PROCESSES AND INTERMEDIATES FOR SYNTHESIS OF

ADAGRASIB

FIELD OF THE INVENTION

[001] The present invention relates to new and improved synthetic routes for synthesis of adagrasib.

BACKGROUND OF THE INVENTION

[002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors regulating a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pbarmcol. 13:39*401).

[003] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see 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, (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428). Single nucleotide substitutions that result 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 a G12C transversion being the most common activating mutation (e.g., see Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1158/1078-0432.CCR- 11-3265).

[004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, no KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8):1797-1801).

[005] KRas G12C inhibitor compound 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l - methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5Z7-pyrido[3,4-d] pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acctonitrile (also known as MRTX849, and also known as adagrasib) has the following structure:

[006] Adagrasib is described, for example, in Example 478 of PCT Application WO 2019/099524.

[007] While WO 2019/099524 describes methods of malting adagrasib, there is a need in the art for new and improved synthetic routes of malting adagrasib.

SUMMARY OF THE INVENTION

[008] The present invention, in one embodiment, provides new and improved methods of making adagrasib.

[009] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the step of a) reacting a compound of the following structure;

with a compound of the following structure: in the presence of a base and a polar solvent to produce a final compound of step (a) with the following structure:

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

[0011] In one embodiment, the method further comprises step (b): b) reacting the final compound of step (a) with a derivative of phosgene in the presence of an acid and a polar aprotic solvent to produce a final compound of step (b) with the following structure:

[0012] In one embodiment, step (b) is carried out at a temperature from about 0 °C to about 120 °C.

[0013] In one embodiment, the method further comprises step (c): c) reacting the final compound of step (b) with in the presence of a base and a polar aprotic solvent to produce a final compound of step (c) with the following structure:

[0014] In one embodiment, step (c) is carried out at a temperature from about 0 °C to about 120 °C.

[0015] In one embodiment, the method further comprises step (d): d) reacting the final product of step (c) with an activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce a final compound of step (d) with the following structure: wherein LG is a leaving group.

[0016] In one embodiment, step (d) is carried out at a temperature from about -20 °C to about 70 °C.

[0017] In one embodiment, the method further comprises step (e); e) reacting the final compound of step (d) with a base in the presence of fS^-2-(piperazin-2- yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce a final compound of step (e) with the following structure: [0018] In one embodiment, the method further comprises step (f): f) reacting the final compound of step (e) with 2-fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0019] In one embodiment, step (f) is carried out at a temperature from about -10 °C to about 50 °C,

[0020] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising

-reacting fluoroaciylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0021] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

- reacting wherein LG is a leaving group, with a base in the presence of (S)-2-{piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

, reacting fluoroaoylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0022] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting with an activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce:

wherein LG is a leaving group;

- reacting the presence of (S)-2(pipcrazin-2-yl)acctqiiitrilc or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

- reacting fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0023] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting the presence of a base and a polar aprotic solvent to produce::

g activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce: , wherein LG is a leaving group;

'^reacting * with a base in the presence of (S)2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to producer

- reacting fluoroacrylic arid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0024] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting with a derivative of phosgene in the presence of an acid and a polar solvent to produce:

-reacting with an activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce: wherein LG is a leaving group;

- reacting , with a base in the presence of ^-2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

fluoroacryiic acid (or corresponding alkah or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0025] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting in the presence of a base and a polar solvent to produce: derivative of phosgene in the presence of an acid and a polar solvent to produce: O

-reacting activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce: , wherein LG is a leaving group;

- reacting with a base in the presence of (S)-2(-piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0026] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

of hydrogen chloride and 2-McTHF to produce:

the presence of sodium terr-amylate and 2-MeTHF to produce:

-reacting with bis(trifluoromcthanesulfonyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce: phnsphate tribasic in the presence of (S)-2(-piperazin-2-yl)acetonitrile dihydrochlonde, 2- MeTHF and MeCN to produce:

* salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasibi

[0027] In another embodiment, the invention provides an alternative route of synthesizing adagrasib. Thus, in one embodiment, the invention provides a method of synthesizing adagrasib, comprising the step of:

a') reacting in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure:

[0028] In one embodiment, step (a') is carried out at a temperature from about 0 °C to about 100 °C.

[0029] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (b’): b’) reacting the final compound of step (a ¹ ) with an alkylating or arylating agent with a base in the presence of a polar solvent to produce a final compound of step (b’) with the following structure:

wherein R is methyl, ethyl, isopropyl, or benzyl

[0030] In one embodiment, step (b*) is carried out at a temperature from about 20 °C to about 120 °C.

[0031] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (c'): c’) reacting the final compound of step (b’) with an oxidizing agent in the presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce a final compound of step (c') with the following structure: wherein R is methyl, ethyl, isopropyl, or benzyl.

[0032] In one embodiment, step (c') is carried out at a temperature from about 0 °C to about 120 °C.

[0033] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (d'); d’J reacting the final product of step (c') with (5^-(l -methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce a final compound of step (d*) with the following structure:

[0034] In one embodiment, step (d*) is earned out at a temperature flora about -20 °C to about 50 °C.

[0035] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (e’): e*) reacting the final product of step (d’) with an activating agent in the presence of a base, an additive and a polar aprotic solvent to produce a final compound of step (e’) with the following structure: , wherein LG is a leaving group.

[0036] In one embodiment, step (e*) is earned out at a temperature from about -20 °C to about 70 °C. [0037] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (f ): f ) reacting the final product of step (e*) with a base, (59-2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce a final compound of step (f ) with the following structure:

[0038] In one embodiment, step (f ) is carried out at a temperature from about 20 °C to about 120 °C.

[0039] In one embodiment, the invention provides a method of synthesizing adagrasib, furflier comprising step (g’): g’) reacting the final compound of step (f ) with 2 -fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0040] In one embodiment, step (g*) is carried out at a temperature from about -10 °C to about 50 °C. [0041] In one embodiment, the invention provides a method of synthesizing adagrasib comprising reacting

2-fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0042] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting wherein LG is a leaving group, with a base, ^-2 -(piperazin-2 -yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0043] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of: -reacting activating agent in the presence of a base, an additive and a polar aprotic solvent to produce. , wherein LG is a leaving group;

-reacting with a base, (S)-

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

- fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagmsib.

[0044] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting wherein R is methyl, ethyl, isopropyl, or benzyl, with (S)-(l-methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce: activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:

, wherein LG is a leaving group;

-reacting with a base, (S)-

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

-reactin fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0045] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting wherein R is methyl, ethyl, isopropyl, or benzyl, with an oxidizing agent in the presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce:

-reacting ^{with an} activating agent in the presence of a base, an additive and a polar aprotic solvent to produce: wherein LG is a leaving group; reacting with a base, (S)-

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce?

- fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasih

[0046] In one embodiment, the invention provides a method of synthesizing adagrasib comprising flic steps of:

-reacting with an alkylating or arylating agent and a base in the presence of a polar solvent to produce: wherein R is methyl, ethyl, isopropyl, or benzyl;

-reacting presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce:

wherein R is methyl, ethyl, isopropyl, or benzyl;

-reacting yl)methanol in the presence of a base and a polar aprotic solvent to produce;:

-reacting activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

-reacting fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0047] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

reacting in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure: alkylating or arylating agent

-reacting and a base in the presence of a polar solvent to produce:



-reacting with fS>-(l-methylpyrrolidin-2- yl)methanol in the presence of a base and a polar aprotic solvent to produce*

-r g activating agent in the presence of a base, an additive and a polar aprotic solvent to produce?-

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

-reacting fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0048] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

•reacting in the presence of MeONa and MeOH to produce:

-reacting with sodium methoxide, sodium tungstate and hydrogen peroxide in the presence of 2 -propanol to produce:

-reacting yl)methanol in the presence of potassium tert-butoxide and THF to produce?

-reacting bis(trifhioromethanesulfonyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce:

-reacting with potassium phosphate tribasic, (S)-2-(piperazin-2-yl)acetomtrile dihydrochloride and MeCN to produce:

the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

[0049] In anoflier embodiment, the invention provides novel intermediate compounds, such as:

DETAILED DESCRIPTION OF THE INVENTION

[0050] The present invention relates to new synthetic routes for synthesizing adagrasib, as well as to novel intermediates used in the provided routes.

[0051] Although there is a known method of synthesizing adagrasib (see WO 2019/099524), the synthesis provided by the present invention is much improved, in that it has fewer steps, provides a higher isolated yield and a higher or similar purity overall.

[0052] The new and improved synthesis of MRTX849 - adagrasib - features five high yielding steps with introduction of expensive building blocks at late-stage of the process.

[0053] The previous synthesis of adagrasib involved the introduction of the 2 expensive chiral pieces back-to-back in the first and second step. Using the new approach these two pieces are introduced toward the end of the synthesis, hence greatly improving the cost effectiveness of the production. [0054] The new route also avoids the use of protecting steps - both Boc and Cbz protecting groups were eliminated - saving time and resources on their introduction and removal, making the route eco-friendlier.

[0055] The new route circumvents the major cost contributor, palladium catalysts. Increasingly more expensive, palladium was used in 2 out of 6 steps in the previous synthesis, dramatically driving cost up. The new procedure disclosed is completely transition metal-free. DEFINITIONS

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.

[0057] As used herein, “KRas G12C” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Glyl2Cys.

[0058] A "KRas G12C-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-assodated cancer.

[0059] As used herein, the term “adagrasib” refers to the compound which has the name: 2- [(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin -2-yl]methoxy]-6,8-dihydro-5Zf- pyrido[3,4-cZ]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)pipera zin-2-ylJacetonitrile (also known as MRTX849) and which has fee following structure:

[0060] Adagrasib is described, for example, in Example 478 of PCT Application WO 2019/099524.

[0061] The term “adagrasib” encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0062] In one embodiment, the term “adagrasib” includes salts of the above compound, for instance salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts formed with organic acids such as acetic add, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic add, and polygalacturonic acid, and salts formed from quaternary ammoniums of the formula — NR+Z-, 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, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0063] Whenever the application refers to a chemical compound, unless specifically stated otherwise, the compound encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0064] “LG" refers to a leaving group and has the meaning conventionally associated with the term "leaving group" in synthetic organic chemistry; that is, an atom or group that is displaceable under alkylating or nucleophilic aromatic substitution conditions. The term "leaving group" includes, but is not limited to, halogen, for example chlorine and bromide; alkanesulfonyloxys, for example methanesulfonyloxy and ethanesulfonyloxy; arenesulfonyloxys, for example benzylsulfonyloxy and tosyloxy; thienyloxy; dihalophospbinoyloxy; tetrahalophosphaoxy; pcrfluoroalkanesulfonyloxys, for example trifluoromethanesulfonyloxy and the like. The leaving group should be selected so as to be chemically less reactive (except of course when the leaving group is bromine wherein it will be equally reactive) than the reacting group, bromine, to ensure proper reaction.

[0065] Unless the application specifies differently, “R" refers to a group such as alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, carbocycle, cycloalkyl, heteroalkyl, heterocycle, aryl , aralkyl, or arylalkyl.

[0066] The term “alkyl" is intended to mean a straight chain or branched aliphatic group having from 1 to 12 carbon atoms, alternatively 1-8 carbon atoms, and alternatively 1-6 carbon atoms. Other examples of alkyl groups have from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms and alternatively 2-6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. A “CO" alkyl (as in “C0-C3alkyl") is a covalent bond.

[0067] The term “alkenyl" is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0068] The term “alkynyl" is intended to mean an unsaturated straight chain or branched aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms. Examples of alkynyl groups include, without limitation, cthynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0069] The terms “alkylene," “alkenylene," or “alkynylene" as used herein are intended to mean an alkyl, alkenyl, or alkynyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Samples of alkylene groups include, wittrout limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0070] The term “carbocycle” as employed herein is intended to mean a cycloalkyl or aryl moiety.

[0071] The term "cycloalkyl" is intended to mean a saturated or unsaturated mono-, bi-, tri- or poly-cyclic hydrocarbon group having about 3 to 15 carbons, alternatively having 3 to 12 carbons, alternatively 3 to 8 carbons, alternatively 3 to 6 carbons, and 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, without limitation, cyclqpenten-2- enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cydohexenyl, cycloheptyl, cyclooctyl, etc.

[0072] The term “heteroalkyl” is intended to mean a saturated or unsaturated, straight chain or branched aliphatic group, wherein one or more carbon atoms in the group are independently replaced by a heteroatom selected from the group consisting of O, S, and N.

[0073] The term "aryl" is intended to mean a mono-, bi-, tri- or polycyclic aromatic moiety, for example a C6-C14aromatic moiety, for example comprising one to three aromatic rings. Alternatively, the aryl group is a C6-C10aryl group, alternatively a C6aryl group. Examples of aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.

[0074] The terms “aralkyl” or "arylalkyl" are intended to mean a group comprising an aryl group covalently linked to an alkyl group. If an aralkyl group is described as “optionally substituted”, it is intended that either or both of the aryl and alkyl moieties may independently be optionally substituted or unsubstituted. Alternatively, the aralkyl group is (Cl-C6)alk(C6-C10)aryl, including, without limitation, benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as “arylalkyl” this term, and terms related thereto, is intended to indicate the order of 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”.

[0075] As used herein, the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to add addition salts formed with inorganic acids (for example, hydrochloric add, hydrobromic add, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric add, succinic acid, malic add, ascorbic acid, benzoic add, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic add, naphthalenedisulfonic add, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula — NR+Z-, 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, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0076] As used herein, the term “mineral add" (or “inorganic acid”) refers to any acid derived from an inorganic compound that dissociates to produce hydrogen ions (H+) in water. Nonlimiting examples of mineral acids include hydrogen halides of the general formula HX (where X is F, Cl, Br or I), nitric acid, phosphoric acid, sulfuric acid, boric acid and perchloric add.

[0077] As used herein, the term “organic add" refers to any organic compound with acidic properties. Nonlimiting examples of organic acids include sulfonic adds of the general formula RSOsH (where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl and are define above), carboxylic acids (with one or several carboxylic add sites) of the general formula RCO2H (where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl and are define above). Nonlimiting examples of organic adds are lactic acid, acetic add, formic acid, citric acid, oxalic add, uric add, malic add, and tartaric add.

