give a thick slurry. The slurry was cooled to 20° C., filtered, and washed with acetonitrile (2×0.20 L). The product was dried under vacuum at NMT 40° C. for 16 hours. 11 was obtained as an off-solid in 83% yield (80.2 g, 98.3 wt%, purity 99.47%). 1 H NMR (400MHz, CDCl3) δ 7.72(dd,J=8.2, 1.3Hz,1H), 7.58(dd,J=8.2, 1.2Hz,1H), 7.51(dd,J=7.4, 1.3Hz,1H), 7.42(t,J=7.8Hz,1H ), 7.31(t,J=7.8Hz,1H), 7.22(dt,J=7.6, 1.2Hz,1H), 4.34(t,J=4.7Hz,2H), 4.11(d,J=17.5Hz,1H), 3.71( dq,J=17.5, 2.0Hz,1H), 3.59-3.49(m,1H), 3.11(tt,J=11.2, 4.0Hz,2H), 2.98-2.85(m,1H), 2.70-2.57(m, 2H), 2.46(d,J=1.7Hz,3H), 2.34-2.23(m,1H), 2.05-1.91(m,1H), 1.89-1.78(m,1H), 1.78-1.64(m,2H)ppm; 13C NMR (101MHz, CDCl3) δ 165.0(d,J=1.9Hz), 159.9, 155.2, 148.8, 137.5, 130.4, 129.7, 128.3, 126.5, 126.2, 125.6, 124.9, 118.6, 113.0, 77.4, 69.9(d,J=1 8.2Hz), 63.9(d,J=3.9Hz), 57.6(d,J=1.8Hz), 50.3(d,J=2.7Hz), 41.7(d,J=8.9Hz), 28.3(d,J=2.3Hz), 23.1(d,J=4.0Hz), 21.9ppm Compound 15:

[0445] 1 H NMR (400MHz, DMSO-d6) δ 10.98(s,2H), 7.90(d,J=1.3Hz,1H), 7.74(d,J=8.1Hz,1H), 7.59(dd,J=7.5,1.2Hz, 1H), 7.52(t,J=7.8Hz,1H), 7.44(t,J=7.8Hz,1H), 7.31(dd,J=7.6,1.2Hz,1H), 3.86( d,J=17.0Hz,1H), 3.52(d,J=17.0Hz,1H), 3.39(ddd,J=12.3,5.7,2.6Hz,1H), 3.08(d dd,J=11.8,9.9,4.3Hz,1H), 2.51(qt,J=7.0,3.7Hz,2H), 2.32(d,J=16.1Hz,1H)ppm; 13 C NMR (101MHz, DMSO-d6) δ 164.0, 151.0, 147.7, 147.2, 137.0, 129.7, 128.8, 128.6, 126.8, 126.0, 125.0, 125.0, 119.6, 103.8, 52.3, 49.3, 20.9ppm Decomposition of compound 11 during crystallization

change

[0446] Solitary Intermediates 11A suspension of (1.0 g) in 20 mL of a 1:1:0.1 mixture of 2-MeTHF / ACN / water was heated at 55° C. for 1 week. The decomposition of 120 was monitored by HPLC. The data are presented below. [Table 1]

[0447] Compound 31: 1 H NMR (400MHz, CDCl3) δ 7.74(d,J=7.88Hz,1H), 7.59(d,J=8.00Hz,1H), 7.52(d,J=6.88Hz,1H), 7.44(t ,J=7.82Hz,1H), 7.33(t,J=7.75Hz,1H), 7.25(d,J=7.50Hz,1H), 4.44(td,J=10. 54, 4.82Hz,1H), 4.23(ddd,J=13.29, 10.91, 6.32Hz,1H), 4.12(brd,J=4.13Hz, 2H), 3.65-3.75(m,1H), 4.06(brs,1H), 3.52-3.61(m,1H), 3.13-3.24(m,1H), 3. 09-3.13(m,1H), 3.08((brd,J=7.75Hz,1H), 2.90-2.99(m,1H), 2.73((brd,J=4 .00Hz,1H), 2.63(brs,1H), 2.60(brs,1H), 2.53(d,J=5.88Hz,3H), 2.45(d,J=1. 63Hz,3H), 2.30-2.35(m,1H), 2.28(brs,1H), 2.05((brd,J=8.38Hz,1H), 1.87( (brd,J=2.75Hz,2H), 1.79-1.86(m,2H), 1.73-1.79(m,2H), 1.72(brs,1H)ppm.; 13 C NMR (101MHz, CDCl3) δ 163.0, 156.7, 154.3, 148.7, 137.4, 130.2, 129.5, 128.2, 126.2, 126.3, 126.0, 125.5, 124.7, 118. 4, 112.4, 70.7, 63.8, 63.7, 57.5, 67.2, 57.1, 50.3, 45.0, 41.5, 41.2, 29.5, 29.0, 22.8, 22.7, 22.4 ppm

[0448] Compound Iso-11: 1 H NMR (400MHz, CDCl3) δ 7.74(dd,J=8.13, 1.25Hz,1H), 7.62(d,J=8.13Hz,1H), 7.48-7.55(m,1H), 7.43(t,J=7.82Hz,1H), 7.29-7.34(m,1H), 7.22(d,J=7.50Hz,1 H), 3.96-4.10(m,1 H), 3.80-3.96(m,2 H), 3.63(brdd,J=16.76, 1.50Hz,1H), 3.50(brdd,J=11.76, 3.88Hz,1H), 3.05-3.13(m,1H), 2.87-3.02(m,1H), 2.76-2.87(m,1H), 2.50-2.57(m ,1H), 2.47(brdd,J=6.19, 3.31Hz,1H), 2.23(d,J=6.25Hz,3H), 1.99-2. 13(m,1H), 1.67-1.80(m,2H), 1.58-1.66(m,1H), 1.39-1.58(m,1H)ppm.; 13 C NMR (101MHz, CDCl3) δ 163.4, 153.3, 147.8, 145.0, 137.3, 129.8, 128.7, 128.3, 126.3, 125.9, 125. 7, 125.5, 118.9, 106.0, 64.0, 56.9, 52.2, 50.1, 43.9, 40.7, 29.7, 22.4, 21.6 ppm;

[0449] Alternative common reaction procedures: [ka] Phase 1 To the isothiourea (1.05 eq, 5 g) in 2-Me THF (75 mL) under nitrogen at 0-5° C., base (1.5 eq) was added dropwise while maintaining the reaction temperature at 0-5° C. The mixture was stirred at 0° C. for 10 min, followed by the ketoester 17 (1.0 equiv.) was added. The resulting slurry was stirred at 0° C. for 3 hours or until the reaction was complete.

[0450] Phase 2 The crude mixture from above was dissolved in anhydrous IPA (50 mL) to give a slurry and cooled to 0°C. tert-Sodium pentoxide (2 eq) was added slowly while maintaining the reaction temperature at <5°C. The reaction was allowed to warm to room temperature and stirred at this temperature for 13 hours, or until the reaction was complete. H2O (20 mL) was added to give a cloudy solution, which was polish filtered through Celite to give a clear solution. HOAc / IPA (1 / 1) was added dropwise until the reaction solution became cloudy. Seeding and continuous stirring gave a fine slurry. The slurry was filtered and the cake was washed with IPA / H2O = 3 / 7 (10 mL) to give the desired sulfide product: 15c , 15d , 15e , 15f , 15g These products were obtained. 15g was used as is except that it was further purified by chromatography. [ka]

[0451] Synthesis of 15b:

[0452] Phase 1 In a 5 L reactor at 0°C 16 To a solution of (1.05 equiv., 154 g) in 2-Me-THF (1000 mL) was added 1.5 equiv. of DIPEA dropwise over 1 h to give a white slurry. 17 (200 g, 95% purity) was added slowly over 15 min, followed by a rinse with 2Me-THF (600 mL). The resulting slurry was stirred at 0° C. for 20 h. Water (400 mL) was added, followed by the dropwise addition of aqueous HCl (1 M, 360 mL) over 20 min to give a white slurry (pH=3). The slurry was allowed to warm to 20° C. to give a clear biphasic mixture. The aqueous solution (1.2 L) was discarded. The organic layer (1600 mL) was concentrated to 500 mL and azeotroped with IPA (2×400 mL) to give a yellow slurry (approximately 500 mL by volume).

[0453] Phase 2 Isopropanol (2 L) was added to the above slurry, and the mixture was cooled to 0°C. 2 equivalents of Na amylate were slowly added to the mixture, followed by rinsing with isopropanol (200 mL). The reaction mixture was stirred at 0°C for 0.5 hours, then warmed to 25°C over 0.5 hours. The yellow slurry was stirred for 15 hours, followed by the addition of HO (800 mL) at 20°C to give a cloudy solution. The solution was polish filtered through Celite to give a clear solution. The solution was quenched by the addition of HOAc / isopropanol (1 / 1) (150 mL) over 20 minutes. The solution (pH = 7.02) began to become cloudy, and seeding (2 g of seed crystals) formed a thick slurry after 3 hours. The slurry was filtered, and the cake was washed successively with isopropanol / H2O (v / v=1 / 1) (2 x 200 mL) and isopropanol (200 mL), and dried at 45°C for 15 hours to obtain sulfides. 15b was obtained as a free-flowing pale yellow solid (182.8 g, 93.7% purity, 76% yield).

