Processes and intermediates for the synthesis of adagrasib

Abstract

The present invention relates to an improved synthetic route for synthesizing adagrasib. The present invention also provides intermediates used in the provided synthetic route.

Description

[Technical field]

[0001] The present invention relates to an 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 that cycles between inactive (GDP-bound) and active (GTP-bound) states and transmits upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate a variety of processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed more than 30 years ago (see, 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 and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with the G12C transversion being the most common activating mutation (see, e.g., Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi:10.1158 / 1078-0432. CCR-11-3265).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations of KRas in various tumor types have made KRas a highly attractive target for the pharmaceutical industry in cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas for the treatment of cancer, KRas inhibitors have yet to demonstrate sufficient safety and / or efficacy to gain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] The KRas G12C 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, also known as adagrasib) has the following structure:

[0006] [ka]

[0007] Adaglasib is described, for example, in Example 478 of WO 2019 / 099524.

[0008] Although WO 2019 / 099524 describes methods for making adagrasib, there is a need in the art for improved synthetic routes to make adagrasib. Summary of the Invention

[0009] The present invention, in one aspect, provides an improved method for making adagrasib.

[0010] In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: a) reacting a compound of the following structure:

[0011] [ka] a free base or salt of a compound of the structure

[0012] [ka] reacting in the presence of a polar aprotic solvent and a base to produce the final compound of step (a) having the structure:

[0013] [ka]

[0014] As an alternative to step (a), the method of the present invention may further comprise the step (a'): a') a compound of the following structure:

[0015] [ka] A compound of the following structure:

[0016] [ka] reacting in the presence of a polar aprotic solvent and a base to produce a compound of the structure:

[0017] [ka] Next

[0018] reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE), and water to produce the final compound of step (a') having the following structure:

[0019] [ka]

[0020] In one aspect, the method of the present invention comprises step (b): b) reacting the final compound of step (a) or step (a') with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (b) having the structure:

[0021] [ka]

[0022] In another aspect, the method of the present invention further comprises step (c): c) reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure:

[0023] [ka]

[0024] In one aspect, the method of the present invention comprises step (d): d) reacting the salt or free base of the final product of step (c) with

[0025] [ka] in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure:

[0026] [ka]

[0027] In one aspect, the method of the present invention comprises step (e): e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the following structure:

[0028] [ka]

[0029] In one aspect, the method of the present invention comprises step (f): f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure:

[0030] [ka]

[0031] In one aspect, the method of the present invention comprises step (g): (g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

[0032] In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising reacting the compound of the following structure:

[0033] [ka] The method includes reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0034] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0035] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0036] [ka] The following structure:

[0037] [ka]

[0038] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0039] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0040] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following structure:

[0041] [ka] -

[0042] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0043] [ka] The following structure:

[0044] [ka] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0045] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0046] [ka] The free base of

[0047] [ka] in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0048] [ka] -

[0049] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following structure:

[0050] [ka] -

[0051] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to give

[0052] [ka] generating The following structure:

[0053] [ka] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0054] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0055] [ka] with an acid to remove the Boc protecting group to produce a salt or free base of the structure:

[0056] [ka] -

[0057] [ka] A salt or free base of

[0058] [ka] in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0059] [ka] -

[0060] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following structure:

[0061] [ka] -

[0062] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0063] [ka] The following structure:

[0064] [ka] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0065] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0066] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0067] [ka] -

[0068] [ka] with an acid to remove the Boc protecting group to produce a salt or free base of the structure:

[0069] [ka] -

[0070] [ka] A salt or free base of

[0071] [ka] in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0072] [ka] -

[0073] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following structure:

[0074] [ka] -

[0075] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0076] [ka] The following structure:

[0077] [ka]

[0078] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0079] In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: a) reacting a compound of the following structure:

[0080] [ka] a free base or salt of a compound of the structure

[0081] [ka] reacting in the presence of a polar aprotic solvent and a base to produce a final compound of step (a) having the structure:

[0082] [ka] b) reacting the final compound of step (a) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (b) having the structure:

[0083] [ka] c) reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure:

[0084] [ka] d) reacting the salt or free base of the final product of step (c) with

[0085] [ka] in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure:

[0086] [ka] e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the following structure:

[0087] [ka] f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure:

[0088] [ka] g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

[0089] In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: a') a compound of the following structure:

[0090] [ka] A compound of the following structure:

[0091] [ka]

[0092] reacting in the presence of a polar aprotic solvent and a base to produce a compound of the structure:

[0093] [ka] Next

[0094] reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE), and water to produce the final compound of step (a') having the following structure:

[0095] [ka]

[0096] reacting the final compound of step (a') with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (b) having the structure:

[0097] [ka]

[0098] reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure:

[0099] [ka]

[0100] Adding the salt or free base of the final product of step (c),

[0101] [ka] in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure:

[0102] [ka]

[0103] reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the structure:

[0104] [ka]

[0105] reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure:

[0106] [ka]

[0107] and reacting the final compound of step (f) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

[0108] In another aspect, the present invention provides novel intermediate compounds of steps (a)-(e) such as the structures below:

[0109] [ka] [Brief description of the drawings]

[0110] [Figure 1A] FIG. 1 is an image of phosphate particle size using the procedure of steps (b) and (c) of Example 2. [Figure 1B] 1 is an image of phosphate particle size using the procedure of steps (b') and (c') of Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0111] The present invention relates to improved synthetic routes for the synthesis of adagrasib, as well as novel intermediates used in the provided routes.

[0112] While there are known methods for synthesizing adagrasib (see WO 2019 / 099524), the synthesis provided by the present invention is much improved in that it has fewer steps, provides higher isolated yields and higher overall purity.

[0113] Furthermore, in the known synthesis, palladium-catalyzed hydrogenation resulted in the formation of by-products. The formation of these by-products is suppressed in the improved process. The use of non-proprietary ligands in both palladium-catalyzed steps, especially in the key C-N bond forming reaction with 1-bromo-8-chloronaphthalene, significantly reduces production costs.

[0114] The yield of the new synthesis is dramatically improved over the previous synthesis, due in part to an increase in the yield of the final coupling step (from 47% to approximately 90% yield), which is likely due to the use of a more stable reagent, sodium 2-fluoroacrylate, and optimized reaction conditions.

[0115] The overall yield of adagrasib was increased at least five-fold (<5%-25%) using the described process and was demonstrated at multi-kilo scale (10-100 kg) with shorter cycle times. In contrast, previous syntheses could not be easily scaled up.

[0116] 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.

[0117] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing a glycine to cysteine ​​amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variant p.Glyl2Cys.

[0118] As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.

[0119] 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 structure:

[0120] [ka]

[0121] Adaglasib is described, for example, in Example 478 of WO 2019 / 099524.

[0122] The term "adagrasib" encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0123] In one embodiment, the term "adagrasib" includes salts of the above compounds, 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 formed from quaternary ammonium salts of the formula -NRZ-, wherein: R is hydrogen, alkyl, or benzyl, and Z is a counterion including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0124] Whenever this application refers to a chemical compound, unless specifically stated otherwise, the compound includes all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0125] The term "alkyl" is intended to mean a straight or branched aliphatic group having 1 to 12 carbon atoms, alternatively 1 to 8 carbon atoms, alternatively 1 to 6 carbon atoms. Other examples of alkyl groups have 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 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.

[0126] The term "alkenyl" is intended to mean an unsaturated linear or branched aliphatic group having one or more carbon-carbon double bonds and having 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0127] The term "alkynyl" is intended to mean an unsaturated linear or branched aliphatic group having one or more carbon-carbon triple bonds and having 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, alternatively 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0128] The terms "alkylene", "alkenylene", or "alkynylene", as used herein, are intended to mean, respectively, an alkyl, alkenyl, or alkynyl group, as defined above, that is located between and serves 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.

[0129] As used herein, the term "carbocycle" is intended to mean a cycloalkyl or aryl moiety.

[0130] 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, the 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.

[0131] The term "heteroalkyl" is intended to mean a saturated or unsaturated, straight-chain or branched aliphatic group, in which one or more carbon atoms in the group are replaced by a heteroatom independently selected from the group consisting of O, S, and N.

[0132] The term "aryl" is intended to mean a monocyclic, bicyclic, tricyclic, or polycyclic aromatic moiety, e.g., a C6-C14 aromatic moiety, e.g., containing 1 to 3 aromatic rings.

[0133] Alternatively, the aryl group is a C6-C10 aryl group, alternatively a C6 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0134] The term "aralkyl" or "arylalkyl" is intended to mean a group that includes an aryl group covalently linked to an alkyl group. When an aralkyl group is described as "optionally substituted", it is intended that either or both of the aryl and alkyl portions can be, 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 described as "arylalkyl", this term and its related terms are intended to indicate the order of the groups in a compound as "aryl-alkyl". Similarly, "alkyl-aryl" is intended to indicate the order of the groups in a compound as "alkyl-aryl".

[0135] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compound and exhibits minimal or no undesired toxicological 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 pharma- ceutically acceptable quaternary salts known to those of skill 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, including chloride, bromide, iodide, --O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0136] 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 a hydrogen ion (H+). Non-limiting examples of mineral acids include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid, and hydroiodic acid.