SYNTHETIC SCHEMES

[0078] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the step of: a) reacting a compound of the following structure;

with a compound of the following structure: in the presence of a base and a polar solvent to produce a final compound of step (a) with the following structure:

[0079] In one embodiment, step (a) is carried out at a temperature from about 20 °C to about 120 °C.

[0080] In one embodiment, the method further comprises step (b): b) reacting the final compound of step (a) with a derivative of phosgene in the presence of an acid and a polar aprotic solvent to produce a final compound of step (b) with the following structure:

[0081] In one embodiment, step (b) is carried out at a temperature from about 0 °C to about 120 °C.

[0082] In one embodiment, the method further comprises step (c): c) reacting the final compound of step the presence of a base and a polar aprotic solvent to produce a final compound of step (c) with the following structure:

[0083] In one embodiment, step (c) is carried out at a temperature from about 0 °C to about 120 °C.

[0084] In one embodiment, the method further comprises step (d): d) reacting the final product of step (c) with an activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce a final compound of step (d) with the following structure: wherein LG is a leaving group.

[0085] In one embodiment, step (d) is carried out at a temperature from about -20 °C to about 70 °C.

[0086] In one embodiment, the method further comprises step (e): e) reacting the final compound of step (d) with a base in the presence of $l-2-(piperazin-2- yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce a final compound of step (e) with the following structure: [0087] In one embodiment, the method further comprises step (f): f) reacting the final compound of step (e) with 2-fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0088] Tn one embodiment, step (f) is carried out at a temperature from about -10 °C to about 50 °C.

[0089] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising

-reflating fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0090] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

•* reacting wherein LG is a leaving group, with a base in the presence of (S)-2(-piperazm-2-y])acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

- reacting with 2- fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0091 ] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting with an activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce?

, wherein LG is a leaving group;

- reacting the presence of ^-2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce: and

- reacting fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in tire presence of a solvent and, optionally, a base to produce adagrasib.

[0092] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting presence of a base and a polar aprotic solvent to produce:

activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce- , wherein LG is a leaving group;

-reacting with a base in the presence of (S)-2-(piperazm-2-yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

-reacting with 2- fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasih.

[0093] In one embodiment, the invention provides a method of synthesizing adagrasih, comprising the steps of:

-reacting presence of an add and a polar solvent to produce:

-reacting activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce; wherein LG is a leaving group;

- reacting the presence of (S)-2(-piperazin-2-yl)acetonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0094] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting in the presence of a base and a polar solvent to produce;: with a derivative of phosgene in the presence of an acid and a polar solvent to produce:

presence of a base and a polar aprotic solvent to produce:

-reacting activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce: , wherein LG is a leaving group;

- reacting with a base in the presence of (S)-2-(piperazin-2-yl)acetoinitnle or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:

fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[0095] In one embodiment, the invention provides a method of synthesizing adagrasib, comprising the steps of:

-reacting in the presence of MeONa and MeOH to produce: with triphosgene in the presence of hydrogen chloride and 2-MeTHF to produce:

presence of sodium tert-amylate and 2-MeTHF to produce:

-reacting bis(trifluoroniethanesulfbnyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce: phosphate tribasic in the presence of (S)-2(-piperazin-2-yl)acetonitrile dihydrochloride, 2- MeTHF and MeCN to produce:

salt of 2-fhioroaciylic acid in the presence of MeCN and propylphosphomc anhydride to produce adagrasib.

[0096] In another embodiment, the invention provides an alternative route of synthesizing adagrasib Thus, in one embodiment, the invention provides a method of synthesizing adagrasib, comprising the step of:

a') reacting in the presence of a base and apolar solvent to produce a final compound of step (a') with the following structure:

[0097] In one embodiment, step (a') is carried out at a temperature from about 0 °C to about 100 °C.

[0098] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (b*): b’) reacting the final compound of step (a ¹ ) with an alkylating or arylating agent with a base in the presence of a polar solvent to produce a final compound of step (b*) with the following structure:

, wherein R is methyl, ethyl, isopropyl, or benzyl.

[0099] In one embodiment, step (b’) is carried out at a temperature from about 20 °C to about 120 °C.

[00100] In one embodiment, tire invention provides a method of synthesizing adagrasib, further c rising step (o’): c*) reacting the final compound of step (b’) with an oxidizing agent in the presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce a final compound of step (c’) with the following structure: wherein R is methyl, ethyl, isopropyl, or benzyl.

[00101] In one embodiment, step (c') is carried out at a temperature from about 0 °C to about 120 °C.

[00102] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (d*): d’) reacting the final product of step (c’) with (5^-(l -methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce a final compound of step (d*) with the following structure:

[00103] In one embodiment, step (d’) is carried out at a temperature from about -20 °C to about 50 °C.

[00104] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (e*): e’) reacting the final product of step (d‘) with an activating agent in the presence of a base, an additive and a polar aprotic solvent to produce a final compound of step (e’) with die following structure:

, wherein LG is a leaving group.

[00105] In one embodiment, step (e‘) is carried out at a temperature from about -20 °C to about 70 °C. [00106] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (P):

P) reacting the final product of step (e’) with a base, (S)-2(-piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce a final compound of step (P) with the following structure:

[00107] In one embodiment, step (P) is carried out at a temperature from about 20 °C to about 120 °C.

[00108] In one embodiment, the invention provides a method of synthesizing adagrasib, further comprising step (g*): g’) reacting the final compound of step (P) with 2-fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[00109] In one embodiment, step (g*) is carried out at a temperature from about -10 °C to about 50 °C. [00110] In one embodiment, the invention provides a method of synthesizing adagrasib comprising reacting

2-fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[00111] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting wherein LG is a leaving group, with a base, (5)-2-(piperazm-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

- fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[00112] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting with an activating agent inthe presence of a base, an additive and a polar aprotic solvent to produce: , wherein LG is a leaving group;

-reacting abase, (S)-

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[00113] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting wherein R is methyl, ethyl, isopropyl, or benzyl, witii (5X1 -methylpyrrolidin-2-yl)methanol in the presence of a base and a polar aprotic solvent to produce: activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:

fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[00114] In one embodiment, the invention provides a method of synthesizing adagmsih comprising the steps of:

-reacting , wherein R is methyl, ethyl, isopropyl, or benzyl, with an oxidizing agent in the presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce:

-reacting yl)methanol in the presence of a base and a polar aprotic solvent to produce:

-reacting with an activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[00115] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting and a base in the presence of apolar solvent to producer presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce;

wherein R is methyl, ethyl, isopropyl, or benzyl;

-reacting yl)methanol in the presence of a base and a polar aprotic solvent to produce:

-reacting activating agent in the presence of a base, an additive and a polar aprotic solvent to produce;

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

-reacting fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.