[0454] [ka] 15b : Light yellow solid (182.8 g, purity 93.7%, yield 76%); R f =0.69 (dichloromethane / methanol = 10 / 1); 1H NMR (400MHz, DMSO-d6) δ 12.60(s,1H), 7.88(dd,J=8.2, 1.3Hz,1H), 7.70(dd,J=8.3, 1.1Hz,1H), 7.54(dd,J=7.5, 1.3H z,1H), 7.49(t,J=7.8Hz,1H), 7.40(t,J=7.8Hz,1H), 7.31(dd,J=7.6, 1.2Hz,1H), 3.95(d,J=1 7.1Hz,1H), 3.84(p,J=6.9Hz,1H), 3.69(dt,J=17.2, 2.2Hz,1H), 3.46-3.38(m,1H), 3.02(ddd ,J=11.8, 10.0, 4.1Hz,1H), 2.78-2.65(m,1H), 2.49-2.42(m,1H), 1.31(dd,J=6.9, 5.1Hz,6H); 13 C NMR (101MHz, DMSO-d6) δ 162.0, 157.8, 157.8, 148.1, 137.0, 129.5, 128.9, 128.5, 126.7, 125.8, 124.9 , 124.6, 118.7, 114.5, 56.9, 49.6, 35.5, 22.5(d,J=1.6Hz), 21.8;HRMS(ESI)C 20 H 21 Calculated for ClN3OS: 386.1089 [M+H] + , Measurement value: 386.1081

[0455] Synthesis of 13a:

[0456] In a 5 L reactor, add the following: HO (560 mL), KPO (2.5 equiv., 191 g), sulfide 15Sodium HCl (140 g, 97% purity) and ACN (1.12 L) were added sequentially. The mixture was heated at 35°C for 15 minutes to dissolve the sulfide, resulting in a two-phase mixture. The phases were split, the lower layer (370 mL) was discarded, and the resulting organic layer was polish filtered. To the filtrate (pH = 12.2) cooled to 10°C, 30 wt% HO (2.5 equiv., 90.2 mL) was added over 1 hour while maintaining the reaction temperature at 8-11°C. The mixture was stirred at 10°C for 25 hours, followed by the dropwise addition of aqueous HCl (220 mL, 1 M) over 15 minutes. The reaction temperature was raised to 20°C, resulting in a cloudy solution (pH = 5.3). 1 g of sulfone was seeded and stirred for 2 hours, resulting in a slurry. To the slurry, aqueous HCl (1M) (150 mL) was added dropwise over 10 min (reaction mixture pH = 1.7), followed by water (720 mL) over 20 min. The slurry was filtered and the cake was washed with a mixture of ACN / HO (= 3 / 7) (2 x 140 mL). The product was dried under vacuum at ambient temperature for 48 h to give the sulfone. 13a was obtained as a light yellow solid (142 g, 98.6% purity, 94% yield).

[0457] [ka] 13a : Light yellow solid (142 g, purity 98.6%, yield 94%); R f =0.47 (dichloromethane / methanol = 10 / 1); 1H NMR (400MHz, DMSO-d6) δ 13.65(s,1H), 7.92(dd,J=8.1, 1.3Hz,1H), 7.75(dd,J=8.3, 1.1Hz,1H), 7.57(d,J=6.1Hz,1 H), 7.54(t,J=7.8Hz,1H), 7.44(t,J=7.8Hz,1H), 7.38(dd,J=7.6, 1.2Hz,1H), 4.20(d,J=17. 2Hz,1H), 4.00(dt,J=17.4, 1.8Hz,1H), 3.82(hept,J=6.8Hz,1H), 3.60-3.50(m,1H), 3.20( ddd,J=12.0, 10.1, 4.1Hz,1H), 3.05-2.92(m,1H), 2.72-2.65(m,1H), 1.26(d,J=6.9Hz,6H); 13 C NMR (101MHz, DMSO-d6) δ 168.0, 163.5, 160.0, 147.7, 137.0, 129.6, 128.8, 128.6, 126.8, 125.9, 125.0 , 124.9, 119.0, 117.3, 57.1, 50.6, 49.2, 22.3, 14.6(d,J=8.4Hz);HRMS(ESI)C 20 H 21 Calculated for ClN3O3S: 418.0992 [M+H] + , Measurement value: 418.0987

[0458] Synthesis of 11:

[0459] In a 5 L reactor, sulfone 13a (140g, purity 98.6%) and prolinol 14To a solution of (1.25 equiv., 46.6 g) of HCl (1.25 equiv., 46.6 g) in 2-Me-THF (1.4 L) cooled to 0° C., Nat-amylate solution in 2-MeTHF (30 wt %, 0.33 L) was added slowly over 1 h. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 15 h. The reaction mixture was then cooled to 0° C., followed by the slow sequential addition of HO (1.4 L) and aqueous HCl (2 M, 0.64 L) over 15 min. The mixture was allowed to warm to room temperature and the layers were separated. The aqueous layer was extracted with 2-Me-THF (1.2 L). To the combined organic layers, 10 M NaOH (140 mL) was added and the pH was adjusted to 8, during which time precipitation began. HO (0.42 L) was added to give a thick slurry. 2-MeTHF (2.1 L) was added to the slurry, and the mixture was heated to 60°C and stirred at this temperature for 1 hour. The aqueous layer was discarded, and the organic layer was polish filtered. The filtrate was concentrated to 1.2 L and diluted with acetonitrile (1.2 L). The mixture was charged with 3 wt% seeds and heated to 40°C. After stirring for 3 hours, the mixture was concentrated to 1.2 L. An additional 1.2 L of acetonitrile was added and concentrated again to 1.2 L to give a thick slurry. The slurry was filtered and washed with ACN (2 x 0.28 L). The product was dried under vacuum at room temperature for 18 hours. 11 was obtained as a light yellow solid (113 g, 97.1% purity, 82% yield).

[0460] [ka] 11 : Gray solid (113 g, purity 97.1%, yield 82%); R f =0.13 (dichloromethane / methanol = 10 / 1); 1H NMR (400MHz, CDCl3) δ 7.72(dd,J=8.2,1.3Hz,1H), 7.58(dd,J=8.2,1.2Hz,1H), 7.51(dd,J=7.4,1.3Hz,1H), 7.42(t,J=7.8Hz,1 H), 7.31(t,J=7.8Hz,1H), 7.22(dt,J=7.6,1.2Hz,1H), 4.34(t,J=4.7Hz,2H), 4.11(d,J=17.5Hz,1H), 3.71 (dq,J=17.5,2.0Hz,1H),3.59-3.49(m,1H),3.11(tt,J=11.2,4.0Hz,2H),2.98-2.85(m,1H),2.70-2.57( m,2H), 2.46(d,J=1.7Hz,3H), 2.34-2.23(m,1H), 2.05-1.91(m,1H), 1.89-1.78(m,1H), 1.78-1.64(m,2H); 13 C NMR (101MHz, CDCl3) δ 165.0(d,J=1.9Hz), 159.9, 155.2, 148.8, 137.5, 130.4, 129.7, 128.3, 126.5, 126.2, 125.6, 124.9, 118.6, 113.0, 77.4, 69.9(d,J=18.2H z), 63.9(d,J=3.9Hz), 57.6(d,J=1.8Hz), 50.3(d,J=2.7Hz), 41.7(d,J=8.9Hz), 28.3(d,J=2.3Hz), 23.1(d,J=4.0Hz), 21.9;HRMS(ESI)C 23 H 26 Calculated value of ClN4O2として:425.1739[M+H] + , measured value: 425.1740

[0461] HRMS(ESI)C 23 H 26 Calculated value of ClN4O2として:425.1739[M+H] + , measured value: 425.1740 Example 3 3.1 Reaction operations

change

[0462] 18のSynthesis:

[0463] In a 2 L reactor, the ketoester 17 To a mixture of thiourea (100 g, 95% purity) and thiourea (1.25 equiv, 64 g) in MeOH (1 L) was slowly added sodium methoxide solution (25 wt%, 192 mL). The reaction was heated under reflux for 4 h and cooled to 0-5°C. Concentrated HCl was slowly charged to the reaction mixture until the pH reached 3-4, during which time the product precipitated, giving a slurry. The slurry was filtered, the cake washed with MeOH (0.5 L), and triturated with water (1 L) at 60°C for 1 h. The slurry was filtered, and the cake washed with water (0.5 L). The product was dried under vacuum at 60°C for 18 h until thermogravimetric analysis (TGA) showed a loss of <0.2 wt% to obtain the thiol. 18 was obtained as a pale yellow solid (95 g, 94% purity, 87% yield).