[0137] As used herein, the term "organic acid" refers to any organic compound having acidic properties. Non-limiting examples of organic acids include lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

[0138] Synthesis scheme In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: a) reacting a compound of the following structure:

[0139] [ka] a free base or salt of a compound of the structure

[0140] [ka]

[0141] reacting in the presence of a polar aprotic solvent and a base to produce the final compound of step (a) having the structure:

[0142] [ka]

[0143] As an alternative to step (a), the method of the present invention may further comprise the step (a'): a') a compound of the following structure:

[0144] [ka] A compound of the following structure:

[0145] [ka] reacting in the presence of a polar aprotic solvent and a base to produce a compound of the structure:

[0146] [ka] Next

[0147] reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE), and water to produce the final compound of step (a') having the following structure:

[0148] [ka] In one aspect, the method of the present invention comprises step (b): b) reacting the final compound of step (a) or step (a') with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (b) having the structure:

[0149] [ka] In another aspect, the method of the present invention further comprises step (c): c) reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure:

[0150] [ka]

[0151] In one aspect, the method of the present invention comprises step (d): d) reacting the salt or free base of the final product of step (c) with

[0152] [ka] in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure:

[0153] [ka]

[0154] In one aspect, the method of the present invention comprises step (e): e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the following structure:

[0155] [ka]

[0156] In one aspect, the method of the present invention comprises the step (f): f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure:

[0157] [ka]

[0158] In one aspect, the method of the present invention comprises step (g): (g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or corresponding alkali and metal salts) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

[0159] In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising reacting the compound of the following structure:

[0160] [ka] The method includes reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0161] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0162] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0163] [ka] The following structure:

[0164] [ka] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0165] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0166] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following structure:

[0167] [ka] -

[0168] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0169] [ka] - The following structure:

[0170] [ka] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0171] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0172] [ka] The free base of

[0173] [ka] in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0174] [ka] -

[0175] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent,

[0176] [ka] generating -

[0177] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to give

[0178] [ka] generating The following structure:

[0179] [ka] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0180] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0181] [ka] with an acid to remove the Boc protecting group to produce a salt or free base of the structure:

[0182] [ka] -

[0183] [ka] A salt or free base of

[0184] [ka] in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0185] [ka] -

[0186] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following structure:

[0187] [ka] -

[0188] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0189] [ka] The following structure:

[0190] [ka] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0191] In another aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: -

[0192] [ka] with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0193] [ka] -

[0194] [ka] with an acid to remove the Boc protecting group to produce a salt or free base of the structure:

[0195] [ka] -

[0196] [ka] A salt or free base of

[0197] [ka] in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following structure:

[0198] [ka] -

[0199] [ka] with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following structure:

[0200] [ka] -

[0201] [ka] with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the structure:

[0202] [ka] The following structure:

[0203] [ka]

[0204] and reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

[0205] In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: a) reacting a compound of the following structure:

[0206] [ka] a free base or salt of a compound of the structure

[0207] [ka] reacting in the presence of a polar aprotic solvent and a base to produce a final compound of step (a) having the structure:

[0208] [ka] b) reacting the final compound of step (a) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (b) having the structure:

[0209] [ka] c) reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure:

[0210] [ka] d) reacting the salt or free base of the final product of step (c) with

[0211] [ka] in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure:

[0212] [ka] e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the following structure:

[0213] [ka] f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure:

[0214] [ka] g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

[0215] In one aspect, the present invention provides a method of synthesizing adagrasib, the method comprising: a') a compound of the following structure:

[0216] [ka] A compound of the following structure:

[0217] [ka] reacting in the presence of a polar aprotic solvent and a base to produce a compound of the structure:

[0218] [ka] Next reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE), and water to produce the final compound of step (a') having the following structure:

[0219] [ka] reacting the final compound of step (a') with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (b) having the structure:

[0220] [ka] reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure:

[0221] [ka] Adding the salt or free base of the final product of step (c),

[0222] [ka] in the presence of a palladium catalyst, a base, a phosphorus based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure:

[0223] [ka] reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the structure:

[0224] [ka] reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure:

[0225] [ka] and reacting the final compound of step (f) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) and a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

[0226] In one embodiment, in step (a) and / or step (a′), the polar aprotic solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP).

[0227] In one embodiment, in step (a) and / or step (a'), the polar aprotic solvent includes one or more of the following, but is not limited to: dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethylsulfoxide (DMSO), and A-methylpyrrolidone (NMP).

[0228] In one embodiment, in step (a) and / or step (a'), the polar aprotic solvent is dimethylacetamide (DMAc).

[0229] In one embodiment, in step (a) and / or step (a'), the base is an organic base.

[0230] In one embodiment, the organic base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethylamine (Et3N), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0231] In one embodiment, the organic base catalyst is N,N-diisopropylethylamine (DIPEA).

[0232] In one embodiment, the inorganic base catalyst is selected from the group consisting of carbonates, bicarbonates, and phosphates.

[0233] In step (a) and / or step (a') above, the compound may be the salt of any organic or mineral acid, ie any organic or mineral salt.

[0234] In one embodiment, the organic salt is selected from the group consisting of fumarates, tartrates, malates, and citrates.

[0235] In one embodiment, the organic salt is a fumarate salt.

[0236] In one embodiment, the mineral salts are selected from the group consisting of hydrochlorides, hydrobromides, sulfates, and phosphates.

[0237] In one embodiment, step (a) is carried out at a temperature of from about -10°C to about 80°C.

[0238] In one embodiment, step (a') is carried out at a temperature of about 0°C to about 10°C.

[0239] In one embodiment, in step (b), the palladium catalyst is in the oxidation state 0 or II.

[0240] In one embodiment, in step (b), the palladium catalyst is selected from the group consisting of Pd2(dba)3, Pd(dba)2, and Pd(OAc)2.

[0241] In one embodiment, in step (b), the palladium catalyst is preactivated. Any preactivated palladium catalyst can be used, including but not limited to the Buchwald series of Pd-G1 to Pd-G6 catalysts, the Organ series such as PEPPSI (pyridine-enhanced precatalyst preparation stabilization and initiation).

[0242] In one embodiment, in step (b), the base is an organic base.

[0243] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0244] In one embodiment, in step (b), the base is an inorganic base.

[0245] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

[0246] In one embodiment, in step (b), the phosphorus based ligand is selected from the group consisting of monodentate phosphorus based ligands and bidentate phosphorus based ligands.

[0247] Monodentate phosphorus-based ligands may have the general formula PR3, where R may be Cy, tBu, Ph, or various combinations thereof, etc.

[0248] Bidentate phosphorus-based ligands include, but are not limited to, (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (R), (S) and rac-(BINAP), xantphos, bis[(2-diphenylphosphino)phenyl]ether (DPEPhos), ferrocene-based backbone ligands (e.g., 1,1'-bis(diphenylphosphino)ferrocene (dppf)), and the like.

[0249] In one embodiment, in step (b), the aprotic solvent is selected from the group consisting of toluene, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0250] In one embodiment, step (b) is carried out at a temperature of from about 20°C to about 120°C.

[0251] In step (c), the removal of the Boc protecting group can be carried out using any mineral acid, including but not limited to hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Any organic acid can be used, including but not limited to trifluoroacetic acid (TFA), citric acid, tartaric acid, etc.

[0252] In one embodiment, in step (c), the final compound may be a tartrate or citrate salt.

[0253] In one embodiment, in step (d), the palladium catalyst is in the oxidation state 0 or II.

[0254] In one embodiment, in step (d), the palladium catalyst is selected from the group consisting of Pd2(dba)3, Pd(dba)2, and Pd(OAc)2.

[0255] In one embodiment, in step (d), the palladium catalyst is preactivated. Any preactivated palladium catalyst can be used, including but not limited to the Buchwald series of Pd-G1 to Pd-G6 catalysts, the Organ series such as PEPPSI.

[0256] In one embodiment, in step (d), the base catalyst is an organic base catalyst.

[0257] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0258] In one embodiment, in step (d), the base is an inorganic base.

[0259] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

[0260] In one embodiment, in step (d), the phosphorus based ligand is selected from the group consisting of monodentate phosphorus based ligands and bidentate phosphorus based ligands.

[0261] Monodentate phosphorus-based ligands may have the general formula PR3, where R may be Cy, tBu, Ph, etc.

[0262] Bidentate phosphorus-based ligands include, but are not limited to, BINAP, xantphos, DPEPhos, ferrocene-based backbone ligands (eg, dppf), and the like.

[0263] In one embodiment, in step (d), the aprotic solvent is selected from the group consisting of toluene, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[0264] In one embodiment, step (d) is carried out at a temperature of about 20°C to about 120°C.

[0265] In one embodiment, in step (e), the first solvent is selected from the group consisting of a ketone-containing solvent and acetonitrile, hi one embodiment, the ketone-containing solvent is selected from the group consisting of acetone, methyl isobutyl ketone (MIBK), and methyl ethyl ketone (MEK).

[0266] In one embodiment, in step (e), the anti-solvent is selected from the group consisting of 2-MeTHF and isopropyl acetate (IPAc).

[0267] In one embodiment, step (e) is carried out at a temperature of about 20°C to about 120°C.

[0268] In one embodiment, in step (f), the thiol or thiolate is selected from the group consisting of 2-mercaptoethanol, dithiothreitol (DTT), 2-(dimethylamino)ethanethiol hydrochloride, and R-SY, where R is selected from the group consisting of H, alkyl, and aryl, and Y is selected from the group consisting of H, alkali, and metal salts.

[0269] In one embodiment, in step (f), the base is an organic base.