[00116] In one embodiment, the invention provides a method of synthesizing adagrasib comprising the steps of:

reacting in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure: with an alkylating or arylating agent and a base in the presence of a polar solvent to produces

-reacting - yl)methanol in the presence of a base and a polar aprotic solvent to produce: : activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:

wherein LG is a leaving group;

-reacting with a base, (S)-

2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:

-reacting fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasih

[00117] In one embodiment,the invention provides a method of synthesizing adagrasib comprising the steps of:

-reacting inthe presence of MeONa and MeOH to produce:

with 2-iodopropane and sodium hydroxide in the presence of methanol to produce:

-reacting tungstate and hydrogen peroxide in the presence of 2 -propanol to produce; yl)methanol in the presence of potassium tert-butoxide and THF to produce;

bis(trifluorometha]iesulfbnyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce:

-reactihg phosphate tribasic, (S?-2-(piperazin-2-yl)acetonitrile dihydrochloride and MeCN to produce:

-reacting with the sodium salt of 2-fluoroacrylic acid in the presence of MeCN and propylphosphonic anhydride to produce adagrasib.

[00118] In one embodiment, in step (a), the polar solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofiiran (2-MeTHF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and an alcohol with a formula R-OH, wherein R is alkyl, allyl or aryl.

[00119] In one embodiment, in step (a), the polar solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP and an alcohol with a formula R-OH, wherein R can be, but is not limited to alkyl, allyl or aryl.

[00120] In one embodiment, in step (a), the polar solvent is methanol (MeOH).

[00121] In one embodiment, in step (a), a base is selected from the group consisting of methoxide, ethoxide, iso-propoxidtee,rt- butoxide and tert-amylate.

[00122] In one embodiment, in step (a), the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iro-propoxide, Zert-butoxide and rert-amylate.

[00123] In one embodiment, in step (a), the base is sodium methoxide, [00124] In one embodiment, in step (b), the phosgene derivative is selected from the group consisting of phosgene, disphosgene, triphosgene, thiophosgene and l.P-carbonyldiimidazole.

[00125] In one embodiment, in step (b), the phosgene derivative comprises, but is not limited to, one or more of the following: phosgene, disphosgene, triphosgene, thiophosgene and 1 ,1 ’-carbonyldiimidazole.

[00126] In one embodiment, in step (b), the phosgene derivative is triphosgene.

[00127] In one embodiment, in step (b), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, andNMP.

[00128] In one embodiment, in step (b), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, andNMP.

[00129] In one embodiment, in step (b), the polar aprotic solvent is 2-MeTHF.

[00130] In one embodiment, in step (b), the mineral acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

[00131] In one embodiment, in step (b), the mineral acid comprises, but is not limited to, one or more of the following: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.

[00132] In one embodiment, in step (b), the mineral acid is hydrogen chloride.

[00133] In one embodiment, in step (c), the base is a bulky alkoxide selected from the group consisting of iso-propoxide, tert-butoxide and rert-amylate.

[00134] In one embodiment, in step (c), the base is a bulky alkoxide which comprises, but is not limited to, one or more of the following: iso-propoxide, tert-butoxide andtert- amylate.

[00135] In one embodiment, in step (c), the base is sodium tert-amylate^

[00136] In one embodiment, in step (c), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. [00137] In one embodiment, in step (c), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, andNMP.

[00138] In one embodiment, in step (c), the polar aprotic solvent is 2-MeTHF.

[00139] In one embodiment, in steps (d) and (e), the activating agent is selected from the group consisting of sulfonyl halide R-SO2X (where R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X is F, Cl or Br), anhydride (trifluoromethanesulfonic anhydride and nonafluorobutanesulfbnic anhydride) and organic triflate reagent R*-N-T6 (where R ¹ is phenyl, 5-chloro-2-pyridine, 2-pyridine).

[00140] In one embodiment, in steps (d) and (e), the activating agent comprises, but is not limited to, one or more of the following: sulfonyl halide R-SOzX (where R can be, but is not limited to tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br), anhydride (trifluoromethanesulfonic anhydride and nonafluorobutanesulfbnic anhydride) and organic triflate reagent R ^l -N-T6 (where R ¹ is phenyl, 5-chloro-2 -pyridine, 2-pyridine).

[00141] In one embodiment, in step (d), the activating agent is bis(trifluoromethanesulfonyl)aniline.

[00142] In one embodiment, in steps (d) and (e), the base is an inorganic base.

[00143] In one embodiment, the inorganic base is selected fromthe group consisting of carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).

[00144] In one embodiment, the inorganic base comprises, but is not limited to, one or more of the following: carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).

[00145] In one embodiment, the inorganic base is used with an alkali salt selected from the group consisting of lithium, sodium, and potassium.

[00146] In one embodiment, the inorganic base is used with an alkali salt that comprises, but is not limited to, one or more of the following: lithium, sodium, and potassium. [00147] In one embodiment, in step (d), the base is potassium phosphate tribasic and dibasic.

[00148] In one embodiment, in steps (d) and (e), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[00149] In one embodiment, in steps (d) and (e), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[00150] In one embodiment, in step (d), the polar aprotic solvent is MeCN.

[00151] In one embodiment, in step (e), the polar aprotic solvent is MeCN.

[00152] In one embodiment, in step (f), 2-fluoroacrylic acid can be used in the neutral form, free acid, or ionic form (as a metal or alkali salt).

[00153] In one embodiment, in step (f), the coupling agent is selected from the group consisting ofpropylphosphonic anhydride (T3P®), carbonyldiimidazole (GDI), the carbodiimide (e.g. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), etfayl-(Ar,N - dimethylamino)propylcarbodiimide hydrochloride (EDC.HC1)), the phosphonium ((benzotriazol- l-yloxy)tris(dimethylaniino)phosphonium hexafluorophosphate (BOP), (benzotriazol- 1 - yloxyjtripyrrolidinophosphonium hexafluorophosphate (PyBOP)) and uronium (O-(benzotriazol- l-yiyN,N,N*»N -tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-l-yl)- IV, IV, AT, N '-tetramethyluronium hexafluorophosphate (HATU)) .

[00154] In one embodiment, in step (f), the base is an organic base,

[00155] In one embodiment, the organic base is selected from the group consisting of

DIPEA, EtsN, DABCO, and DBU.

[00156] In one embodiment, wherein in step (f), the base is an inorganic base.

[00157] In one embodiment, the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. [00158] In one embodiment, in step (f), the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP,

[00159] In one embodiment, in step (f), the solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[00160] In one embodiment, in steps (a') and (b’), the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol with a formula R-OH, wherein R is alkyl, allyl or aryl.

[00161] In one embodiment, in steps (a') and (b*), the polar solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP and an alcohol with a formula R-OH, wherein R can be, but is not limited to alkyl, allyl or aryl.

[00162] In one embodiment, in step (a'), the polar solvent is MeOH.

[00163] In one embodiment, in step (a'), a base is selected from the group consisting of methoxide, ethoxide, iso-propoxide, tert-butoxide andtert- amylate.

[00164] In one embodiment, in step (a'), the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iso-propoxide, /ert-butoxide and /ert-amylate.

[00165] In one embodiment, in step (a'), the base is sodium methoxide.

[00166] In one embodiment, in step (b*), the alkylating or arylating agent is selected from the group consisting of aryl halides or alkyl halides R-X (where R is methyl, ethyl, isopropyl, or benzyl and X is Cl, Rr, 1, alkyl sulfonate, aryl sulfonate, triflate or nonaflate), di-alkyl sulfate and carbonate.