[0464] [ka] 18 : Light yellow solid (95 g, purity 94%, yield 87%); R f =0.67 (dichloromethane / methanol = 10 / 1)

[0465] 1 H NMR (400 MHz, DMSO-d) δ 12.46(s,1H), 12.32(s,1H), 7.90(d,J=8.1Hz,1H), 7.74(d,J=8.1Hz,1H), 7.58(d,J=7.4Hz,1H), 7.52(t,J=7.8Hz,1H), 7.43(t,J=7.8Hz,1H), 7.30( d,J=7.5Hz,1H), 3.96(d,J=17.4Hz,1H), 3.57(d,J=17.4Hz,1H), 3.38(m,1 H), 3.09(td,J=11.0, 4.2Hz,1H), 2.61-2.50(m,2H), 2.35(d,J=16.6Hz,1H)

[0466] 13C NMR (101MHz, DMSO-d6) δ 174.2, 160.9, 147.5, 147.5, 137.0, 129.7, 128.7, 128.7, 126.8, 126.0, 125.2, 125.0, 119.4, 109.8, 52.0, 48.9, 21.0

[0467] HRMS(ESI)C 17 H 15 Calculated for ClN3OS: 344.0624 [M+H] + , Measurement value: 344.0620

[0468] Synthesis of 15a:

[0469] In a 2 L reactor, sulfide 18 (65 g, 94% purity), MeOH (195 mL), and 3M NaOH (3.5 equiv.) were charged, and the mixture was stirred to form a solution. Isopropyl iodide (2 equiv.) was added to the solution in one portion. The resulting mixture was heated to 50° C. and stirred at this temperature for 2 hours. 2-MeTHF (650 mL) and water (260 mL) were added to the solution. The mixture was cooled to 17-20° C., and the layers were separated. The bottom aqueous layer was discarded, and the top organic layer was washed three times with 325 mL of NaOH (0.5 M). The resulting organic layer was concentrated to approximately 100 mL and slowly added to a mixture of 650 mL of DCM and 325 mL of aqueous NaOH (0.5 M). After stirring for 17 hours, the slurry was filtered and washed with 325 mL of aqueous Na2CO3 (0.15 M). The wet cake was dried under vacuum at 40°C for 22 hours to remove sulfides. 15a was obtained as a pale yellow solid (66 g, 94% purity, 86% yield).

[0470] [ka] 15a : Light yellow solid (66 g, purity 94%, yield 86%); R f =0.69 (dichloromethane / methanol = 10 / 1)

[0471] 1H NMR (400MHz, DMSO-d6) δ δ 7.87(dd,J=8.2, 1.1Hz,1H), 7.66(d,J=7.6Hz,1H), 7.54(dd,J=7.4, 1.2Hz,1H), 7.49(t,J= 7.8Hz,1H), 7.45-7.37(m,1H), 7.28(dd,J=7.6, 0.8Hz,1H), 3.84(d,J=15.9Hz,1H), 3.74(p ,J=6.8Hz,1H), 3.56(d,J=15.9Hz,1H), 3.46-3.38(m,1H), 3.00(ddd,J=11.7,9.9,4.3Hz,1 H), 2.63(ddd,J=15.9, 9.9, 5.8Hz,1H), 2.37(d,J=16.4Hz,1H), 1.27(dd,J=6.8, 1.7Hz,1H)

[0472] 13 C NMR (101MHz, DMSO-d6) δ 172.3, 165.5, 156.4, 149.1, 137.1, 129.2, 129.1, 128.4, 126.8, 125.7, 124.9, 123.8, 118.0, 110.3, 57.2, 51.3, 33.5, 23.5, 22.8

[0473] HRMS(ESI)C 20 H 21 Calculated for ClN3OS: 386.1089 [M-Na+2H] + , Measurement value: 386.1081

[0474] Synthesis of 13a: In a 100 mL reactor, sulfide 15a(5 g, 94% purity), Na2WO4·2H2O (0.05 equiv., 0.19 g), HO (25 mL), and CH3CN (50 mL) were charged. The mixture was stirred to obtain a solution and cooled to 5 °C. HO2 (30 wt%, 3 equiv., 3.52 mL) was added over 5 h, and the mixture was stirred at 5 °C for 12 h. The reaction was quenched with aqueous NaHSO3 (1 equiv., 1.2 g NaHSO3 in 20 mL water) to a pH of approximately 7. CH3CN was distilled off at approximately 40 °C, followed by the slow addition of AcOH (1.5 equiv., 0.98 mL) at room temperature, during which a precipitate formed. The slurry was filtered and washed with water (2 × 25 mL). The cake was dried at 40 °C overnight to give a yellow solid (3.89 g, 97% purity, 81% yield).

[0475] [ka] 13a : Light yellow solid (3.89 g, purity 97%, yield 81%); R f =0.47 (dichloromethane / methanol = 10 / 1)

[0476] 1 H NMR (400MHz, DMSO-d6) δ 13.65(s,1H), 7.92(dd,J=8.1, 1.3Hz,1H), 7.75(dd,J=8.3, 1.1Hz,1H), 7.57(d,J=6.1Hz,1 H), 7.54(t,J=7.8Hz,1H), 7.44(t,J=7.8Hz,1H), 7.38(dd,J=7.6, 1.2Hz,1H), 4.20(d,J=17 .2Hz,1H), 4.00(dt,J=17.4, 1.8Hz,1H), 3.82(hept,J=6.8Hz,1H), 3.60-3.50(m,1H), 3.20 (ddd,J=12.0, 10.1, 4.1Hz,1H), 3.05-2.92(m,1H), 2.72-2.65(m,1H), 1.26(d,J=6.9Hz,6H)

[0477] 13C NMR (101MHz, DMSO-d6) δ 168.0, 163.5, 160.0, 147.7, 137.0, 129.6, 128.8, 128.6, 126.8, 125.9 , 125.0, 124.9, 119.0, 117.3, 57.1, 50.6, 49.2, 22.3, 14.6(d,J=8.4Hz)

[0478] HRMS(ESI)C 20 H 21 Calculated for ClN3O3S: 418.0992 [M+H] + , Measurement value: 418.0987

[0479] Example 4 Section 5. Synthesis of 11 via triphosgene route 5.1 Reaction Procedure: [ka]

[0480] Synthesis of 13b: thiol 18 To a solution of (15 g) in 2-Me-THF (300 mL) at 0-5° C., HCl solution (4 M in dioxane, 10.1 mL) was slowly added, followed by triphosgene (1.2 eq, 14.5 g). The reaction mixture was allowed to warm to 25° C. and stirred at this temperature for 15 hours to give a slurry. The slurry was filtered and the cake was rinsed with ACN (75 mL) followed by MTBE (75 mL). The product was dried under vacuum at room temperature for 18 hours to remove the chloride. 13b was obtained as a pale yellow solid (13.5 g, 93.4% purity, 81% yield).

[0481] [ka] 13b : White solid (13.5 g, purity 93.4%, yield 81%); R f =0.58 (dichloromethane / methanol = 10 / 1); 1H NMR (400 MHz, DMSO-d) δ 7.89(dd,J=8.2, 1.3Hz,1H), 7.72(dd,J=8.2, 1.1Hz,1H), 7.55(dd,J=7.4, 1.3Hz,1H), 7.51(t,J=7.8Hz,1H), 7.42(t,J=7.8Hz,1H), 7.33(dd,J=7 .6, 1.2Hz,1H), 4.00(d,J=17.4Hz,1H), 3.78(dt,J=17.4, 2.1Hz,1H), 3.5 0-3.40(m,1H), 3.14-3.04(m,1H), 2.83-2.70(m,1H), 2.56-2.46(m,1H); 13 C NMR (101MHz, DMSO-d6) δ HRMS(ESI)C 17 H 14 Calculated for Cl2N3O: 346.0509 [M+H] + , Measurement value: 346.0491

[0482] Synthesis of 11: 2-Me chloride in THF (205 mL) at 0 °C 13b (41g, purity 93%), Prolinol 5(1.5 equiv., 17.8 g) and Nat-amylate (5 equiv., 56.7 g) were added successively, and the reactor was rinsed with 2-MeTHF (205 mL). The mixture was heated to 75° C. and stirred at this temperature for 48 h. The reaction mixture was cooled to 0° C., followed by the addition of HO (0.41 L) and aqueous HCl (2 M, 0.24 L). The bottom aqueous layer was separated and extracted with 2-MeTHF (0.41 L). To the combined organic layers was added aqueous NaOH (10 M, 140 mL). Precipitation began at pH 8. 2-MeTHF (0.41 L) was added to the mixture, which was heated to 55° C. and stirred at this temperature for 1 h. The biphasic mixture was separated, and the bottom aqueous layer was extracted with 2-MeTHF (0.41 L). The two organic layers were combined and concentrated to 0.41 L, followed by the addition of 0.2 L of acetonitrile. The mixture was seeded with 4 wt% seed crystals and stirred at room temperature for 15 hours. The resulting slurry was filtered and washed with ACN (2 x 0.2 L). The product was dried under vacuum at room temperature for 18 hours. 11 was obtained as a light yellow solid (41.9 g, 94.8% purity, 79% yield). The NMR data of the product are as described above. 11 This was consistent with the NMR data.