[0270] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0271] In one embodiment, in step (f), the base is an inorganic base.

[0272] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

[0273] 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, and NMP.

[0274] In one embodiment, step (f) is carried out at a temperature of about 20°C to about 120°C.

[0275] In one embodiment, in step (g), the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, dichloromethane (DCM), ethyl acetate (EtOAc), IPAc, and NMP.

[0276] In one embodiment, in step (g), 2-fluoroacrylic acid may be used in neutral form, the free acid, or in ionic form (as a metal or alkali salt).

[0277] In one embodiment, in step (g), the coupling agent is selected from the group consisting of propylphosphonic anhydride (T3P®), carbonyldiimidazole (CDI), carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride (EDC.HCl)), phosphonium ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), phosphonium hexafluorophosphate, ... hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)), and uronium (uronium (O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)).

[0278] In one embodiment, in step (g), the base is an organic base.

[0279] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0280] In one embodiment, in step (g), the base is an inorganic base.

[0281] In one embodiment, the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates.

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

[0283] The following examples are intended to illustrate further certain embodiments of the present invention and are not intended to limit the scope of the invention. EXAMPLES

[0284] [Example 1] Step (a)

[0285] [ka]

[0286] N,N-Dimethylacetamide (371.9 kg) was charged to a 3000 L glass-lined reactor and stirred for 5-10 minutes. The mixture was sampled to ensure the moisture level was less than 0.1%, and Karl Fischer analysis demonstrated that the actual moisture content was 0.01%. MR84905 fumarate (ASYM-124583) (136.7 kg, 135.2 kg corrected for purity, 360.2 mol, 1.1 equiv.) was added to the mixture at a temperature of 10-30 °C, and the mixture was stirred for 15-30 minutes. The mixture was adjusted to a temperature of 10-20 °C, set at 13.6 °C.

[0287] Diisopropylethylamine (DIPEA, 88.4 kg, 683.9 mol, 2.0 equiv.) was added to the reaction mixture, followed by MR84906 (ASYM-124584) (106.3 kg, 104.0 kg corrected by HPLC assay, 341.9 mol, 1.0 equiv.). The reactor walls were rinsed with N,N-dimethylacetamide (41.7 kg) and the mixture was stirred for 30-60 min.

[0288] After this, the reaction mixture was sparged with nitrogen from the bottom port for 5-10 minutes. The mixture was allowed to react at 10-20°C, and after 2 hours, the mixture was sampled by HPLC every 1-3 hours until the area % of MR84906 was ≦1.0 area %. After stirring for 4 hours and 26 minutes at 15°C, the area % of MR84906 was 0.3%. At this point, the reaction was diluted with MTBE (754.1 kg) at 10-30°C. The temperature of the reaction mixture was adjusted to 30-40°C and set at 32.6°C. Purified water (532.9 kg) was added to the mixture at a temperature of 30-40°C and stirred for 20-30 minutes. The stirring was stopped and the layers were allowed to settle to form a clear phase. The aqueous layer was removed at 30-40°C. The organic phase was then washed with a sodium chloride solution at 30-40°C prepared from purified water (528.8 kg) and sodium chloride (27.6 kg). The biphasic mixture was stirred for an additional 20-30 minutes, allowed to settle to form separate layers, and then the aqueous phase was removed at 30-40°C. The organic phase remaining in the reactor was concentrated under reduced pressure (≦-0.06 MPa) at a temperature of ≦40°C until 780.0-884.0 L (7.5-8.5 vol) remained. The temperature was adjusted to 30-40°C and set at 30.9°C. The mixture was stirred at a temperature of 30-40°C for 4-6 hours, at which point a significant amount of solid had precipitated from the mixture. n-Heptane (143.6 kg) was added to the mixture at 30-40°C, resulting in a thick slurry. The slurry was slowly cooled to a temperature of 15-25°C and set at 23.5°C. The temperature was maintained at this level for 2-3 hours during crystallization.

[0289] The supernatant was sampled for assay analysis of MR84907. An assay of ≦0.5% was desired and the actual value was 0.4%. The slurry was decanted and filtered through an agitated Nutsche filter dryer. The reactor was rinsed with n-heptane (71.0 kg), which was then transferred to the filter to rinse the filter cake. The filter cake was swept with nitrogen for 1-2 hours and dried on a T-line with agitation until the combined MTBE and n-heptane residuals were less than ≦2.0% and the water level was less than 1.0% as demonstrated by KF analysis. ジャケット Drying was performed at ≦45° C. Actual values ​​were 0.0% and 0.3%, respectively. After drying was complete, the filter jacket was cooled to a temperature of 20-30° C. (actual 22.4° C.). MR84907 was obtained as an off-white solid (160.4 kg, 160.4 kg corrected for purity, 100.5 assay w / w%, 89.0% yield).

[0290] Mp:128.7~128.8℃.

[0291] 1 H NMR(400MHz,DMSO-d6)δ ppm 1.44(s,9H),2.62-2.75(m,2H),2.92(br,J=5.6Hz,1H),2.95-3.12(m,2H),3.17-3.34(m,3H),3.61-3.70(m,1H) ),3.85-4.03(m,3H),4.24-4.38(m,1H),4.40-4.51(m,1H),4.54-4.63(m,1H),5.14(s,2H),7.28-7.47(m,5H). 13 C NMR(101MHz,DMSO-d6)δ ppm 18.2,25.5,26.8,28.0,47.1,47.9,48.1,48.3,48.7,66.8,79.5,113.9 ,118.3,127.6,127.9,128.4,136.4,153.5,154.2,156.2,163.5,165.6. HRMS(ESI)C 26 H 32 Calculated for ClN6O4: 527.2174 [M+H] +, Actual value: 527.2283.

[0292] Alternatively, step (a') can be utilized to obtain MR84907.

[0293] [ka]

[0294] DMAc (120 mL) and MR849109 (30 g, 0.153 mol, 1 equiv.) were charged to a 1000 mL reactor at 20 °C. Diisopropylethylamine (79.2 g, 0.612 mol, 4 equiv.) was added dropwise while maintaining the temperature at 10-20 °C, and the mixture was cooled to 0-10 °C. MR84906 (46.5 g, 0.153 mol, 1 equiv.) was charged in portions while maintaining the temperature at 0-10 °C. The reaction mixture was held at 0-10 °C for 1-2 h and then sampled for analysis of residual MR84906. Once the sample reached ≤ 2.0% of MR84906, MTBE (150 mL) and sodium carbonate (8.11 g, 0.0765 mol, 0.5 equiv. in 90 mL of water) were added to the reaction mixture at 0-10 °C. If the reaction failed to meet 2.0% IPC for MR84906, additional MR849109 was added based on the amount of residual MR84906. CbzCl (33.9 g, 0.199 mol, 1.3 equiv) was added dropwise to the biphasic reaction at 0-10 °C. The mixture was then warmed to 20-30 °C and held for 2 h. The mixture was checked for residual intermediates less than 1.0% and additional CbzCl was added correspondingly based on the amount of residual intermediates. Once the level of intermediates was ≦1.0%, MTBE (150 mL) and water (60 mL) were added at 20-40 °C and the mixture was stirred for 30 min to obtain a homogenous mixture. The biphasic mixture was separated at 30-40 °C and the aqueous layer was discarded. The organic layer was washed with 10% aqueous NaCl (150 mL). The organic layer was concentrated to 8 volumes (240 mL) at a temperature below 45 °C. 0.3 wt% MR84907 seed crystals were added to promote crystal growth at 30-40 °C. The mixture was stirred for 4-6 h, at which point significant crystal growth was observed. n-heptane (60 mL) was charged to the mixture at 30-40 °C. Stirring was continued for 1-2 h. The mixture was slowly cooled to 25-35 °C at a rate of 3-5 °C / h, then stirred for 10 h. The slurry was filtered and the solid was rinsed with 30 mL of MTBE / n-heptane (4:1). The solid was dried at ≤45 °C until the sum of MTBE and n-heptane was ≤2.0% and the moisture content was <1.0%.74.0 g of MR84907 was obtained, with a purity of 99.2% as determined by HPLC area percent, and 98.31 assay weight %, resulting in an isolated yield of 91.1%. Spectroscopic and chromatographic characterization was consistent with reported data for MR84907.