[00167] In one embodiment, in step (b*), the alkylating or arylating agent comprises, but is not limited to, one or more of the following: aryl halides, alkyl halides R-X (where R can be, but is not limited to, methyl, ethyl, isopropyl, or benzyl and X can be, but is not limited to, Cl, Br, I, alkyl sulfonate, aryl sulfonate, triflate or nonaflate), di-alkyl sulfete and carbonate. [00168] In one embodiment, the alkylating agent is 2-iodopropane.

[00169] In one embodiment, in step (b*), the base is an inorganic base*

[00170] In one embodiment, fee inorganic base is selected from the group consisting of hydroxide, carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).

[00171] In one embodiment, fee inorganic base comprises, but is not limited to, one or more of the following: hydroxide, carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).

[00172] In one embodiment, fee inorganic base is used wife an alkali salt selected from the group consisting of lithium, sodium, and potassium.

[00173] In one embodiment, in step (b*), the base is sodium hydroxide.

[00174] In one embodiment, in step (c'), the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide and urea hydrogen peroxide.

[00175] In one embodiment, in step (c'), the oxidizing agent comprises, but is not limited to, one or more of the following: peracid (such as meta-chloroperbenzoic acid or peracetic add), oxone, bleach, hydrogen peroxide and urea hydrogen peroxide.

[00176] In one embodiment, in step (c’), the catalyst is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogensulfete.

[00177] In one embodiment, in step (c'), the catalyst comprises, but is not limited to, one or more of the following: sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogensulfete.

[00178] In one embodiment, in step (c‘), the catalyst is sodium tungstate.

[00179] In one embodiment, in step (c'), a base is selected from fee group consisting of methoxide, ethoxide, iro-propoxide, tert- butoxide and tert-amylate.

[00180] In one embodiment, in step (c'), the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iso-propoxide, tert-butoxide and tert-amylate. [00181] In one embodiment, in step (o’), the ammonium or alkali salt is selected from the group consisting of lithium, sodium, and potassium.

[00182] Tn one embodiment, in step (c’)> the ammonium or alkali salt comprises, but is not limited to, one or more of the following: lithium, sodium, and potassium.

[00183] In one embodiment, in step (c’), the base is sodium methoxide^

[00184] In one embodiment, in step (c'), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol and NMP.

[00185] In one embodiment, in step (c'), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol and NMP.

[00186] In one embodiment, in step (d’),the base is a bulky alkoxide selected fromthe group consisting of iro-propoxide, ter/-butoxide andtert- amylate.

[00187] In one embodiment, in step (d’), the base is a bulky alkoxide which comprises, but is not limited to, one or more of the following: iro-propoxide, tert-butoxide and rerf-amylate.

[00188] In one embodiment, in step (d’), the base is potassium tert-butoxide.

[00189] In one embodiment, in step (d‘), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1 ,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[00190] In one embodiment, in step (d*), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1 ,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[00191] In one embodiment, in step (d*), the polar aprotic solvent is THF.

[00192] In one embodiment, in steps (e’) and (f ), the activating agent is selected from the group consisting of sulfonyl halide R-SO2X (where R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X is F, Cl or Br), anhydride (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride) and organic triflale reagent R*-N-Tfi (where R* is phenyl, 5-chloro-2-pyridine, 2-pyridine).

[00193] In one embodiment, in steps (e*) and (f ), the activating agent comprises, but is not limited to, one or more of the following: sulfonyl halide R-SChX (where R can be, but is not limited to tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br), anhydride (trifluoromethanesulfonic anhydride and nonafluorobutanesulfonic anhydride) and organic triflate reagent R’-N-Tf2 ₍ where R ¹ is phenyl, 5-chloro-2 -pyridine, or 2-pyridine).

[00194] In one embodiment, the activating agent in steps (e*) and/or (f ) is bis(trifluoromethanesulfonyl)aniline.

[00195] In one embodiment, in steps (e’) and (f ), the base is an inorganic base.

[00196] In one embodiment, the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).

[00197] In one embodiment, the inorganic base comprises, but is not limited to, one or more of the following: carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).

[00198] In one embodiment, the inorganic base is used with an alkali salt selected from the group consisting of lithium, sodium, and potassium.

[00199] In one embodiment, the inorganic base is used with an alkali salt that comprises, but is not limited to, one or more ofthe following: lithium, sodium, and potassium.

[00200] In one embodiment, in step (e*), the inorganic base is potassium phosphate tribasic and dibasic.

[00201] In one embodiment, in steps (e*) and (f ), the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP. [00202] In one embodiment, in steps (e’) and (f ), the polar aprotic solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1 ,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.

[00203] In one embodiment, in steps (e’) and (f ), the polar aprotic solvent is MeCN.

[00204] In one embodiment, in step (g*), 2-fluoroacrylic acid can be used in the neutral form, free acid, or ionic form (as a metal or alkali salt).

[00205] In one embodiment, in step (g*), the coupling agent is selected from the group consisting of T3P®, GDI, the carbodiimide (e.g. DCC, DIG, EDC.HC1), BOP, PyBOP, HBTU, HATU .

[00206] In one embodiment, in step (g’), the base is an organic base.

[00207] In one embodiment, the organic base is selected from the group consisting of DIPEA, EtaN, DABCO, and DBU.

[00208] In one embodiment, wherein in step (g*), the base is an inorganic base.

[00209] In one embodiment, the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.

[00210] 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, DCM, EtOAc, IPAc, and NMP.

[00211] In one embodiment, in step (g*), the solvent comprises, but is not limited to, one or more of the following: DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.

[00212] The following Examples are intended to illustrate further certain embodiments of die invention and are not intended to limit the scope of the invention. EXAMPLE 1

Step (a)

[00213] Methyl l-(8-chloronaphthden-l-yl)-5-hydroxy- 1,2,3, 6-tetrahydropyridine-4- carboxylate (75 g, 236 mmol, 1.0 equiv.) was charged into a 2 L glass-lined reactor followed by thiourea (54 g, 708 mmol, 3 equiv.). Methanol (750 mL) was then added. Reaction was stirred at 20°C. Sodium methoxide (34 g, 590 mmol, 2.5 equiv.) was added in one portion to the reaction at 20°C. Following this, the reaction was allowed to react at 60°C until starting material area was <1.0 area% (co. 4 h). The mixture was then cooled to 20°C and purified water (750 mL) was added. Mixture was filtered through a pad of celite and transferred to a dan reactor. A 2N hydrochloric add solution was slowly added to the reaction at 15-25 °C until pH = 4-5. Heavy precipitation is observed upon addition of the hydrochloric acid solution. The solid was then filtered off and re-slurried with purified water (375 mL) before a second filtration. Solid was dried until constant mass under nitrogen flow and low vacuum at T <45°C. 7-(8- Chloronaphthalen-l-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[ 3,4-d]pyrimidin-4(J.//)-one was obtained as a light yellow solid (77 g, 225 mmol, 95% yidd).

[00214] M.p.: 237.5 - 237.6 °C (dec.).

[00215] ^J H NMR (500 MHz, DMSO-rfc) 8 ppm 2.35 (br d, J = 16.4 Hz, 1H), 2.51 - 2.59 (m, 1H), 3.05 - 3.16 (m, 1H), 3.36 - 3.45 (m, 1H), 3.57 (br d, J= 17.0 Hz, 1H), 3.94 (d, J= 17.5 Hz, 1H), 7.27 - 7.36 (m, 1H), 7.39 - 7.48 (m, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.59 (dd, J = 7.4, 1.4 Hz, 1H), 7.74 (d, J= 7.7 Hz, 1H), 7.85 - 7.96 (m, 1H), 11.68 - 12.50 (br s, 1H).