[0483] Example 5 Activate / S N Synthesis of 13 via Ar sequence 6.1 General reaction procedures:

[0484] Phase 1 : 11 To a mixture of (1 g, 97.1% purity) and DIPEA (2.5 equiv., 1 mL) in DCM (7 mL) at 0 °C, 1.1 equiv. of activating reagent (ArSO2Cl / Tf2O / MsCl) and 0.05 equiv. of DMAP were added sequentially. The reaction mixture was stirred at 0 °C for 15 min and allowed to warm to room temperature. H2O (3 mL) was added to the reaction mixture and the bottom organic layer was separated. The top organic layer was dried (over MgSO4) and concentrated to give the crude intermediate 25 was obtained, which was used directly in the next step.

[0485] Phase 2 : Crude intermediate 25 A mixture of piperazine (1.5 equiv.), K3PO4 (3 equiv.) in DMAc (3 mL) was stirred at room temperature for 2 hours. [ka]

[0486] Example 5A 6.2 Triflate-mediated synthesis of 13: [ka] Phase 1 : 11 To a mixture of (40 g, 97.2% assay, 91.5 mmol) and NaHCO (10.0 g, 119 mmol) in ACN (400 mL) at −15° C., TfO (27.8 g, 137 mmol) was added dropwise. The reaction mixture was stirred at −15° C. for 1 h.

[0487] Phase 2 To the mixture obtained in step 1, piperazine side chain (88.9 g, 110 mmol) and KPO (77.7 g, 366 mmol) were added sequentially at -15 °C. The reaction was then allowed to warm to room temperature over 1 h. The mixture was stirred at room temperature for 6 h. To the resulting slurry, 10% KOH solution (240 mL) was added and stirred for 10 min. The top organic layer was separated, followed by the addition of HO (500 mL) until the mixture became cloudy. 0.3 wt% seed crystals were added to the mixture. The mixture was then stirred at room temperature for 18 h. HO (500 mL) was added slowly over 2 h to give a white slurry. The slurry was filtered, and the wet cake was washed with 120 mL of a 1 / 3 (v / v) ACN / HO mixture and subsequently with 100 mL of HO. The wet cake was dried under vacuum at 40°C for 18 hours to give the product. 13 was obtained as a white solid (50 g, 89.0 wt%, 91.5% yield, 99.5% purity).

[0488] Alternate operation: [ka] In a 100 mL flask, 11 (4 g, 97.1% purity) and DCM (40 mL) were charged, and the resulting solution was cooled to -5 °C. Pyridine (1.1 equiv., 0.8 mL) was added, followed by the slow addition of TfOH (1.1 equiv., 0.9 mL, exothermic). TfO (1.2 equiv., 1.83 mL) was added slowly to the resulting mixture (exothermic!). The reaction was stirred at -5 °C for 2 h and quenched with 5% aqueous NaHCO (20 mL). The organic layer was drained into a separate reactor and cooled to 5 °C. Piperazine side chain (1.08 equiv., 2 g) was added, followed by triethylamine (3.6 equiv., 4.5 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 15% aqueous NaCO (30 mL), and the aqueous layer (pH = 9.8) was discarded. A solvent switch from DCM to 8 mL of DMAc was performed by distillation at 40°C. To the resulting DMAc solution, water (6 mL) was added to give a cloudy mixture. Seed crystals were added to the mixture to precipitate the product. The remaining water (4 mL) was added to precipitate the remaining product. The slurry was stirred for 1 hour, filtered, and washed successively with 6 mL of water / DMAc (v / v=60 / 40) and 20 mL of water. The product was dried in a vacuum oven at 40°C. 13 was obtained as a yellow solid (3.7 g, 92% purity, 70% yield). [ka]

[0489] In a 500 mL flask, 11 (20 g, 97.1% purity), 2-Me-THF (300 mL) was charged, and the resulting solution was cooled to −5° C. CsCO (2 equiv., 30 g) and PhNTf (1.2 equiv., 19.6 g) were added sequentially, and the reaction was maintained at approximately −5° C. with stirring for 2 h. 11 After consumption, acetonitrile (100 mL) was added, followed by 12(1.2 equiv., 10.8 g) and Cs2CO3 (4 equiv., 60 g) were added. The reaction was stirred at -5 °C for 15 h, then HO (100 mL) was added, resulting in a biphasic mixture. The aqueous layer was separated and extracted with 2-Me-THF (100 mL). The organic layers were combined, washed with brine (200 mL), and concentrated. To the resulting crude mixture in 2-Me-THF (200 mL) were added 2 M HCl (114 mL, 5 equiv.) and HO (100 mL) successively. The organic layer was separated and treated with 2 M HCl (23 mL, 1 equiv.) and HO (20 mL). The two aqueous layers were combined, and the pH of the solution was adjusted to 10-12 with NaOH (10 M). The aqueous solution was extracted with 2-Me-THF (200 mL). The organic solution was washed with brine (200 mL), solvent switched to acetonitrile, and concentrated to a final volume of approximately 80 mL with acetonitrile. H2O (100 mL) was added to give a cloudy solution, followed by seeding with 1 wt% seed crystals. The slurry was stirred at room temperature for 15 hours, followed by the dropwise addition of H2O (40 mL). The resulting slurry was filtered, and the filter cake was washed with a 1 / 4 ACN / H2O mixture (2 x 40 mL). The product was dried in a vacuum oven and 13 was obtained as a white solid (20.8 g, 91% purity, 78% yield).

[0490] Example 5B 6.3 Synthesis of 13 via the 2-nosylate: [ka] Phase 1 : 11 To a mixture of (3.0 g, 97.1% assay, 6.85 mmol) and 2-NOPhSOCl (1.8 g, 8.23 ​​mmol) in DMAc (18 mL) at 0° C. was added DIPEA (1.6 mL, 8.91 mmol). The reaction mixture was stirred at 0° C. for 10 minutes, allowed to warm to room temperature, and stirred for 1 hour.

[0491] Phase 2The mixture from step 1 was cooled to 0°C, and piperazine side chain (1.6 g, 8.23 ​​mmol) and KPO (7.3 g, 34.3 mmol) were added sequentially. The reaction was then allowed to warm to room temperature. The mixture was stirred at room temperature for 6 hours. To the resulting slurry was added HO (18 mL). KOH (0.77 g, 137.7 mmol) was then added to the reaction mixture, maintaining the temperature at 35°C, until a clear, two-phase solution was formed. The top organic layer was separated, followed by the addition of HO (2 mL) until the mixture became cloudy. 2 wt% seed crystals were added to the mixture. The mixture was then stirred at room temperature for 15 hours. HO (36 mL) was added over 2 hours, resulting in a white slurry. The slurry was filtered, and the cake was washed successively with 9 mL of a 1 / 3 (v / v) DMAc / HO mixture (9 mL) and 6 mL of HO. The wet cake was dried under vacuum at room temperature for 18 hours to give the product. 13 was obtained as a white solid (3.5 g, 91.1 wt%, 87.7% yield, 99.4% purity). 1 H NMR (400MHz, DMSO-d6) δ 7.86(dd,J=8.2, 1.3Hz,1H), 7.68(d,J=8.1Hz,1H), 7.53(dd,J=7.5, 1.3Hz,1H), 7.48(t,J=7.8Hz,1H), 7.40(t,J=7.8 Hz,1H), 7.31-7.23(m,1H), 4.23(dd,J=10.8, 4.8Hz,1H), 4.17(dd,J=17.1, 3.2Hz,1H), 4.00(ddd,J=10.4, 6.4, 3.6Hz, 1H), 3.84(d,J=11.7Hz,1H), 3.67(d,J=16.7Hz,1H), 3.43(s,2H), 3.40(s,1H), 3.20-2.73(m,8H), 2.73-2.63(m,3H), 2.47(ddd,J=8.8, 4.6, 2.3Hz,1H), 2.29(d,J=1.5Hz,3H), 2.10(q,J=8.4Hz,1H), 1.92-1.81(m,1H), 1.67-1.50(m,3H); 13C NMR (101MHz, DMSO-d6) δ 165.7(d,J=15.2Hz), 163.9(d,J=8.3Hz), 162.1(d,J=2.4Hz), 148.1(d,J=2.2Hz), 137.0, 129.4, 128.9, 128.5, 126 .8, 125.8, 125.0, 124.6, 118.7(d,J=1.9Hz), 118.7(d,J=2.2Hz), 108.3(d,J=20.4Hz), 68.8(d,J=4.3Hz), 63.4, 58 .7(d,J=6.7Hz), 57.0(d,J=3.9Hz), 51.7(d,J=8.5Hz), 50.9(d,J=41.1Hz), 50.0(d,J=5.5Hz), 47.7(d,J=25.3Hz), 44.6(d,J=2.9Hz), 41.2(d,J=1.7Hz), 28.5(d,J=4.5Hz), 25.7(d,J=8.3Hz), 22.5, 21.2(d,J=20.0Hz);HRMS(ESI)C 29 H 35 Calculated for ClNO: 532.2586 [M+H] + , Measurement value: 532.2593

[0492] Alternative synthesis of 13 via the 2-nosylate: [ka] Phase 1 : 11 To a mixture of 2-NOPhSOCl (50 g, 97.1% purity) and DIPEA (2.5 equiv., 50 mL) in DCM (350 mL) at 0 °C, 2-NOPhSOCl (1.1 equiv., 27.8 g) and DMAP (0.05 equiv., 0.28 g) were added sequentially. The reaction mixture was stirred at 0 °C for 15 min, allowed to warm to room temperature, and stirred at this temperature for 1.5 h. H2O (150 mL) was added to the reaction mixture and the layers were separated. The bottom organic layer was separated, dried (MgSO4), and concentrated to give the crude intermediate 25 was obtained, which was used directly in the next step.