[0295] [Example 2] Steps (b) and (c)

[0296] [ka]

[0297] 2-MeTHF (1336.9 kg) was charged to a 5000 L glass-lined reactor. After stirring for 5-10 min, the water content was checked by Karl Fischer analysis to confirm a level of less than 0.5% (actual 0.03%). MR84907 (156.5 kg, 297.0 mol, 1.0 eq. corrected by HPLC assay) was added to the mixture at a temperature of 10-30 °C and stirred until a visual check confirmed that the solids were completely dissolved. Anhydrous potassium phosphate (190.0 kg, 891.0 mol, 3 eq.) was added to the mixture at a temperature of 10-30 °C, followed by (S)-(1-methylpyrrolidin-2-yl)methanol (MR84908, 51.1 kg, 443.7 mol, 1.5 eq.) at a temperature of 10-30 °C. The mixture was degassed by bubbling nitrogen through the bottom port of the reactor at 10-30 °C until the oxygen content reached a level of ≦0.1% (actual oxygen content was 0.01%). (R)-BINAP (5.6 kg, 8.9 mol, 3 mol%) and Pd2(dba)3 (4.1 kg, 4.5 mmol, 1.5 mol%) were added to the mixture at a temperature of 10-30 °C under nitrogen protection. After the addition was complete, the mixture was degassed for 0.5-1 h by bubbling nitrogen through the bottom port until the oxygen content reached a level of ≦0.1% (actual oxygen content was 0.01%). The mixture was then heated to 70-80 °C (actual 75.9 °C). The mixture was allowed to react at 70-80°C for 20 hours, at which point the mixture was sampled for HPLC purity analysis every 4-8 hours until the area % of MR84907 / (MR84907+MR84909) was ≤3.0%. After 30 hours and 8 minutes, the value was 0.6%. The mixture was then cooled to a temperature of 10-30°C (actually 22.9°C), at which point purified water (780.0 kg) was added to the mixture at a temperature of 15-30°C. It should be noted that the addition of water is highly exothermic during the first 10% of the addition and the rate of addition should be carefully controlled. After the water was added, the mixture was stirred at a temperature of 15-30°C for 20-30 minutes and the layers were allowed to settle and then separated.The bottom aqueous layer was removed from the bottom valve, and then the organic phase was washed with a sodium chloride solution prepared by adding sodium chloride (17.2 kg) to purified water (305.6 kg). The mixture was stirred for 20-30 min at a temperature of 15-30 °C and the layers were allowed to settle and then separated. The bottom aqueous layer was removed from the bottom valve. A hydrochloric acid solution was added to the organic phase remaining in the reactor at 15-25 °C. A hydrochloric acid solution was prepared by adding concentrated hydrochloric acid (210.8 kg) to purified water (690.2 kg). The mixture was stirred for 20-30 min at a temperature of 15-25 °C and the layers were allowed to settle and then separated. The lower aqueous phase contained the product and was transferred to a 5000 L reactor to be incorporated in step 3 (Boc deprotection and crystallization as the L-tartrate salt). The aqueous phase was reacted at a temperature of 15-25 °C (actual temperature was 21.1-22.5 °C).

[0298] After 15 hours, the mixture was sampled for HPLC purity analysis every 1-3 hours until the area % of MR84909 / (MR84909+MR84910) was ≦1.0% (0.1 area % after 22 hours 57 minutes). 2-MeTHF (269.3 kg) was added to the reaction mixture at 15-25 °C. The mixture was stirred for an additional 20-30 minutes at 15-25 °C, then the layers were allowed to settle before separating them and discarding the organic layer (2-MeTHF). The pH of the aqueous phase was adjusted to 8-9 at a temperature of 15-25 °C using potassium carbonate solution (957.6 kg) prepared from purified water (667.8 kg) and potassium carbonate (289.3 kg). After the pH reached 8-9, the mixture was continued to stir for an additional 0.5-1 hour and the pH was retested until it no longer changed (actual pH=8). The mixture was adjusted to a temperature of 25-35 °C. Sodium chloride (249.8 kg) was then added to the mixture. The mixture was stirred until a visual check confirmed that the solids were completely dissolved. 2-MeTHF (1338.6 kg) was added to the mixture at a temperature of 15-25 °C. The mixture was stirred for 20-30 minutes and then the layers were allowed to settle. The organic phase was collected and the aqueous phase was returned to the reactor for a second extraction with 2-MeTHF (666.9 kg). The two 2-MeTHF layers were combined and transferred to a 5000 L glass-lined reactor and concentrated under reduced pressure (P ≤ -0.06 MPa) at a temperature of ≤ 40 °C until 546-702 L (3.5-4.5 volumes) remained. 2-MeTHF (534.0 kg) was added to the mixture at a temperature of ≤ 40 °C. The mixture was sampled for moisture content and found to be ≤ 0.5%. Karl Fischer analysis showed the moisture content to be 0.6%. As a result, the mixture was concentrated again under reduced pressure (P≦-0.06 MPa) at a temperature ≦40° C. until 546-702 L (3.5-4.5 volumes) remained. 2-MeTHF (523.9 kg) was added to the mixture at a temperature ≦40° C. The mixture was sampled for water content and found to have a value ≦0.5%. Karl Fischer analysis showed the water content to be 0.2%. The mixture was then circulated through a CUNO filtration system at a temperature of 25-40° C. The piping and CUNO filter were rinsed with 2-MeTHF (201.3 kg).The mixture was heated to a temperature of 45-55°C (actually 50.0°C). L-tartaric acid solution, prepared by dissolving L-tartaric acid (43.8 kg, 291.2 mol, 1.0 equiv.) in isopropanol (499.3 kg) at a temperature of 45-55°C, was added to the reaction mixture at a temperature of 45-55°C. The mixture was stirred at a temperature of 45-55°C for 1-2 hours. The mixture was slowly cooled to a temperature of 20-30°C (actually 28.6°C) to initiate crystallization.

[0299] After 2 hours, the mixture was sampled every 1-3 hours for assay analysis of MR84910 in the supernatant layer until it was ≦0.5 wt% as determined by HPLC. In the first sample, the wt% of MR84910 was 0.3%, so the mixture was filtered in a stainless steel Nutsche centrifuge. The reactor walls were rinsed with 2-MeTHF (134.2 kg), which was then transferred to the filter and rinsed, and the filter cake was filtered. The wet filter cake was dried in a rotary cone dryer with a T jacket ≦40° C. and P ≦−0.06 MPa until the total of 2-MeTHF and isopropanol residuals was ≦2.0% (actually 1.6%) as determined by GC. After drying was completed, the jacket was cooled to a temperature of 20-30° C. and the intermediate (MR84910) was collected in a plastic bag, backfilled with nitrogen, sealed in an aluminum bag, and then stored under dry conditions. The L-tartrate of MR84910 is very sensitive to moisture and should be handled under nitrogen protection. The product was obtained as a white solid (167.8 kg, 156.2 kg corrected for assay purity, 71.8% assay w / w% (free base), 80.2% yield).

[0300] Mp:61.2~61.3℃.

[0301] 1H NMR(500MHz,D2O)δ ppm 1.90-2.00(m,1H),2.02-2.10(m,1H),2.11-2.20(m,1H),2.26-2.37(m,1H),2.71-2.82(m,1H),2.82-2.96(m,4H),2.99(br s,3H),3.07-3.22(m,2H),3.23-3.32(m,2H),3.33-3.40(m,1H),3.46(s,1H),3.64-3.84(m,2H),3.98(br dd,J=12.32,6.30Hz,3H),4.22(s,2H)4.30(s,2H),4.45-4.53(m,1H),4.62(br dd,J=12.59,2.74Hz,2H),5.09(d,J=7.67Hz,2H),7.24-7.38(m,5H). 13 C NMR(126MHz,D2O)8ppm 19.3,22.7,26.9,39.7,41.6,41.9,45.9,47.7,48.7,49.3,57.9,59.4,65.1,68.6,70. 5,74.2,108.0,119.6,128.5,129.1,129.4,136.7,156.9,158.4,162.2,166.7,178.4. HRMS(ESI)C 27 H 36 Calculated value for N7O3: 506.2880 [M+H] + , Actual value: 506.3000.

[0302] Alternatively, steps (b') and (c') can be used to obtain MR84907. These steps make it possible to reduce the amount of palladium consumed in the production of MRTX849. This technique can reduce the palladium loading by a factor of 3 to 6. The key differences are the use of xantphos as ligand instead of R-BINAP and the milling of K3PO4 to reduce the particle size of the phosphate.

[0303] Steps (b') and (c')

[0304] [ka]

[0305] MR84908 (1.64 g, 14.23 mmol, 1.50 equiv), anhydrous K3PO4 (6.04 g, 28.46 mmol, 3.00 equiv), Xantphos (43.9 mg, 75.9 μmol, 0.008 equiv), Pd2(dba)3 (43.4 mg, 47.4 μmol, 0.005 equiv), MR84907 (5.0 g, 9.49 mmol, 1.00 equiv), and dry 2-MeTHF (30 mL, 6.0 V) were charged to a reactor equipped with an overhead stirrer under a nitrogen atmosphere. A rotor-stator homogenizer was added to the reaction manifold to grind the potassium phosphate. The overhead stirrer was turned on and set to a stirring speed of 300 rpm. The mixture was purged with nitrogen for 5 minutes. The homogenizer was turned on and set to a speed of 15,000 rpm. The mixture was heated to 75 °C. After 5 h, the homogenizer was stopped and the reaction mixture was sampled for HPLC analysis to monitor reaction completion. When the level of MR84907 was ≤ 2.0%, the mixture was cooled to 20 °C. If the level of MR84907 exceeded 2.0% after 20 h, additional catalyst was added to account for the amount of residual MR84907. Water (25 mL, 5 V) was charged to the reaction mixture while maintaining the temperature below 25 °C, and the mixture was stirred until all solids were completely dissolved. The biphasic layers were separated and the organic layer was collected. Fresh MeTHF (25 mL, 5 V) was added to the aqueous layer and stirred for 15 min. The phases were split and the organic layer was retained. The two organic layers were combined and washed with 5 wt% aqueous NaCl (2 V). The biphasic layers were separated and the aqueous layer was discarded. 14 wt% aqueous HCl (5 equiv) was added to the organic layer while maintaining the temperature at 15-25 °C. The biphasic mixture was allowed to settle and the phases were split. The aqueous layer was retained and stirred at 20 °C until HPLC analysis showed the level of MR84909 to be ≦1.0%. MeTHF (10 mL, 2 V) was charged to the stirred mixture. The phases were allowed to settle, then they were separated and the aqueous layer was collected. A 50 wt% aqueous solution of K2CO3 (7 equiv.) was added to the aqueous layer at 15-25 °C until the pH reached a value of 9-10. Solid NaCl (5.0 g, 1.0 w / w) was added to the aqueous mixture and the mixture was stirred until all solids were dissolved. The mixture was extracted with MeTHF (50 mL, 10 V). The phases were split and the organic layer was retained.The aqueous portion was back-extracted with MeTHF (25 mL, 5 V). The layers were split and the organic fractions were combined and concentrated under reduced pressure at ≤40 °C. MeTHF (20 mL, 4 V) was added to the concentrate, which was concentrated again under reduced pressure at ≤40 °C. MeTHF (50 mL, 10 V) was added to the concentrate and the mixture was heated to 45-55 °C. A solution of L-tartaric acid (1.42 g, 9.49 mmol, 1 equiv) in isopropanol (20 mL, 4 V) was added at 45-55 °C. The mixture was stirred and held at this temperature for 2 h. The mixture was slowly cooled to 20 °C at a rate of 3-5 °C / min. The mixture was held at 20 °C for 16 h. The mixture was filtered and the filter cake was rinsed three times with MeTHF (10 mL, 2 V) under an inert atmosphere. The cake was dried at ≤40 °C. 5.39 g of MR84910 tartrate was obtained with an HPLC purity of 94.8%.