[00216] ¹³ C NMR (126 MHz, DMSO-d ₆ ) 8 ppm 21 .6, 49.7, 53.5, 109.8, 119.7, 125.5,

126.5, 127.3, 129.1, 129.3, 130.1, 137.5, 148.3, 150.1, 161.9, 172.9, 174.9.

[00217] HUMS (ESI) calculated for CnHjsCDWS: 344.0624 [M+Hf, Found: 344.0779. EXAMPLE 2

Step (b)

[00218] 7-(8-Chloronaphthalen-l-yl)-2-thioxo-2,3,5,6,7,8-hexahydropy rido[3,4- d]pyrimidin-4(7/Z)-one (10 g, 29 mmol, 1.0 equiv.) was charged into a 400 mL EasyMax reactor followed by 2-McTHF (200 mL). Reaction was stirred at 25 °C. Hydrogen chloride 4N in dioxane (7.3 mL, 29 mmol, 1.0 equiv.) was then charged. Triphosgene (8.6 g, 29 mmol, 1.0 equiv.) was added to the reaction at 25°C. Following this, the reaction was allowed to react at 25 °C until starting material area was <0.5 area% (ca. 24 h). The mixture was then cooled to 15 °C and purified water (50 mL) was added. A IN sodium hydroxide solution was slowly added to the reaction at 15-25 °C until pH = 5-6 under stirring. Following this, the mixture was stirred for 10 min at a temperature of 15 °C, and the layers were allowed to settle before separation. Aqueous phase was discarded, and organic phase was concentrated until solution volume is ca 30 mL. Heptane (50 mL) was then added and then volatiles were removed from the slurry. Solid was dried until constant mass under nitrogen flow and low vacuum at T <45 °C. 2-Chloro-7-(8- chloronaphthalen-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimi din-4(3H)-one was obtained as a yellow solid (8.5 g, 25 mmol, 85% yield).

[00219] M.p.: 200.7 - 200.8 °C (dec.).

[00220] *H NMR (500 MHz, DMSO-406 ppm 2.54 (br s, 1H), 2.71 - 2.85 (m, 1H), 3.11 (br s, 1H), 3.44 - 3.52 (m, 1H), 3.82 (m, 1H), 3.99 (m, 1H), 7.33 - 7.37 (m, 1H), 7.44 (t, J= 7.7 Hz, 1H), 7.53 (t, J - 7.9 Hz, 1H), 7.57 (dd, J = 7.4, 1.4 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.91 (dd, J= 8.2, 1.1 Hz, 1H), 13.39 (m, 1H). [00221]

129.3, 129.1, 127.3, 126.4, 125.5, 125.4, 119.5, 104.4, 57.1, 49.8, 22.3.

[00222] HRMS (ESQ calculated for C17H14CI2N3O: 346.0514 [M+H] ⁺ , Found: 346.0668.

EXAMPLE S

Step (c)

[00223] 2-Chloro-7-(8-chloronaphthalen- 1 -yl)-5 _s 6,7,8-tetrahydropyrido[3,4-d]pyrimidin- 4(3H)-one (100 mg, 0.29 mmol, 1 equiv.) was charged into a 8 mL vial followed by 2-MeTHF (1.0 mL). Reaction was stirred at 20 °C. (S)-(l-methylpyrrolidin-2-yI)methanol (41 pL, 0.35 mmol, 1.2 equiv.) was then added. Then sodium terZ-amylate (160 mg, 0.87 mmol, 5.0 equiv.) was added to the reaction mixture. Following this, the reaction was allowed to react at 60 °C until startine material area was <0.5 area% (ca 16 h). The mixture was cooled to 20 °C and 1.0 mL of a 10% w/w of citric acid in water was added to the reaction mixture. Organic phase was discarded, and aqueous phase was washed further with 0.5 mL of 2-MeTHF. The organic phase was discarded again and 1.0 mL of fresh 2-MeTHF was added before the pH of the aqueous solution was taken to neutral (6.5 < pH < 7.5). Organic phase was kept aside while the neutral aqueous phase was back-extracted with fresh 0.5 mL of 2-MeTHF. Combined organic phases were concentrated to half before 1.0 mL of heptane was added. After removal of volatiles, the solid was dried under nitrogen flow and low vacuum at T <45 °C until constant mass. (S?-7-(8- chloronaphthalen-l-yl)-2-((l-methylpyrrolidin-2-yl)methoxy)- 5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4(3H)-one was obtained as a light beige solid (107 mg, 0.25 mmol, 87% yield).

[00224] M.p.: 140.9- 141.0 °C,

[00225] ’H NMR (500 MHz, DMSO-d ₆ ) 8 ppm 1.51 - 1.61 (m, 1H), 1.66 (br d, J = 8.2 Hz, 2H), 1.84 - 1.94 (m, 1H), 2.14 - 2.25 (m, 1H), 2.33 (s, 3H), 2.42 (m, 1H), 2.52 - 2.60 (m, 1H), 2.62 - 2.72 (m, 1H), 2.90 - 2.98 (m, 1H), 3.01 - 3.09 (m, 1H), 3.42 - 3.48 (m, 1H), 3.63 - 3.70 (m, 1H), 3.88 (d, J = 17.0 Hz, 1H), 4.16 - 4.27 (m, 2H), 7.34 (d, J= 7.1 Hz, 1H), 7.40 - 7.46 (m, 1 H), 7.51 (t, J = 7.9 Hz, 1 H), 7.57 (dd, J = 7.4, 1.4 Hz, 1 H), 7.72 (d, J = 7.7 Hz, 1H), 7.90 (dd, J = 8.2, 1.1 Hz, 1H), 12.2 (br s, 1H).

[00226] ¹³ C NMR (126 MHz, DMSO-dk) 5 ppm 163.6, 157.8, 156.0, 148.6, 137.6, 130.0,

129.4, 129.0, 127.3, 126.4, 125.5, 125.1, 119.2, 112.4, 69.6, 63.7, 57.5, 57.3, 50.4, 41.6, 28.4, 23.1, 22.2.