[0493] Phase 2 : Piperazine side chain (1.2 eq, 27.0 g) and crude intermediate 25To a mixture of 145 g of KPO (6 equivalents, 145 g) in 150 mL of DMAc at 10 °C was added. The mixture was stirred at room temperature for 2.5 hours. To the resulting slurry, 250 mL of DMAc and 400 mL of H2O were added sequentially, maintaining the reaction temperature at approximately 40 °C, until a clear, two-phase solution was formed. The top organic layer was separated, followed by the addition of H2O until the mixture began to become cloudy. 2 wt% seed crystals were added, and the mixture was stirred at room temperature for 15 hours. H2O (640 mL) was added slowly over 6 hours to give a white slurry. The slurry was filtered, and the cake was washed successively with 100 mL of a 1 / 2 (v / v) mixture of DMAc and H2O (100 mL). The product was dried under vacuum at room temperature for 18 hours. 9 was obtained as a white solid (60 g, 90.1% assay, 90% yield).

[0494] 13 : White solid (60 g, 90.1% assay, 90% yield); R f =0.15 (dichloromethane / methanol = 5 / 1); 1 H NMR (400MHz, DMSO-d6) δ 7.88(dd,J=8.3, 1.3Hz,1H), 7.71(d,J=8.1Hz,1H), 7.55(dd,J=7.4, 1.3Hz,1H), 7.50(t,J=7.8Hz,1H), 7.42(t, J=7.8Hz,1H), 7.29(ddd,J=7.6, 2.9, 1.2Hz,1H), 4.24(dd,J=10.8, 4.8Hz,1H), 4.17(dd,J=17.2, 2.9Hz,1H), 4. 06-3.94(m,1H), 3.89-3.81(m,1H), 3.73-3.64(m,1H), 3.45(s,1H), 3.41(s,2H), 3.16-2.74(m,8H), 2.74-2.62 (m,3H), 2.52-2.42(m,1H), 2.31(d,J=1.5Hz,3H), 2.12(q,J=8.5Hz,1H), 1.94-1.81(m,1H), 1.71-1.50(m,3H); 13C NMR (101MHz, DMSO-d6) δ 165.9(d,J=14.7Hz), 164.1(d,J=8.0Hz), 162.3(d,J=2.5Hz), 148.3(d,J=2.2Hz), 137.2, 129.7, 129.1, 128.8, 127.1 , 126.1, 125.2, 124.9(d,J=2.0Hz), 119.0(d,J=1.6Hz), 118.9(d,J=1.9Hz), 108.5(d,J=20.0Hz), 69.0(d,J=4.0Hz), 6 3.7, 58.9(d,J=6.9Hz), 57.2(d,J=3.8Hz), 51.9(d,J=8.4Hz), 51.1(d,J=41.1Hz), 50.3(d,J=5.7Hz), 47.9(d,J=25.3H z), 44.9(d,J=2.5Hz), 41.4(d,J=1.7Hz), 28.8(d,J=4.6Hz), 25.9(d,J=8.4Hz), 22.7, 21.4(d,J=19.9Hz);HRMS(ESI)C 29 H 35 Calculated value of ClN7Oとして:532.2586[M+H] + , measured value: 532.2593

[0495] Example 6 Reaction operations:

change

[0496] Reaction setup: 14 To a mixture of 1.76 g (1.7 equiv) and DMF (0.1 equiv) in acetonitrile (25 mL) was added the coupling reagent at 0° C. The reaction mixture was stirred at 0° C. for 1 h, and then a solution of 13 (5.0 g, 9.26 mmol) in acetonitrile (25 mL) was added over 10 min.

[0497] Post-processing: After the reaction was completed, 20 wt% K3PO4 (8V) was added to obtain a clear two-phase solution (pH = 12). The bottom aqueous layer was discarded, and the organic layer was concentrated to 15 mL. 2-MeTHF (60 mL) was added to the mixture and concentrated to 15 mL to remove the remaining acetonitrile. The azeotropic process was repeated twice, and 2-MeTHF (45 mL) was added to the resulting mixture. The mixture was washed with H2O (25 mL), and the resulting organic layer was concentrated to 15 mL. Isopropanol (50 mL) was added to the mixture and concentrated to 15 mL to remove the remaining 2-MeTHF. The azeotropic process was repeated twice, and isopropanol (35 mL) was added to the resulting mixture. The mixture was heated to 55 °C, and 1% activated carbon (Darco G-60) was added. After stirring at 55 °C for 20 minutes, the mixture was filtered to obtain a clear solution. n-Heptane (10 mL) was added and the mixture was cooled to 45°C over 2 hours. 2% seed crystals were added and the temperature was maintained at 45°C for 2 hours, then it was cooled to 35°C over 3 hours. The temperature was maintained at 35°C for 4 hours, then it was cooled to 25°C in 3 hours. The temperature was maintained at 25°C for 6 hours, then it was cooled to 0°C in 8 hours. The resulting slurry was filtered and the cake was rinsed twice (10 mL*2) with a mixed solution of IPA / heptane (v / v=3 / 2). The solid was dried under vacuum at 40°C to obtain the product. 1 was obtained as a white solid (79% yield for entry 7).

[0498] Synthesis by T3P: [ka]

[0499] 14 To a suspension of (9.8 g, 87.99 mmol) in dry MeCN (90 mL) in a 400 mL EazyMax reactor, a 50% solution of T3P in ethyl acetate (462 mL, 77.64 mmol) was added over 20 minutes at 20 °C and stirred for 16 hours. This mixture was added with azeotropic drying with MeCN to prepare T3P. 13A solution of (30 g, 51.76 mmol) in MeCN (110 mL) (300 mL x 2; KF = 680 ppm) was charged over 2 minutes and stirred for 3 hours. 13 After the solubility was consumed, aqueous KCO (12 wt%, 5.0 w / w) was charged over 30 min. The organic layer was separated and washed with aqueous KPO (20 wt%, 3.75 w / w). The organic layer was allowed to concentrate to 3.5 V at NMT 40 °C. 2-MeTHF (6.5 V) was added to the mixture and concentrated twice to 3.5 V remaining. Additional 2-MeTHF (6.5 V) was added to the mixture and washed with 5% brine solution (2 × 150 mL). The organic phase was collected and concentrated to 3.5 V remaining. IPA (8 V) was charged and concentrated twice to 3.5 V remaining. Additional IPA was added to make an 8 V solution and heated to 60 °C. n-Heptane (2 V) was charged to the crude solution in IPA while maintaining a temperature of NLT 58 °C. The mixture was stirred at the same temperature for 1 h and then cooled to 45 °C over 3 h. Seed crystals (4 w / w%) were charged as a slurry in IPA / heptane, and the mixture was stirred at 45°C for an additional 3 hours. The mixture was cooled to 35°C over 5 hours and stirred for an additional 5 hours. The mixture was then cooled to 22°C over 3 hours and stirred for an additional 6 hours. The slurry was wet-milled using a homogenizer at 22°C for 2 hours and then stirred at the same temperature for an additional 1 hour. The mixture was cooled to 3°C over 8 hours and stirred for an additional 8 hours. The solid was filtered, washed with an IPA / heptane mixture (2:1; 2x2V), vacuum dried for 2 hours, and then oven dried at 35°C for 60 hours to give an off-white solid. 1 was obtained in 89% yield (28.15 g, 98.7% by weight, purity 99.7%). 1H NMR(400MHz、DMSO-d6) δ 7.91(dd,J=8.2、1.3Hz,1H)、7.57(dt,J=7.4、1.1Hz,1H)、7.52(q,J=7.7Hz,1H)、7.43(t,J=7.8Hz,1H)、7.33(ddd,J=15.9、7.6、1.2Hz,1H)、5.38(dd,J=18.0、4.1Hz,1H)、5.36-5.18(m,1H)、4.84(s,1H)、4.26-4.21(m,1H)、4.18(dd,J=16.1、9.5Hz,1H)、4.08-3.94(m,2H)、3.91-3.86(m,1H)、3.75(dd,J=20.2、17.4Hz,1H)、3.47(q,J=7.3Hz,1H)、3.23(dd,J=13.7、3.7Hz,1H)、3.18-2.99(m,3H)、2.98-2.88(m,2H)、2.70-2.52(m,1H)、2.48-2.46(m,1H)、2.32(d,J=3.5Hz,3H)、2.14(qd、J=8.7、2.2Hz,1H)、1.90(dq,J=12.1、8.2Hz,1H)、1.71-1.50(m,3H)ppm.; 13 C NMR(101MHz、DMSO-d6) δ 165.9、164.3(d,J=14.5Hz)、162.1(d,J=2.1Hz)、160.8(dd,J=31.7、12.2Hz)、155.6(d,J=266.7Hz)、148.0(d,J=20.4Hz)、137.0(d,J=2.9Hz)、129.4(d,J=2.1Hz)、128.9(d,J=4.3Hz)、128.5、126.8(d,J=2.6Hz)、125.8、125.0(d,J=5.6Hz)、124.7(d,J=6.1Hz)、118.7(d,J=2.6Hz)、118.1(d,J=3.9Hz)、108.7(d,J=20.7Hz)、99.9(d,J=14.3Hz)、68.9(d,J=7.0Hz)、63.4(d,J=2.7Hz)、58.5(d,J=25.8Hz)、57.0(d,J=4.0Hz)、50.0、49.0、48.2、47.3(d,J=36.2Hz)、46.4、41.2(d,J=2.9Hz)、28.5(d,J=7.1Hz)、25.2(d,J=35.0Hz)、22.5、18.1 ppm.; 19F NMR(101MHz, DMSO-d6) δ -105.18(d,J=334.7Hz)ppm;HRMS(ESI)C 32 H 36 Calculated for ClFN7O2: 604.2598 [M+H] + , Measurement value: 604.2607