[0306] Figures 1A and 1B illustrate the advantages of steps (b') and (c') over steps (b) and (c). Figure 1A shows the particle size of the phosphate when steps (b) and (c) are used. Figure 1B shows the particle size of the phosphate when steps (b) and (c) are used. Figure 1B shows the reduction in particle size of the phosphate. The particle size appears to decrease from about 200 μm (Figure 1A) to about 20-50 μm (Figure 1B) when milled or when magnetic stirring breaks up the phosphate. This increases the reaction rate as seen in Figures 1A and 1B. MR84909 increases the AY yield from 24% to 82% under otherwise identical conditions.

[0307] [Example 3] Steps (d) and (e)

[0308] [ka]

[0309] Purified water (467.7 kg) was charged to a 3000 L glass-lined reactor at 20-30 °C and stirring was started. L-tartrate of MR84910 (163.1 kg, 117.1 kg as MR84910 free base corrected by HPLC assay, 231.6 mol, 1.0 equiv.) was added to the reactor with stirring at a temperature of 20-30 °C. The mixture was then stirred until a visual check confirmed that the solids were completely dissolved. 2-MeTHF (1218.1 kg) was then added to the mixture. The mixture was adjusted to a pH of 8-9 at a temperature of 10-30 °C using a 30% solution of potassium carbonate (319.6 kg) prepared using potassium carbonate (96.2 kg) and purified water (223.4 kg). The mixture was then continued to stir for an additional 0.5 h and the solution pH was retested to confirm (actually pH 8). Sodium chloride (117.2 kg) was then added to the mixture and the mixture was stirred for 20-30 minutes at a temperature of 10-30°C. The layers were allowed to settle and then separated. The aqueous layer was discarded and the upper organic layer was washed with a sodium chloride solution prepared from sodium chloride (58.6 kg) and purified water (233.9 kg). The mixture was stirred for 20-30 minutes at a temperature of 10-30°C and then the layers were allowed to settle and then separated. The organic phase was diluted with T until 3-4 volumes (351-468 L) remained. ジャケット The mixture was concentrated under reduced pressure (P≦-0.08 MPa) at ≦50° C., and then 2-MeTHF (305.2 kg) was added to the mixture. The mixture was concentrated at T until 3-4 volumes (351-468 L) remained. ジャケット The mixture was again concentrated under reduced pressure (P≦-0.08 MPa) at ≦50°C. The mixture was sampled for moisture content and found to be less than ≦0.5%. Karl Fischer analysis revealed a moisture level of 1.3%, so the drying process was repeated. Another charge of 2-MeTHF (302.2 kg) was added to the mixture, which was then concentrated in T until 3-4 volumes (351-468 L) remained. ジャケットThe mixture was concentrated again at ≦50°C under reduced pressure (P≦-0.08 MPa). The mixture was sampled for moisture content to confirm that the value was less than ≦0.5%, and this time Karl Fischer analysis revealed a moisture level of 0.2%. The mixture was adjusted to a temperature of 10-30°C (actually 27.1°C) and the mixture was circulated through a CUNO filtration system. 2-MeTHF (497.4 kg) was added to another 5000 L glass-lined reactor, followed by anhydrous potassium phosphate (196.8 kg, 926 mol, 4 equiv.) at 10-30°C. After addition, the mixture was stirred for 20-30 min and then recirculated through a wet mill at 10-30°C for 2-3 h until the particle size D(90) was less than 50 μm (actually 22 μm). The MR84910 solution in the 3000 L reactor was transferred to the 5000 L reactor and passed through a CUNO filter, then the 3000 L reactor was rinsed with 2-MeTHF (202.5 kg) and transferred through the CUNO filter to the 5000 L reactor. MR84914 (58.5 kg, 243 mol, 1.05 equiv.) was added to the mixture in the 5000 L reactor at a temperature of 10-30° C., then the mixture was degassed by bubbling nitrogen through the bottom port of the reactor until the oxygen content reached a level of less than 0.1% (actually 0.00%). (R)-BINAP (5.8 kg, 9.3 mol, 4 mol%) and Pd(OAc)2 (1.0 kg, 4.6 mol, 2 mol%) were added to the mixture at 10-30°C under nitrogen protection, and the mixture was degassed again by bubbling nitrogen through the bottom port of the reactor until the oxygen content reached a level of less than 0.1% (actually 0.04%). The reactor was heated to a temperature of 75-85°C (actually 78.5°C) and the reaction was allowed to proceed (76.8-80.8°C).

[0310] After 20 hours, the mixture was sampled for HPLC purity analysis every 3-6 hours until the area % of MR84910 / (MR84910+MR84915) was less than 3.0% (29 hours 44 minutes, 2.2 area %). The mixture was then cooled to a temperature of 20-30°C (actually 26.0°C). After cooling, purified water (585.4 kg) was slowly added to the mixture at 20-30°C. The addition of water is very exothermic during the first 10% of the addition, which corresponds to the dissolution of potassium phosphate, and the rate of addition should be carefully controlled. The later parts were less exothermic. The mixture was stirred for 20-30 minutes at a temperature of 20-30°C, then the layers were separated after settling. The aqueous fraction was discarded. A sodium chloride solution prepared from sodium chloride (87.8 kg) and purified water (585.2 kg) was added to the organic phase at 20-30°C. The mixture was stirred for 20-30 minutes at a temperature of 20-30°C, then the layers were separated after settling. The aqueous fraction was discarded. A citric acid solution prepared from citric acid monohydrate (1.1 kg), sodium chloride (52.7 kg), and purified water (351.6 kg) was added to the organic phase at a temperature of 20-30°C. The mixture was stirred at this temperature for 1-2 hours, then the layers were separated after settling.

[0311] The organic phase was sampled for HPLC purity analysis until the area % of MR84910 dropped below 0.5 area % (actually 0.2 area %). The organic phase was sampled for T until 4-5 volumes (468-585 L) remained in the reactor. ジャケット The mixture was concentrated under reduced pressure (P≦-0.08 MPa) at ≦60°C. 2-MeTHF (302.7 kg) was added to T ジャケット The organic phase was added to the remaining mixture at a temperature of ≦60° C. until 4-5 volumes (468-585 L) remained in the reactor. ジャケット The mixture was concentrated under reduced pressure (P≦-0.08 MPa) at ≦60° C. 2-Me-THF (100.9 kg) was added to T ジャケットto the mixture at ≦60° C., and then the mixture was sampled to confirm that the water content was less than 0.5%. Karl Fischer analysis revealed a water content of 0.3%. Acetone (463.4 kg) was added to the mixture. A solution of p-toluenesulfonic acid monohydrate (39.3 kg, 1.0 equivalent to MR84915 assay) in 2-MeTHF (100.6 kg) was prepared and 34.9 kg of the solution was added to the 5000 L reactor at a temperature of 20-30° C. over 5 hours. A mixture containing acetone (38.5 kg) and seed crystals (0.6 kg) was added to the mixture at a temperature of 15-35° C. The slurry was maintained at a temperature of 20-30° C. for 2-3 hours. The remainder of the p-toluenesulfonic acid monohydrate solution was added to the mixture in the 5000 L reactor over 10 hours. The mixture was then heated to a temperature of 50-60°C (actually 50.7°C). The mixture was maintained at that temperature and stirred for 1.5-2.5 hours, after which it was cooled to a temperature of -15--5°C (actually -6.8°C). The slurry was stirred at this temperature, and after 8 hours the mixture was sampled for assay weight % of M84915 in the supernatant every 1-3 hours until a level of less than 0.8% was achieved (actually 0.8%). The mixture was filtered through a Halar-lined Nutsche centrifuge, and the reactor was rinsed twice with acetone (140.2 kg, then 139.4 kg, pre-cooled to a temperature of -15-5°C), then transferred to the centrifuge to rinse the filter cake. The filter cake was filtered through a Halar-lined Nutsche centrifuge, and the reactor was rinsed twice with acetone (140.2 kg, then 139.4 kg, pre-cooled to a temperature of -15-5°C) and then transferred to the centrifuge to rinse the filter cake. The filter cake was filtered through a Halar-lined Nutsche centrifuge, and the reactor was rinsed twice with acetone (140.2 kg, then 139.4 kg, pre-cooled to a temperature of -15-5°C) until the combined 2-MeTHF and acetone residue was less than 2.0% by GC. ジャケット Drying was performed in a rotary cone dryer at ≦65° C. and P≦-0.06 MPa. After drying was complete, the jacket was cooled to 20-30° C. MR84915 tosylate salt was obtained as an off-white solid (127.3 kg, 101.8 kg corrected for assay weight %, 80.4 assay weight %, 66.0% yield).