[00227] HRMS (ESI) calculated for

EXAMPLE 4

Steps (d) and (e)

[00228] ^-7-(8-chioronaphthalen-l -yl)-2-((l-methylpyrrolidin-2-yl)methoxy)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (3.0 g, 7.06 mmol, 1 equiv.), potassium phosphate tribasic (3.0 g, 14.12 mmol, 2 equiv.) and potassium phosphate dibasic (1.2 g, 7.06 mmol, 1 equiv.) were charged into a 100 mL reactor followed by MeCN (30.0 mL). Reaction was stirred at 0 °C and bis(trifluoromethanesulfonyl)aniline (4.5 g, 12.71 mmol, 1.8 equiv.) was added slowly to the reaction mixture. Following this, the reaction was allowed to react at 0 °C until starting material area was <5 area% (ca. 24 h). To the same mixture was then added potassium phosphate tribasic (1.5 g, 7.06 mmol, 1 equiv.) followed by (S)-2(-piperazm-2-yl)acetonitrile dihydrochloride (g, 8.47 mmol, 1.2 equiv.). Following this, the reaction was allowed to react at 20 °C until the inflate intermediate area was <0.5 area% (ca. 16 h). To the mixture was added 30.0 mL of water. Phase cut was performed and the organic phase was concentrated to dryness and then diluted with 9.0 mL of DMAc. Then 3.0 mL of water was added and mixture was seeded with the final crystalline product (1% w/w). The mixture was stirred for 10 h, then 9.0 mL of water was slowly added over 3 h. The slurry was stirred at r.L until the assay of the supernatant was <1 area%. The crystalline solid was then filtered, washed with 6.0 mL of water and the solid was then dried under nitrogen flow and low vacuum at T <45 °C until constant mass and KFNMT 10%. 2-((5)-4-(7-(8-chloronaphthalen-l-yl)-2-((fS)-l-methylpyrrol idin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrirmdin-4-yl)pi perazin-2-yl)acetonitrile was obtained as an off-white solid (2.6 g, 4.94 mmol, 70% yield).

[00229] M.p.: 60.3 - 60.4 °C.

[00230] *H NMR (400 MHz, DMSO-d ₆ ) 8 ppm 1.52 - 1.73 (m, 3H), 1.84 - 1.96 (m, 1H), 2.13 (q, J = 8.7 Hz, 1H), 2.32 (d, J = 1.8 Hz, 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 (hr s, 2H), 3.42 - 3.51 (m, 1H), 3.72 (s, 1H), 3.85 (hr d, J = 12.4 Hz, 1H) 4.01 (ddd, J = 10.5, 6.7, 33 Hz, 1H), 4.17 (br d, J = 17.4 Hz, 1H), 4.24 (dd, J = 10.7, 4.9 Hz, 1H) 7.31 (ddd, J= 7.6, 3.4, 0.9 Hz, 1H), 7.43 (t, J= 7.8 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.57 (dd, J= 7.6, 1.3 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.87 - 7.95 (m, 1H).

[00231] ^U C NMR (101 MHz, DMSO-dk) 3 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.

[00232] HRMS (ESI) calculated for C29H35CIN7O: 532.2592 [M+H] ⁺ , Found:

EXAMPLE S

Step (f) [00233] Acetonitrile (1093.0 kg) was added into a 3000 L glass-lined reactor. Next, MR84916 (81.6 kg, 68.1 kg corrected by HPLC assay wt%, 128.0 mol, 1.0 equiv.) was added to the reactor. The mixture was concentrated at a temperature below <45 °C under reduced pressure (P <-0.06 MPa) until (204-272 L) 3-4 vol remained. Acetonitrile (268.0 kg) was then added into the mixture at a temperature below 45 °C. The mixture was concentrated at a temperature below 45 °C under reduced pressure (P <-0.06 MPa) until (204—272 L) 3-4 vol remained. The mixture was sampled to confirm moisture content was below 0.3% as judged by Karl-Fischer analysis (0.1%, actual). The mixture was cooled to a temperature between 10-25 °C (16.5 °C, actual). Acetonitrile (163.9 kg) was added into a separate 3000 L hastelloy reactor. The mixture was sampled to confirm moisture content below 0.3% (0.02%, actual). Sodium 2- fluoroacrylate (25.0 kg, 218 mol, 1.7 equiv.) was added into the hastelloy reactor under the protection of nitrogen at a temperature between 10-20 °C. It was confirmed that the sodium 2- fluoroacrylate was a finely powdered state prior to addition. The reactor wall was rinsed with acetonitrile (13.7 kg). A 50 w/w% propylphosphosphonic anhydride solution in ethyl acetate (124.7 kg, 192 mol, 1.5 equiv.) was added into the sodium 2-fluoroacrylate solution in the hastelloy reactor at a temperature between 10-20 °C under the protection of nitrogen. The mixture was stirred for not less than 2 h at a temperature between 10-20 °C. The mixture containing MR84916 in the 3000 L glass-lined reactor was slowly added into the mixture containing the 2 -fluoroacrylate in the 3000 L hastelloy reactor at a temperature between 10-20 °C. The 3000 L glass-lined reactor containing MR84916 was rinsed with acetonitrile (18.2 kg) which was transferred into the Hastelloy reactor with the acrylate. The reaction proceeded at 10- 20 °C (14.5-18.0 °C), and after 1 h, the mixture was sampled for HPLC purity analysis every 1-3 h until the area% of MR84916 / (MR84916 + MRTX849) was less than 0.4% (0.3% observed at 5 h and 1 min). At a temperature between 10-30 °C, the mixture was adjusted to apH of 8-9 with a potassium carbonate solution (348.3 kg) which was prepared from potassium carbonate (41.6 kg) and purified water (307.2 kg). The mixture continued to stir for another 0.5 h and was then pH was retested for confirmation (pH 8, actual). The mixture was adjusted to a temperature of 25-35 °C, stirring was stopped, and the layers were allowed to settle prior to separation. The aqueous phase was removed and kept The phase was washed with a potassium phosphate tribasic solution which was prepared from potassium phosphate tribasic (50.1 kg) and purified water (204.4 kg) at a temperature of 25-35 °C. The mixture was stirred for an additional 0.5-3 h and allowed to settle prior to separation at a temperature of 25-35 °C. The aqueous phase was removed and kept The aqueous layers were combined and extracted with 2-McTHF (175.9 kg). The mixture was stirred for an additional 20-30 min, and the layers were allowed to settle prior to separation at a temperature between 25-35 °C. The organic fractions were combined, and then the combined mixture was concentrated at a temperature <45°C under reduced pressure (P <-0.06 MPa) until (136-204 L) 2-3 vol remained. Isopropanol (429.2 kg) was added into die mixture at a temperature <45 °C. The mixture was concentrated at a temperature <45 °C under reduced pressure (P <-0.06 MPa) until (136-204 L) 2-3 vol remained. Isopropanol (320.1 kg) was added into the mixture at a temperature <45 °C. The mixture was circulated through a CUNO filtration system. Then isopropanol (106.9 kg) was used to rinse the CUNO filter and added into the reactor. The mixture was concentrated at a temperature of <45 °C under reduced pressure (P <- 0.06 MPa) until 4.5-5.5 vol (306-374 L) remained. The mixture was sampled to confirm that residual acetonitrile residuals were less than 1.5% (0.05%, actual). The mixture was adjusted to a temperature of 33-38 °C (35.3 °C, actual). Purified water (170.0 kg) was added into the mixture at 33-38 °C. Form 2 seed crystal (0.2 kg) was added into the mixture at a temperature between 33-38 °C. The mixture was maintained at this temperature and stirred for 2-3 h. The mixture was slowly cooled to 15-20 °C. The mixture was maintained at this temperature and stirred for 6-10 h. Purified water (170.0 kg) was added into the reactor at a temperature between 15-20 °C. The mixture was cooled to -3 to 7 °C slowly (4.8 °C, actual). The mass was stirred at -3 to 7 °C for crystallization, and after 8 h, the mixture was sampled every 3-5 h 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 with a stainless-steel centrifuge. Purified water (102.6 kg) and isopropanol (16.4 kg) were added into a 3000 L hastelloy-lined reactor, and then transferred into a stainless-steel centrifuge to rinse the filter cake. The wet filter cake was swept with nitrogen for 6-8 h, dried in a rotary conical dryer at T <40 °C until the moisture content was not more than 1% as judged by Karl-Fischer analysis. After completion of drying, the solid was cooled to 20-30 °C. Isopropanol (368.4 kg) was added into a 1000 L glass-lined reactor, and then the stirrer was started. The solids from the filter cake were added to the 1000 L reactor, and the mixture was heated to a temperature between 55-60 °C (57.2 °C, actual). The mixture was maintained at this temperature and stirred until the solid dissolved completely as confirmed by a visual check. The mixture was then filtered into a 1000 L hastelloy reactor (Pre- heated to Tacket=55-60 °C) through a filtration system heated to 55-60 °C. The mixture was held at 55-60 °C. n-Heptane (80.5 kg) was added into the reactor, first passing through the filter for rinsing. The mixture was stirred for 0.5 h in the reactor. After the solid dissolved completely, the mixture was cooled to a temperature of 43-47 °C. A seed slurry was prepared by addition of isopropanol (5.5 kg) and n-heptane (1.3 kg) into a 20 L four-neck flask through a capsule filter, followed by addition of Form 2 seed crystals (MRTX849 Form 2, 0.8 kg) held at a temperature between 20-25 °C. The mixture was stirred until evenly mixed, and then it was recycled through a wet mill. Prior to addition of the slurry feed to the reactor, the reactor was checked to confirm full dissolution of MRTX849 and that precipitation had not occurred. After this, the Form 2 seed slurry was added into the 1000 L Hastelloy reactor at a temperature between 43-47 °C. The mixture was stirred for 3-4 h at 43-47 °C. The mixture was then cooled to a temperature of 28-32 °C and stirred for 4-5 h at that temperature (30.6 °C, actual). After this time, the mixture was cooled to 18-22 °C and stirred for 4-5 h (20.9 °C, actual). The mixture was then cooled to -3 to 7 °C (3.5 °C, actual) with stirring. After 12 h, the supernatant ofthe mixture was sampled every 3- 5 h to checkthe assay wt% of MRTX849 in the mother liquors, and to confirm when the level was not more than 12% or alternatively, when the difference between samples is equal to or less than 0.2%. During the crystallization, nitrogen was bubbled intermittently through the bottom port of the reactor. On checking the mother liquours, the assay wt% of MRTX849 was found to be 1.0%. The mixture was recycled through a wet mill at -3 to 10 °C, and the batch temperature can be expected to rise by 2-3 °C during this process. The solid was sampled for particle size until the D(90) was not more than 100 pm (22 pm, actual). The mixture was maintained at -3 to 7 °C for 0.5-1 h. The mixture was then filtered with a stainless steel Nutsche filter. The reactor wall was rinsed with a mixed solvent system of n-heptane (15.9 kg) and isqpropanol (74.1 kg) through ^a liquid material filter. Then the wet mill was rinsed with these rinsing liquors, which were transferred into the reactor and then discharged into the filter to rinse the filter cake. The above operation was repeated once more with the mixed solvent of n-heptane (15.9 kg) and isqpropanol (74.2 kg). The filtration was noted to be quite slow as a result of the small particle size from wet milling. The solid inthe filter was swept with nitrogen at Tjw±er=20-30 °C for 8-10 h, and then dried at Tj.ek«t=35-45 °C until th iesopropanol residual was not more than 6300 ppm (3488 ppm, actual) and the n-heptane residual was not more than 3500 ppm (not detected, LOD 432 ppm) as measured by GC. After drying completed, the solid was cooled to a temperature between 20-30 °C. The solid was sieved until the appearance of the product was uniform and without blocking. The operation area RH% should be not more than 50%. The product (MRTX849) was obtained as an off-white solid (51.1 kg, 50.0 kg corrected for assay wt%, 100.4 assay wt%, 64.7% yield).