[0500] While the invention has been described in relation to particular embodiments thereof, it will be understood that the invention is capable of further modifications and that this application is generally intended to cover any such changes, uses, or adaptations of the invention as may be adapted to its essential features described above, including departures from the present disclosure, in accordance with the principles of the invention as are within known or customary practice in the art to which the invention pertains, and in accordance with the scope of the appended claims.

Claims

1. Step (a): The following structural formula: 【Chemistry 1】 is reacted with a 4-halobutyric acid ester, an aprotic solvent, iodide, and a base to produce a compound of the following structure: 【Chemistry 2】 producing the final compound of step (a) represented by A method for synthesizing adagrasib, comprising:

2. 10. The method of claim 1, wherein step (a) is carried out at a temperature of from about 20°C to about 120°C.

3. 4-halobutyric acid ester is 4-X(CH ２ ) ３ CO ２ 2. The method of claim 1, wherein R is any alkyl or (hetero)aryl group selected from the group consisting of methyl, ethyl, propyl, and trifluoroethyl, and X is any leaving group selected, in one embodiment, from the group consisting of Cl, Br, I, MsO, TsO, and TfO.

4. 2. The method of claim 1, wherein the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and diethylene glycol dimethyl.

5. 2. The method of claim 1, wherein the iodide is selected from the group consisting of sodium iodide, potassium iodide, and alkylated ammonium iodides.

6. 10. The method of claim 1, wherein the base is an organic base.

7. The organic base is diisopropylethylamine (DIPEA), triethylamine (Et ３ 7. The method of claim 6, wherein the aryl group is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,8-diazabicyclo[5.4.0]undec-7-ene (DABCO), triethylenediamine (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

8. 10. The method of claim 1, wherein the base is an inorganic base.

9. 9. The method of claim 8, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

10. Step (b): b) reacting the final compound of step (a) with 2-halo-N-methoxy-N-methylacetamide, an aprotic solvent and a base to produce a compound of the following structure: 【Transformation 3】 and producing the final compound of step (b) represented by The method of claim 1 further comprising:

11. 11. The method of claim 10, wherein step (b) is carried out at a temperature of from about 20°C to about 150°C.

12. 2-halo-N-methoxy-N-methylacetamide is XCH ２ 11. The method of claim 10, wherein X is selected from the group consisting of Cl, Br, I, MsO, TsO, and TfO.

13. 11. The method of claim 10, wherein the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

14. 11. The method of claim 10, wherein step (b) further comprises adding iodide.

15. 15. The method of claim 14, wherein the iodide is selected from the group consisting of sodium iodide, potassium iodide, and alkylated ammonium iodides.

16. 11. The method of claim 10, wherein the base is an organic base.

17. The organic base is DIPEA, Et ３ 17. The method of claim 16, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

18. 11. The method of claim 10, wherein the base is an inorganic base.

19. 19. The method of claim 18, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

20. Step (c): c) reacting the final compound of step (b) with a base and an aprotic solvent to produce a compound of the following structural formula: 【Chemistry 4】 and producing the final compound of step (c) represented by The method of claim 1 further comprising:

21. 21. The method of claim 20, wherein step (c) is carried out at a temperature of from about -80°C to about 25°C.

22. 21. The method of claim 20, wherein the base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).

23. 21. The method of claim 20, wherein the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

24. Step (d): d) reacting the final compound from step (c) with an S-alkylated isothiourea salt, a solvent and a base to obtain a compound of the following structure: 【Transformation 5】 and producing the final compound of step (d) represented by 21. The method of claim 20, further comprising:

25. 25. The method of claim 24, wherein step (d) is carried out at a temperature of from about -20°C to about 50°C.

26. The alkyl group in the S-alkylated isothiourea salt is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl, t-hexyl, cyclohexyl, and benzyl, and the counter ion is Cl. － ,Br － , I － , MsO － , TsO － , TfO － , B.F. ４ － , SbF ６ － , C.F. ３ COO － , NO ３ － , and S.O. ４ ２－ 25. The method of claim 24, selected from the group consisting of:

27. 25. The method of claim 24, wherein the solvent is an alcoholic solvent.

28. 25. The method of claim 24, wherein the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

29. 25. The method of claim 24, wherein the base is an organic base.

30. The organic base is DIPEA, Et ３ 30. The method of claim 29, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

31. 25. The method of claim 24, wherein the base is an inorganic base.

32. 32. The method of claim 31 , wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

33. Step (e): e) reacting the final compound of step (d) with an acid or a mesylating / triflating agent and an aprotic solvent to produce a compound of the following structural formula: 【Transformation 6】 and producing the final compound of step (e) represented by 25. The method of claim 24, further comprising:

34. 34. The method of claim 33, wherein step (e) is carried out at a temperature of from about -20°C to about 80°C.

35. 34. The method of claim 33, wherein the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, diethylene glycol dimethyl, DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

36. 34. The method of claim 33, wherein the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid, and HCl.

37. The triflating agent is Tf ２ O, CF ３ SO ２ Cl, and CF ３ SO ２ Br; and the mesylating agent is selected from the group consisting of, but not limited to, MsCl or (MeSO ２ ) ２ 34. The method of claim 33, wherein the compound may comprise O.

38. Step (f): f) reacting the final compound of step (e) with an oxidizing agent, a base and / or alkoxide, a polar solvent, and optionally a catalyst to form a compound of the following structural formula: 【Transformation 7】 and producing the final compound of step (f) represented by 34. The method of claim 33, further comprising:

39. 39. The method of claim 38, wherein step (f) is carried out at about -15°C to about 60°C.

40. Oxidizing agents include peracid, oxone, bleach, hydrogen peroxide, and NaIO ４ 39. The method of claim 38, wherein the urea hydrogen peroxide is selected from the group consisting of perborates, percarbonates, and urea hydrogen peroxide.

41. 39. The method of claim 38, wherein the oxidizing agent is hydrogen peroxide.

42. 39. The method of claim 38, wherein the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

43. 39. The method of claim 38, wherein the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amylate, or ammonium or alkali salts thereof.

44. 39. The method of claim 38, wherein the base is an inorganic base.

45. 45. The method of claim 44, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

46. 39. The method of claim 38, wherein the polar solvent is selected from the group consisting of acetonitrile and ROH, where R is methyl, ethyl, or 2-propyl.

47. Process (g): g) reacting the final compound of step (f) with an alkoxide and a polar aprotic solvent to produce a compound of the following structure: 【Transformation 8】 and producing the final compound of step (g) represented by 39. The method of claim 38, further comprising:

48. 48. The method of claim 47, wherein step (g) is carried out at about -20°C to about 100°C.

49. 48. The method of claim 47, wherein the alkoxide is selected from the group consisting of isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

50. 48. The method of claim 47, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

51. Process (h): h) reacting the final compound of step (g) with an activating agent, a base, a polar aprotic solvent, and an additive to produce a compound of the following structural formula: 【Chemistry 9】 wherein R is a substituted phenyl, methyl, ethyl, propyl, C ４ F ９ , C.F. ３ and toluene. and producing the final compound of step (h) represented by 48. The method of claim 47, further comprising:

52. 52. The method of claim 51, wherein step (h) is carried out at a temperature of from about -80°C to about 120°C.