[0312] Mp: 150.6~150.7℃.

[0313] 11H NMR (400 MHz, DMSO-d6) δ ppm 1.77 - 1.97 (m, 2H), 1.98 - 2.10 (m, 1H), 2.17 - 2.26 (m, 1H), 2.27 (s, 3H), 2.82 - 3.17 (m, 9H), 3.37 (br s, 3H), 3.48 - 3.65 (m, 2H), 3.70 - 3.84 (m, 2H), 3.88 - 4.13 (m, 3H), 4.21 (dd, J = 17.31, 8.72 Hz, 1H), 4.39 - 4.49 (m, 1H), 4.51 - 4.66 (m, 2H), 5.06 - 5.23 (m, 2H), 7.08 - 7.13 (m, 2H), 7.33 - 7.45 (m, 6H), 7.45 - 7.52 (m, 3H), 7.53 - 7.61 (m, 2H), 7.73 - 7.79 (m, 1H), 7.90 - 7.96 (m, 1H), 9.67 (s, 1H). 13 13C NMR (126 MHz, DMSO-d6) δ ppm 18.1, 20.7, 21.8, 25.5, 26.2, 35.8, 46.8, 47.2, 48.2, 49.9, 56.4, 58.4, 58.7, 64.0, 66.8, 109.0, 118.5, 118.8, 124.8, 124.9, 125.4, 125.9, 126.8, 127.6, 127.9, 128.0, 128.4, 128.6, 128.8, 129.5, 136.4, 137.0, 137.6, 145.7, 148.0, 154.2, 161.2, 164.3, 165.9. HRMS (ESI) C 37 H 41 Calculated for C + H

[0314] [Example 5] Step (f)

[0315] [Chemical formula]

[0316] N,N-Dimethylacetamide (289.6 kg) was charged to a 3000 L glass-lined reactor and stirring was started. MR84915 tosylate (123.1 kg, 99.0 kg corrected as free base, 146.8 mol, 1.0 equiv.) was added to the mixture. The reactor walls were rinsed with N,N-Dimethylacetamide (58.0 kg). Under nitrogen protection, anhydrous potassium phosphate (124.8 kg, 587 mol, 4 equiv.) was added. The mixture was heated to 40-50°C (actually 41.2°C), and then nitrogen was bubbled through the mixture from the bottom port of the reactor at a temperature of 40-50°C for 1-2 hours. After degassing, 2-mercaptoethanol (23.4 kg, 294 mol, 2 equiv.) was added to the mixture at 40-50°C under nitrogen protection. The mixture was heated to a temperature of 75-80°C (actually 75.1°C). The mixture was reacted at 70-80°C.

[0317] After 10 hours, the mixture was sampled for HPLC purity analysis every 2-6 hours until the area % of MR84915 / (MR84915+MR84916) was less than 0.5%. After 25 hours and 5 minutes, the ratio reached 0.3%. The mixture was then cooled to 20-30°C (actually 27.5°C). Purified water (307.6 kg) was added to the mixture at a temperature below 45°C, then the temperature of the mixture was adjusted to 35-45°C (actually 37.1°C). The reaction was maintained at this temperature and stirred for 0.5-1 hour. The stirring was stopped and the layers were allowed to settle and then separated. The aqueous phase was discarded and the organic phase was kept in the reactor. The temperature of the organic phase was set at a temperature of 15-25°C (actually 25.0°C). Purified water (86.1 kg) was added to the organic phase, then seed crystals (0.6 kg) were added. The mixture was maintained and stirred at a temperature of 15-25°C for 12-16 hours, at which point a large amount of solid was observed to precipitate. The mixture was sampled for supernatant assay wt% for informational purposes only (FIO reference value: 4.5%), and 4.1% was observed to be in the supernatant. Purified water (221.4 kg) was added to the reactor at 15-25°C. The mixture was stirred at a temperature of 15-25°C for 12-16 hours, and after 8 hours the mixture was sampled for supernatant assay wt% analysis every 2-4 hours until the level was less than 0.7% (0.7% was observed). The mixture was filtered through a stirred Nutsche filter dryer. Purified water (112.7 kg) and Na-dimethylacetamide (70.5 kg) were added to a 3000 L glass-lined reactor and the temperature was adjusted to 15-25°C. The mixture was transferred to a stirred Nutsche filter dryer to rinse the filter cake.

[0318] Purified water (370.0 kg) and acetonitrile (28.1 kg) were added to a 3000 L glass-lined reactor and the temperature was then adjusted to 15-30°C. The filter cake was added to the water / acetonitrile mixture and the mixture was stirred for 2-3 hours at a temperature of 15-30°C. The slurry from the reactor was filtered in a centrifuge. Purified water (184.6 kg) was added to the 3000 L glass-lined reactor and then transferred to the centrifuge to rinse the filter cake. The wet filter cake was centrifuged until the moisture content was less than 15% as determined by Karl Fischer analysis.ジャケット Drying was performed in a rotary cone dryer at ≦45° C. After drying was complete, the jacket temperature was cooled to a temperature of 20-30° C. MR84916 was obtained as a brown solid (82.0 kg, 67.8 kg corrected for assay weight %, 97.2 assay weight % on a dry basis, 85.7% yield).

[0319] Mp:60.3~60.4℃.

[0320] 1 H NMR(400MHz,DMSO-d6)δ ppm 1.52-1.73(m,3H),1.84-1.96(m,1H),2.13(q,J=8.67Hz,1H),2.32(d,J=1. 77Hz,3H),2.44-2.49(m,1H),2.61-2.83(m,5H),2.85-2.98(m,3H),3.07(br s,3H),3.37(br s,2H),3.42-3.51(m,1H),3.72(s,1H),3.85(br d,J=12.38Hz,1H)4.01(ddd,J=10.48,6.69,3.28Hz,1H),4.17(br d,J=17.43Hz,1H),4.24(dd,J=10.74,4.93Hz,1H)7.31(ddd,J=7.58,3.41,0.88Hz,1H),7.43(t,J=7.83H z,1H),7.52(t,J=7.71Hz,1H),7.57(dd,J=7.58,1.26Hz,1H),7.72(d,J=8.08Hz,1H),7.87-7.95(m,1H). 13 C NMR(101MHz,DMSO-d6)δ ppm 21.2,22.5,25.6,28.5,41.2,44.6,47.6,50.0,51.0,51.6,56.9,58.6,63.4,68.7,108.2,118. 7,118.8,124.6,124.9,125.9,126.8,128.5,128.8,129.5,137.0,148.0,162.1,163.8,165.6. HRMS(ESI)C 29 H 35 Calculated for ClNO: 532.2592 [M+H] +, Actual value: 532.2706.

[0321] [Example 6] Step (g)

[0322] [ka]

[0323] Acetonitrile (1093.0 kg) was added to a 3000 L glass-lined reactor. MR84916 (81.6 kg, 68.1 kg corrected by HPLC assay wt%, 128.0 mol, 1.0 equiv.) was then added to the reactor. The mixture was concentrated under reduced pressure (P≦-0.06 MPa) at a temperature below ≦45° C. until 3-4 volumes (204-272 L) remained. Acetonitrile (268.0 kg) was then added to the mixture at a temperature below 45° C. The mixture was concentrated under reduced pressure (P≦-0.06 MPa) at a temperature below 45° C. until 3-4 volumes (204-272 L) remained. The mixture was sampled to confirm that the water content was less than 0.3% (actual 0.1%) as determined by Karl Fischer analysis. The mixture was cooled to a temperature of 10-25° C. (actual 16.5° C.). Acetonitrile (163.9 kg) was added to another 3000 L Hastelloy reactor. The mixture was sampled to ensure that the moisture content was less than 0.3% (actually 0.02%). Sodium 2-fluoroacrylate (25.0 kg, 218 mol, 1.7 eq) was added to the Hastelloy reactor under nitrogen protection at a temperature of 10-20 °C. It was ensured that the sodium 2-fluoroacrylate was in fine powder form before addition. The reactor walls were rinsed with acetonitrile (13.7 kg). A 50 w / w% solution of propylphosphosphonic anhydride in ethyl acetate (124.7 kg, 192 mol, 1.5 eq) was added to the sodium 2-fluoroacrylate solution in the Hastelloy reactor under nitrogen protection at a temperature of 10-20 °C. The mixture was stirred for not less than 2 hours at a temperature of 10-20 °C. The mixture containing MR84916 in the 3000 L glass-lined reactor was slowly added to the mixture containing 2-fluoroacrylate in the 3000 L Hastelloy reactor at a temperature of 10-20° C. The 3000 L glass-lined reactor containing MR84916 was rinsed with acetonitrile (18.2 kg), which was transferred to the Hastelloy reactor along with the acrylate.

[0324] The reaction was allowed to proceed at 10-20°C (14.5-18.0°C) and the mixture was sampled for HPLC purity analysis every 1-3 hours until after 1 hour the area % of MR84916 / (MR84916+MRTX849) was less than 0.4% (0.3% was observed at 5 hours 1 minute). At a temperature of 10-30°C, the mixture was adjusted to a pH of 8-9 using potassium carbonate solution (348.3 kg) prepared from potassium carbonate (41.6 kg) and purified water (307.2 kg). The mixture was kept stirring for another 0.5 hours and then the pH was retested to confirm (actually pH 8). The mixture was adjusted to a temperature of 25-35°C, stirring was stopped and the layers were allowed to settle and then separated. The aqueous phase was removed and kept. This phase was washed at a temperature of 25-35°C using tripotassium phosphate solution prepared from tripotassium phosphate (50.1 kg) and purified water (204.4 kg). The mixture was stirred for an additional 0.5-3 h, allowed to settle, and then allowed to separate at a temperature of 25-35 °C. The aqueous phase was removed and kept. The aqueous layers were combined and extracted with 2-MeTHF (175.9 kg). The mixture was stirred for an additional 20-30 min, allowed to settle, and then allowed to separate at a temperature of 25-35 °C. The organic fractions were combined, and the combined mixture was then concentrated under reduced pressure (P ≦ -0.06 MPa) at a temperature of ≦ 45 °C until 2-3 volumes (136-204 L) remained. Isopropanol (429.2 kg) was added to the mixture at a temperature of ≦ 45 °C. The mixture was concentrated under reduced pressure (P ≦ -0.06 MPa) at a temperature of ≦ 45 °C until 2-3 volumes (136-204 L) remained. Isopropanol (320.1 kg) was added to the mixture at a temperature of ≦ 45 °C. The mixture was circulated through a CUNO filtration system. Isopropanol (106.9 kg) was then used to rinse the CUNO filter and added to the reactor. The mixture was concentrated under reduced pressure (P≦-0.06 MPa) at a temperature of ≦45° C. until 4.5-5.5 volumes (306-374 L) remained. The mixture was sampled to confirm that the residual acetonitrile residue was less than 1.5% (actually 0.05%). The mixture was adjusted to a temperature of 33-38° C. (actually 35.3° C.). Purified water (170.0 kg) was added to the mixture at 33-38° C. Form 2 seed crystals (0.2 kg) were added to the mixture at a temperature of 33-38° C. The mixture was maintained at this temperature and stirred for 2-3 hours.The mixture was slowly cooled to 15-20°C. The mixture was maintained at this temperature and stirred for 6-10 hours. Purified water (170.0 kg) was added to the reactor at a temperature of 15-20°C. The mixture was slowly cooled to -3-7°C (actually 4.8°C). The mass was stirred at -3-7°C for crystallization and after 8 hours the mixture was sampled every 3-5 hours until the mother liquor assay wt% of MRTX849 was less than 0.7% or the difference between two consecutive samples was ≦0.1 wt% (0.7 wt% observed). The mixture was filtered through a stainless steel centrifuge. Purified water (102.6 kg) and isopropanol (16.4 kg) were added to a 3000 L Hastelloy lined reactor and then transferred to a stainless steel centrifuge to rinse the filter cake. The wet filter cake was swept with nitrogen for 6-8 hours and dried in a rotary cone dryer at T ≤ 40 °C until the moisture content was 1% or less as determined by Karl Fischer analysis. After drying was complete, the solids were cooled to 20-30 °C. Isopropanol (368.4 kg) was added to a 1000 L glass-lined reactor and then the agitator was started. The solids from the filter cake were added to the 1000 L reactor and the mixture was heated to a temperature of 55-60 °C (actually 57.2 °C). The mixture was maintained at this temperature and stirred until a visual check confirmed that the solids were completely dissolved. The mixture was then filtered through a filtration system heated to 55-60 °C into a 1000 L Hastelloy reactor (T jacket = preheated to 55-60 °C). The mixture was held at 55-60 °C. n-Heptane (80.5 kg) was added to the reactor and passed through the filter first for rinsing. The mixture was stirred in the reactor for 0.5 hours. After the solids were completely dissolved, the mixture was cooled to a temperature of 43-47°C. A seed slurry was prepared by adding isopropanol (5.5 kg) and n-heptane (1.3 kg) through a capsule filter to a 20 L four-neck flask, followed by the addition of Form 2 seed crystals (MRTX849 Form 2, 0.8 kg) held at a temperature of 20-25°C. The mixture was stirred until homogeneously mixed and then recirculated it through a wet mill. Prior to adding the slurry feed to the reactor, the reactor was checked to ensure complete dissolution and no precipitation of MRTX849 had occurred.After this, the Form 2 seed slurry was added to a 1000 L Hastelloy reactor at a temperature of 43-47°C. The mixture was stirred at 43-47°C for 3-4 hours. The mixture was then cooled to a temperature of 28-32°C and stirred at that temperature (actually 30.6°C) for 4-5 hours. After this, the mixture was cooled to 18-22°C and stirred for 4-5 hours (actually 20.9°C). The mixture was then cooled to -3-7°C (actually 3.5°C) with stirring. After 12 hours, the mixture supernatant was sampled every 3-5 hours to check the assay weight % of MRTX849 in the mother liquor to see when the level was below 1.2% or when the difference between samples was below 0.2%. Nitrogen was bubbled intermittently through the bottom port of the reactor during crystallization. The mother liquor was checked and the assay weight % of MRTX849 was found to be 1.0%. The mixture was recirculated through the wet mill at -3 to 10°C and the batch temperature can be expected to rise 2 to 3°C during the process. The solids were sampled for particle size until D(90) was 100 μm or less (actually 22 μm). The mixture was maintained at -3 to 7°C for 0.5 to 1 hour. The mixture was then filtered through a stainless steel Nutsche filter. The reactor walls were rinsed with a mixed solvent system of n-heptane (15.9 kg) and isopropanol (74.1 kg) through a liquid material filter. The wet mill was then rinsed with these rinses which were transferred to the reactor and then drained into the filter to rinse the filter cake. The above operation was repeated once more using a mixed solvent of n-heptane (15.9 kg) and isopropanol (74.2 kg). Filtration was noted to be very slow as a result of the small particle size from the wet mill. The solids in the filter were swept with nitrogen at T-jacket = 20-30°C for 8-10 hours and then dried at T-jacket = 35-45°C until isopropanol residuals were below 6300 ppm (actual 3488 ppm) and n-heptane residuals were below 3500 ppm (not detected, LOD 432 ppm) as measured by GC. After drying was completed, the solids were cooled to a temperature of 20-30°C. The solids were sieved until the product was uniform in appearance and not blocking. Operating area RH% should be below 50%.The product (MRTX849) was obtained as an off-white solid (51.1 kg, 50.0 kg corrected for assay weight %, 100.4 assay weight %, 64.7% yield).

[0325] Mp:128.3~128.4℃.

[0326] 1 H NMR(400MHz,DMSO-d6)δ ppm 1.56-1.77(m,3H),1.96(br dd,J=11.87,7.58Hz,1H),2.20(dd,J=8.21,2.40Hz,1H),2.37(d,J=3.54Hz,3H),2.72(br d,J=1.77Hz,1H),2.91-3.03(m,2H),3.04-3.23(m,4H),3.28(br dd,J=13.77,3.66Hz,1H),3.33-3.63(m,4H),3.73-3.86(m,1H),3.89-3. 98(m,1H),3.99-4.15(m,3H),4.17-4.36(m,2H),5.22-5.41(m,1H),5.42 -5.50(m,1H),7.34-7.44(m,1H),7.46-7.53(m,1H),7.58(q,J=7.58Hz,1 H),7.63(dt,J=7.45,1.07Hz,1H),7.75-7.83(m,1H),7.93-8.00(m,1H). 13 C NMR(101MHz,DMSO-d6)δ ppm 22.5,25.0,25.3,25.5,26.8,28.5,41.2,47.5,50.0,57.0,58.4,58.7,63.4,68.9,99.5,108.6,118.1,118.8,124.7,124 .9,125.9,126.9,128.5,128.9,129.5,137.0,148.0,155.5(d,J=266.39Hz),161.0(d,J=11.71Hz),162.0,164.3,165.9. 19 F NMR(376MHz,DMSO-d6)δ ppm-106.4. HRMS(ESI)C 32 H 36Calculated for CIFN7O2: 604.2603 [M+H] + , Actual value: 604.2690.

[0327] [Example 7] Optional isolation of MRTX849 as the tartrate salt: 3.5 L of ethanol was added to the reactor charged with MRTX849 (875 g) and stirred until completely dissolved. In a separate reactor, 1 M L-tartaric acid in THF was prepared by adding 1.59 L of THF and 0.24 kg of L-tartaric acid and heated to 35-40 °C. The above prepared tartaric acid solution was added to the ethanol reaction mixture of MRTX849 at 45-50 °C. MRTX849 free base seed (60 mg) was added at 45-50 °C and precipitate formation was observed slowly. The slurry was stirred at 45-50 °C for at least 1 hour, then filtered, washed with cold ethanol, and dried in vacuum at 40 °C for 24 hours.

[0328] While the invention has been described in relation to particular embodiments thereof, it will be understood that it is capable of further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention in accordance with the principles of the invention generally, within known or customary practice in the art to which the invention pertains, which may be applied to the essential features described above, and which include departures from the present disclosure as follows within the scope of the appended claims.