53. The activator is a sulfonyl halide R—SO ２ X (where R is selected from the group consisting of tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, Br, Oms, or OTs), an anhydride, and an organic triflating agent: R １ -N-Tf ２ (where R １ is phenyl, 5-chloro-2-pyridine, or 2-pyridine).

54. 52. The method of claim 51, wherein the base is an organic base.

55. The organic base is DIPEA, Et ３ 55. The method of claim 54, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

56. 52. The method of claim 51 , wherein the base is an inorganic base.

57. 57. The method of claim 56, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

58. 52. The method of claim 51, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

59. 52. The method of claim 51, wherein the additive is selected from the group consisting of pyridine and substituted pyridines.

60. Step (i): i) reacting the final compound of step (h) with 【Chemistry 10】 , a base, and a polar aprotic solvent to form a compound of the following structural formula: 【Chemistry 11】 and producing the final compound of step (i) represented by 52. The method of claim 51, further comprising:

61. 61. The method of claim 60, wherein step (i) is carried out at a temperature of from about 0°C to about 100°C.

62. 61. The method of claim 60, wherein the salt is selected from the group consisting of HCl, TFA, and HBr.

63. 61. The method of claim 60, wherein the base is an organic base.

64. The organic base is DIPEA, Et ３ 64. The method of claim 63, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

65. 61. The method of claim 60, wherein the base is an inorganic base.

66. 66. The method of claim 65, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

67. 61. The method of claim 60, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

68. Process (j): j) reacting the final compound of step (i) with a salt of 2-fluoroacrylic acid, a solvent, and optionally a base to produce adagrasib.

61. The method of claim 60, further comprising:

69. 69. The method of claim 68, wherein step (j) is carried out at a temperature of from about -10°C to about 50°C.

70. 69. The method of claim 68, wherein the salt is a lithium, sodium, potassium, or ammonium salt.

71. 69. The method of claim 68, wherein the base is an organic base.

72. The organic base is DIPEA, Et ３ 72. The method of claim 71, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

73. 69. The method of claim 68, wherein the base is an inorganic base.

74. 74. The method of claim 73, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

75. 69. The method of claim 68, wherein the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula R-OH, wherein R is alkyl, allyl, or aryl.

76. Step (d'): d') reacting the final compound of step (c) with an alkoxide and a polar solvent to form a compound of the following structure: 【Chemistry 12】 and producing the final compound of step (d') represented by 21. The method of claim 20, further comprising:

77. 77. The method of claim 76, wherein step (d') is carried out at a temperature of from about 20°C to about 120°C.

78. 77. The method of claim 76, wherein the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula R-OH, wherein R is alkyl, allyl, or aryl.

79. 77. The method of claim 76, wherein the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amylate, or ammonium or alkali salts thereof.

80. Process (e'): e') reacting the final compound of step (d') with an alkylating agent, an inorganic base and / or an alkoxide, and a polar solvent to form a compound of the following structural formula: 【Chemistry 13】 and producing the final compound of step (e') represented by 77. The method of claim 76, further comprising:

81. 81. The method of claim 80, wherein step (e') is carried out at a temperature of from about 20°C to about 120°C.

82. 81. The method of claim 80, wherein the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol of the formula R-OH, where R is alkyl, allyl, or aryl.

83. 81. The method of claim 80, wherein the alkylating agent is selected from the group consisting of alkyl halides R-X (where R is methyl, ethyl, isopropyl, or benzyl and X is Cl, Br, I, alkyl, sulfonate, arylsulfonate, triflate, or nonaflate), dialkyl sulfates, and carbonates.

84. 81. The method of claim 80, wherein the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

85. 81. The method of claim 80, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, hydroxides, and alkali salts thereof.

86. Process (f'): f') reacting the final compound of step (e') with an oxidizing agent, a base and / or alkoxide, a polar solvent, and optionally a catalyst to form a compound of the following structural formula: 【Chemistry 14】 and producing the final compound of step (f') represented by 81. The method of claim 80, further comprising:

87. 87. The method of claim 86, wherein step (f') is carried out at about -15°C to about 60°C.

88. Oxidizing agents include peracid, oxone, bleach, hydrogen peroxide, and NaIO ４ 87. The method of claim 86, wherein the compound is selected from the group consisting of perborates, percarbonates, and urea hydrogen peroxide.

89. 89. The method of claim 88, wherein the oxidizing agent is hydrogen peroxide.

90. 87. The method of claim 86, wherein the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogen sulfate.

91. 87. The method of claim 86, wherein the alkoxide is selected from the group consisting of methoxide, ethoxide, isopropoxide, tert-butoxide, and tert-amylate, or ammonium or alkali salts thereof.

92. 87. The method of claim 86, wherein the base is an inorganic base.

93. 93. The method of claim 92, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

94. 87. The method of claim 86, wherein the polar solvent is selected from the group consisting of acetonitrile and ROH, where R is methyl, ethyl, or 2-propyl.

95. Process (d'''): d''') Reacting the final compound of step (c) with an S-alkylated isothiourea salt, a solvent, and a base to obtain a compound of the following structure: 【Chemistry 15】 and producing the final compound of step (d''') represented by 21. The method of claim 20, further comprising:

96. 96. The method of claim 95, wherein step (d''') is carried out at a temperature of from about -20°C to about 50°C.

97. The alkyl group in the S-alkylated isothiourea salt is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, cyclopropyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, i-pentyl, s-pentyl, t-pentyl, cyclopentyl, n-hexyl, i-hexyl, s-hexyl, t-hexyl, cyclohexyl, and benzyl, and the counter ion is Cl. － ,Br － , I － , MsO － , TsO － , TfO － , B.F. ４ － , SbF ６ － , C.F. ３ COO － , NO ３ － , and S.O. ４ ２－ 96. The method of claim 95, selected from the group consisting of:

98. 96. The method of claim 95, wherein the solvent is an alcoholic solvent.

99. 96. The method of claim 95, wherein the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

100. 96. The method of claim 95, wherein the base is an organic base.

101. The organic base is DIPEA, Et ３ 101. The method of claim 100, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

102. 96. The method of claim 95, wherein the base is an inorganic base.

103. 103. The method of claim 102, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

104. Process (e'''): e''') Reacting the final compound of step (d''') with a water miscible solvent and a base to form a compound of the following structural formula: 【Chemistry 16】 and producing the final compound of step (e''') represented by 96. The method of claim 95, further comprising:

105. 105. The method of claim 104, wherein step (e''') is carried out at a temperature of about -20°C to about 50°C.

106. 105. The method of claim 104, wherein the water-miscible solvent is selected from the group consisting of 2-propanol, tert-butanol, and acetonitrile.

107. 105. The method of claim 104, wherein the base is an organic base.

108. The organic base is DIPEA, Et ３ 108. The method of claim 107, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

109. 105. The method of claim 104, wherein the base is an inorganic base.

110. 110. The method of claim 109, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

111. Process (e''): (e″) reacting the final compound of step (d′) with phosgene or a phosgene derivative, a polar aprotic solvent, and optionally a mineral acid to form a compound of the following structural formula: 【Chemistry 17】 and producing the final compound of step (e″) represented by 77. The method of claim 76, further comprising:

112. 112. The method of claim 111, wherein step (e'') is carried out at a temperature of from about 0°C to about 120°C.

113. 112. The method of claim 111, wherein the phosgene derivative is selected from the group consisting of diphosgene, triphosgene, thiophosgene, and 1,1'-carbonyldiimidazole.

114. 112. The method of claim 111, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

115. 112. The method of claim 111, wherein the mineral acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

116. Process (f''): (f″) reacting the final compound of step (e″) with an alkoxide and a polar aprotic solvent to produce a compound of the following structural formula: [Chemistry 18] and producing the final compound of step (f″) represented by 112. The method of claim 111, further comprising:

117. 117. The method of claim 116, wherein step (f'') is carried out at a temperature of from about 0°C to about 120°C.

118. 117. The method of claim 116, wherein the alkoxide is selected from the group consisting of isopropoxide, tert-butoxide, tert-amylate, and alkali salts thereof.

119. 117. The method of claim 116, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

120. Process (h'): (h') reacting the final compound of step (g) with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base to obtain a compound of the following structural formula: 【Chemistry 19】 and producing the final compound of step (h') represented by 48. The method of claim 47, further comprising:

121. 121. The method of claim 120, wherein step (h') is carried out at a temperature of from about -80°C to about 50°C.

122. The triflating agent is Tf ２ O, CF ３ SO ２ Cl, and CF ３ SO ２ 121. The method of claim 120, wherein said alkyl group is selected from the group consisting of Br.

123. 121. The method of claim 120, wherein the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, and HCl.

124. 121. The method of claim 120, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

125. 121. The method of claim 120, wherein the base is an organic base.

126. The organic base is DIPEA, Et ３ 126. The method of claim 125, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

127. 121. The method of claim 120, wherein the base is an inorganic base.