Claims

1. A method for synthesizing adagrasib, comprising either step (a) or step (a′), wherein step (a) comprises: a) reacting a compound of the following structure: 【Chemical 1】 a free base or salt of a compound of the following structure: 【Chemistry 2】 in the presence of a polar aprotic solvent and an organic or inorganic base to produce a final compound of step (a) having the structure: 【Chemistry 3】 Step (a') a') reacting a compound of the following structure: 【Chemistry 4】 a compound of the following structure: 【Chemistry 5】 reacting in the presence of a polar aprotic solvent and a base to produce a compound of the structure: 【Chemistry 6】 Next reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE), and water to produce the final compound of step (a') having the following structure: 【Chemistry 7】

2. Step (b):

10. The method of claim 1, further comprising: b) reacting the final compound of step (a) or step (a′) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (b) having the following structure: 【Chemistry 8】

3. Step (c):

3. The method of claim 2, further comprising: c) reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure: 【Chemistry 9】

4. Step (d): d) reacting the salt or free base of the final product of step (c) with 【Chemistry 10】 4. The method of claim 3, further comprising reacting in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (d) having the following structure: 【Chemistry 11】

5. Step (e):

5. The method of claim 4, further comprising: e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the following structure: 【Chemistry 12】

6. Step (f):

6. The method of claim 5, further comprising: f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the following structure: 【Chemistry 13】

7. Step (g):

7. The method of claim 6, further comprising: (g) reacting the final compound of step (f) with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid using a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

8. A method for synthesizing adagrasib, comprising reacting the following compound: 【Chemistry 14】 1. A process comprising the step of reacting 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid with a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

9. 1. A method for synthesizing adagrasib, comprising: - the following compound: 【Chemistry 15】 with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the compound 【Chemistry 16】 - the following compound: 【Chemistry 17】 reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

10. 1. A method for synthesizing adagrasib, comprising: - the following compound: 【Chemistry 18】 with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following compound: 【Chemistry 19】 - the following compound: 【Chemistry 20】 with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the compound 【Chemical 21】 - the following compound: 【Chemical 22】 reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

11. 1. A method for synthesizing adagrasib, comprising: - the free base of the following compound: 【Chemical 23】 The following compounds: 【Chemistry 24】 reacting in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following compound: 【Chemistry 25】 - the following compound: 【Chemical 26】 with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following compound: 【Chemical 27】 - the following compound: 【Chemical 28】 with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the compound 【Chemical 29】 - the following compound: 【Chemistry 30】 reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

12. 1. A method for synthesizing adagrasib, comprising: - the following compound: 【Chemical 31】 reacting with an acid to remove the Boc protecting group to produce a salt or free base of the compound: 【Chemical 32】 - a salt or free base of the following compound: 【Chemical 33】 The following compounds: 【Chemical 34】 reacting in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following compound: 【Chemistry 35】 - the following compound: 【Chemical 36】 with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following compound: 【Chemical 37】 - the following compound: 【Chemical 38】 with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the compound 【Chemical 39】 - the following compound: 【Chemistry 40】 reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

13. 1. A method for synthesizing adagrasib, comprising: - the following compound: 【Chemistry 41】 with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following compound: 【Chemistry 42】 - the following compound: 【Chemistry 43】 reacting with an acid to remove the Boc protecting group to produce a salt or free base of the compound: 【Chemical 44】 - the salts or free bases of the following compounds: 【Chemistry 45】 The following compounds: 【Chemistry 46】 reacting in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the following compound: 【Chemistry 47】 - the following compound: 【Chemistry 48】 with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the following compound: 【Chemistry 49】 - the following compound: 【Chemistry 50】 with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the compound 【Chemistry 51】 - the following compound: 【Chemistry 52】 reacting the coupling agent with 2-fluoroacrylic acid or an alkali or metal salt of 2-fluoroacrylic acid in the presence of a solvent and optionally a base to produce adagrasib.

14. 1. A method for synthesizing adagrasib, comprising: a) reacting a compound of the following structure: 【Chemistry 53】 a salt of a compound of the following structure: 【Chemical 54】 reacting in the presence of a polar aprotic solvent and an organic or inorganic base to produce the final compound of step (a) having the structure: 【Chemistry 55】 b) reacting the final compound of step (a) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (b) having the following structure: 【Chemical 56】 c) reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure: 【Chemical 57】 d) reacting the salt or free base of the final product of step (c) with 【Chemistry 58】 reacting in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure: 【Chemical Formula 59】 e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the following structure: 【Chemistry 60】 f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure: 【Hua 61】 g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) using a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

15. 1. A method for synthesizing adagrasib, comprising: a') reacting a compound of the following structure: 【Hua 62】 a compound of the following structure: 【Chemistry 63】 reacting in the presence of a polar aprotic solvent and a base to produce a compound of the structure: 【Hua 64】 Next reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE), and water to produce the final compound of step (a′) having the following structure: 【Chemistry 65】 b) reacting the final compound of step (a′) with (S)-(1-methylpyrrolidin-2-yl)methanol in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (b) having the following structure: 【Hua 66】 c) reacting the final compound of step (b) with an acid to remove the Boc protecting group from the final compound of step (b) to produce a salt or free base of the final compound of step (c) having the structure: 【Hua 67】 d) reacting the salt or free base of the final product of step (c) with 【Chemistry 68】 reacting in the presence of a palladium catalyst, a base, a phosphorus-based ligand, and an aprotic solvent to produce the final compound of step (d) having the structure: 【Chemical Formula 69】 e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of a first solvent and an anti-solvent to produce the final compound of step (e) having the following structure: 【Chemistry 70】 f) reacting the final compound of step (e) with a thiol or thiolate in the presence of a base and a polar aprotic solvent to produce the final compound of step (f) having the structure: 【Chemical 71】 g) reacting the final compound of step (f) with 2-fluoroacrylic acid (or a corresponding alkali or metal salt) using a coupling agent in the presence of a solvent and optionally a base to produce adagrasib.

16. 16. The method of claim 14 or 15, wherein in step (a) or step (a'), the polar aprotic solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP).

17. 16. The method of claim 14 or 15, wherein in step (a) or step (a'), the polar aprotic solvent is dimethylacetamide (DMAc).

18. 16. The method according to claim 14 or 15, wherein in step (a) or step (a'), the base is an organic base.

19. The organic base is N,N-diisopropylethylamine (DIPEA), triethylamine (Et ３ 19. The method of claim 18, wherein the aryl group is selected from the group consisting of 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

20. 1. A method for synthesizing adagrasib, comprising: a) reacting a compound of the following structure: 【Chemical 72】 a fumarate salt of a compound of the following structure: 【Chemical 73】 reacting in the presence of DIPEA and DMAc to produce the final compound of step (a) having the following structure: 【Chemical 74】 b) The final compound of step (a) is reacted with (S)-(1-methylpyrrolidin-2-yl)methanol and Pd ２ (dba) ３ ,(R)-BINAP,K ３ P.O. ４ and 2-MeTHF to produce the final compound of step (b) having the structure: 【Chemistry 75】 c) reacting the final compound of step (b) with hydrochloric acid and L-tartaric acid to remove the Boc protecting group from the final compound of step (b) to produce the L-tartrate salt of the final compound of step (c) having the structure: 【Chemical 76】 d) reacting the free base of the final product of step (c) with 【Chemical 77】 Pd ２ (dba) ３ ,(R)-BINAP,K ３ P.O. ４ and 2-MeTHF to produce the final compound of step (d) having the structure: 【Chemical 78】 e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of acetone and 2-MeTHF to produce the final compound of step (e) having the following structure: 【Chemical Formula 79】 f) The final compound of step (e) is reacted with 2-mercaptoethanol and K ３ P.O. ４ and DMAc to produce the final compound of step (f) having the structure: 【Chemistry 80】 g) reacting the final compound of step (f) with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

21. 1. A method for synthesizing adagrasib, comprising: a') reacting a compound of the following structure: 【Chemistry 81】 a compound of the following structure: 【Chemistry 82】 reacting in the presence of DIPEA and DMAc to produce a compound of the following structure: 【Chemistry 83】 Next reacting this compound with benzyl chloroformate in the presence of sodium carbonate, methyl tert-butyl ether (MTBE), and water to produce the final compound of step (a′) having the following structure: 【Chemistry 84】 b) The final compound of step (a') is reacted with (S)-(1-methylpyrrolidin-2-yl)methanol and Pd ２ (dba) ３ , Xantphos, K ３ P.O. ４ and 2-MeTHF to produce the final compound of step (b) having the structure: 【Chemistry 85】 c) reacting the final compound of step (b) with hydrochloric acid and L-tartaric acid to remove the Boc protecting group from the final compound of step (b) to produce the L-tartrate salt of the final compound of step (c) having the structure: 【Chemistry 86】 d) reacting the free base of the final product of step (c) with 【Hua 87】 and Pd ２ (dba) ３ ,(R)-BINAP,K ３ P.O. ４ and 2-MeTHF to produce the final compound of step (d) having the structure: 【Hua 88】 e) reacting the final compound of step (d) with p-toluenesulfonic acid in the presence of acetone and 2-MeTHF to produce the final compound of step (e) having the following structure: 【Chemistry 89】 f) The final compound of step (e) is reacted with 2-mercaptoethanol and K ３ P.O. ４ and DMAc to produce the final compound of step (f) having the structure: 【Chemistry 90】 g) reacting the final compound of step (f) with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

22. A compound selected from the group consisting of the following compounds: 【Chemistry 91】

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