128. 128. The method of claim 127, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

129. 10. The method of claim 1, wherein the additive is selected from the group consisting of pyridine and substituted pyridines.

130. Process (i'): i') reacting the final compound of step (h') with 【Chemistry 20】 , a base, and a polar aprotic solvent to produce a compound of the following structural formula: 【Chemistry 21】 and producing the final compound of step (i') represented by 121. The method of claim 120, further comprising:

131. 131. The method of claim 130, wherein step (i') is carried out at a temperature of from about 0°C to about 100°C.

132. 131. The method of claim 130, wherein the salt is selected from the group consisting of HCl, TFA, and HBr.

133. 131. The method of claim 130, wherein the base is an organic base.

134. The organic base is DIPEA, Et ３ 134. The method of claim 133, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

135. 131. The method of claim 130, wherein the base is an inorganic base.

136. 131. The method of claim 130, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

137. 131. The method of claim 130, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

138. Process (h''): (h″) reacting the final compound of step (g) with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base to obtain a compound of the following structural formula: 【Chemistry 22】 and producing the final compound of step (h″) represented by 48. The method of claim 47, further comprising:

139. 139. The method of claim 138, wherein step (h'') is carried out at a temperature of about -80°C to about 50°C.

140. 139. The method of claim 138, wherein the triflating agent is selected from the group consisting of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine, 1-(trifluoromethanesulfonyl)imidazole, 1-(trifluoromethanesulfonyl)-1H-benzotriazole, N-(2-pyridyl)bis(trifluoromethanesulfonimide), and N-phenylbis(trifluoromethanesulfonimide).

141. 139. The method of claim 138, wherein the acid is selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, and HCl.

142. 139. The method of claim 138, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

143. 139. The method of claim 138, wherein the base is an organic base.

144. The organic base is DIPEA, Et ３ 144. The method of claim 143, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

145. 139. The method of claim 138, wherein the base is an inorganic base.

146. 146. The method of claim 145, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

147. 139. The method of claim 138, wherein the additive is selected from the group consisting of pyridine and substituted pyridines.

148. Process (i''): (i″) The final compound of step (h″) 【Chemistry 23】 , a base and a polar aprotic solvent to form a compound of the following structural formula: 【Chemistry 24】 and producing the final compound of step (i″) represented by 139. The method of claim 138, further comprising:

149. 149. The method of claim 148, wherein step (i'') is carried out at a temperature of about 0°C to about 100°C.

150. 149. The method of claim 148, wherein the salt is selected from the group consisting of HCl, TFA, and HBr.

151. 149. The method of claim 148, wherein the base is an organic base.

152. The organic base is DIPEA, Et ３ 152. The method of claim 151, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

153. 149. The method of claim 148, wherein the base is an inorganic base.

154. 154. The method of claim 153, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

155. 149. The method of claim 148, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

156. Process (h'''): (h''') reacting the final compound of step (g) with an aryl- or heteroarylsulfonyl, a base, a polar aprotic solvent, and an additive to produce a compound of the following structural formula: 【Chemistry 25】 and producing the final compound of step (h''') represented by 48. The method of claim 47, further comprising:

157. 157. The method of claim 156, wherein step (h''') is carried out at a temperature of about -30°C to about 100°C.

158. Aryl- or heteroarylsulfonyl is ArSO ２ 157. The method of claim 156, wherein X, wherein Ar is a substituted aromatic or heteroaromatic group, is selected from the group consisting of F, Cl, Br, OMs, and OTs.

159. 159. The method of claim 158, wherein Ar is selected from the group consisting of tolyl, mesityl, and nosyl.

160. 157. The method of claim 156, wherein the base is an organic base.

161. The organic base is DIPEA, Et ３ 161. The method of claim 160, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

162. 157. The method of claim 156, wherein the base is an inorganic base.

163. 157. The method of claim 156, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

164. 157. The method of claim 156, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP.

165. 157. The method of claim 156, wherein the base is an organic base.

166. The organic base is DIPEA, Et ３ 166. The method of claim 165, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

167. 157. The method of claim 156, wherein the base is an inorganic base.

168. 168. The method of claim 167, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

169. 157. The method of claim 156, wherein the additive is selected from the group consisting of pyridine and substituted pyridines.

170. Process (i'''): (i''') The final compound of step (h''') is 【Chemistry 26】 , a base and a polar aprotic solvent to form a compound of the following structural formula: 【Chemistry 27】 and producing the final compound of step (i''') represented by 157. The method of claim 156, further comprising:

171. 171. The method of claim 170, wherein step (i''') is carried out at a temperature of about 0°C to about 100°C.

172. 171. The method of claim 170, wherein the salt is selected from the group consisting of HCl, TFA, and HBr.

173. 171. The method of claim 170, wherein the base is an organic base.

174. The organic base is DIPEA, Et ３ 174. The method of claim 173, wherein the nucleotide sequence is selected from the group consisting of N, DABCO, and DBU.

175. 171. The method of claim 170, wherein the base is an inorganic base.

176. 176. The method of claim 175, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, phosphates, and alkali salts thereof.

177. 171. The method of claim 170, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol, and NMP. [Request Item 178] [Chemistry 28] with a salt of 2-fluoroacrylic acid, a base and a solvent to produce adagrasib. 【Request Item 179】 【Chemistry 29】 reacting with an activator, a base, a polar aprotic solvent, and an additive; 【Transformation 30】 where R is a substituted phenyl, methyl, ethyl, propyl, C ４ F ９ and toluene; 【Chemistry 31】 of 【Chemistry 32】 a salt of, a base and a polar aprotic solvent, 【Transformation 33】 generating 【Transformation 34】 reacting with a salt of 2-fluoroacrylic acid, a base, and a solvent to produce adagrasib; A method for synthesizing adagrasib, comprising: 【Request Item 180】 【Chemistry 35】 reacting with an S-alkylated isothiourea salt, a solvent and a base; 【Transformation 36】 generating 【Chemistry 37】 reacting with an acid, a triflating agent, and an aprotic solvent; 【Transformation 38】 generating 【Chemistry 39】 reacting with an oxidizing agent, a base and / or an alkoxide, a polar solvent, and optionally a catalyst; 【Chemistry 40】 generating 【Chemistry 41】 reacting with an alkoxide and a polar aprotic solvent; 【Chemistry 42】 generating 【Chemistry 43】 reacting with an activator, a base, a polar aprotic solvent, and an additive; 【Chemistry 44】 where R is a substituted phenyl, methyl, ethyl, propyl, C ４ F ９ and toluene; 【Chemistry 45】 of 【Chemistry 46】 a salt of, a base and a polar aprotic solvent, 【Chemistry 47】 generating 【Chemistry 48】 reacting with a salt of 2-fluoroacrylic acid, a base, and a solvent to produce adagrasib; A method for synthesizing adagrasib, comprising: 【Request Item 181】 【Chemistry 49】 reacting with an alkoxide and a polar solvent; [Transformation 50] generating 【Chemistry 51】 with an alkylating agent, an inorganic base and / or an alkoxide, and a polar solvent; 【Chemistry 52】 and 【Chemistry 53】 reacting with an oxidizing agent, a base and / or an alkoxide, a polar solvent, and optionally a catalyst; 【Chemistry 54】 To generate A method for synthesizing adagrasib, comprising:

182. The following structural formula: 【Transformation 55】 a first reaction in which a compound of the formula: a second reaction in which 2-halo-N-methoxy-N-methylacetamide, an aprotic solvent, and a base are added to the vessel; A base and an aprotic solvent are added to the vessel to form a compound having the following structural formula: 【Transformation 56】 and a third reaction to produce a compound of the formula A method for synthesizing adagrasib, comprising: 【Request Item 183】 【Chemistry 57】 with an S-alkylated isothiourea salt, a solvent, and a base in a vessel; The acid, triflating agent, and aprotic solvent are added to the vessel to produce a compound of the following structural formula: 【Transformation 58】 a second reaction to produce a compound of the formula A method for synthesizing adagrasib, comprising: 【Request Item 184】 【Chemistry 59】 with an activator, a base, a polar aprotic solvent, and an additive in a vessel; 【Transformation 60】 A salt of the formula: 【Chemistry 61】 a second reaction to produce a compound of the formula A method for synthesizing adagrasib, comprising: 【Request Item 185】 【Chemistry 62】 a first reaction in which the compound is reacted in a vessel with a triflating agent, an acid, a polar aprotic solvent, an additive, and optionally a base; 【Transformation 63】 A salt of the formula: 【Chemistry 64】 a second reaction to produce a compound of the formula A method for synthesizing adagrasib, comprising: 【Request Item 186】 【Chemistry 65】 a first reaction in which the compound is reacted with an aryl- or heteroarylsulfonyl, a base, a polar aprotic solvent, and an additive in a vessel; 【Chemical Formula 66】 A salt of the formula: 【Transformation 67】 a second reaction to produce a compound of the formula A method for synthesizing adagrasib, comprising:

187. The following structural formula: 【Transformation 68】 A compound selected from:

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