[00234] M.p.: 128.3 - 128.4 °C.

[00235] ¹ H NMR (400 MHz, DMSO-d ₆ ) 5 ppm 1.56 - 1.77 (m, 3H), 1.96 (br dd, J = 11.9,

7.6 Hz, 1H), 220 (dd, J = 8.2, 2.4 Hz, 1H), 2.37 (d, J= 3.5 Hz, 3H), 2.72 (br d, J= 1.8 Hz, 1H), 2.91 - 3.03 (m, 2H), 3.04 - 3.23 (m, 4H), 3.28 (br dd, J - 13.8, 3.7 Hz, 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 = 7.6 Hz, 1H), 7.63 (dt, J= 7.5, 1.1 Hz, 1H), 7.75 - 7.83 (m, 1H), 7.93 - 8.00 (m, 1H).

[00236] ¹³ C NMR (101 MHz, DMSO-d ₆ ) 5 ppm 22.5, 25.0, 25.3, 25.5, 26.8, 28.5, 412,

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= 266.39 Hz), 161.0 (d, J= 11.71 Hz), 162.0, 164.3, 165.9.

[00237] ¹⁹ F NMR (376 MHz, DMSO-ds) 3 ppm -106.4,

[00238] HRMS (ESI) calculated for C32H36CIFN7O2: 604.2603 [M+Hf, Found: 604.26901

Example 6

Optional isolation of MRTX849 as tartrate salt:

[00239] 3.5 L of ethanol was added to a reactor charged with MRTX849 (875 g) and stirred until fully 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 45-50 °C and precipitate formation was slowly observed. The slurry was stirred at 45-50 °C for at least 1 h before being filtered, washed with cold ethanol, and dried in a vacuum over at 40 °C for 24 hours.

EXAMPLE 7

[00240] Methyl 1 -(8-chloronaphthalen- l-yl)-5-hydroxy- 1,2,3, 6-tetrahydropyridine-4- carboxylaie (75 g, 236 mmol, 1.0 equiv.) was charged into a 2 L glass-lined reactor followed by thiourea (54 g, 708 mmol, 3 equiv.). Methanol (750 mL) was then added. Reaction was stirred at 20°C. Sodium methoxide (34 g, 590 mmol, 2.5 equiv.) was added in one portion to the reaction at 20°C. Following this, the reaction was allowed to react at 60 °C until starting material area was <1.0 area% (co. 4 h). The mixture was then cooled to 20 °C and purified water (750 mL) was added. Mixture was filtered through a pad of celite and transferred to a clan reactor. A 2N hydrochloric acid solution was slowly added to the reaction at 15-25 °C until pH = 4-5. Heavy precipitation is observed upon addition of the hydrochloric acid solution. The solid was then filtered off and re-slurried with purified water (375 mL) before a second filtration. Solid was dried until constant mass under nitrogen flow and low vacuum at T <45°C. 7-(8- Chloronaphthalen-l-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[ 3,4-d]pyrimidin-4(27Z)-one was obtained as a light yellow solid (77 g, 225 mmol, 95% yield).

[00241] M.p.: 237.5 -237.6 °C (dec.).

[00242] ’H NMR (500 MHz, DMSO-d ₆ ) 6 ppm 2.35 (br d, J = 16.4 Hz, 1H), 2.51 - 2.59 (m, 1H), 3.05 - 3.16 (m, 1H), 3.36 - 3.45 (m, 1H), 3.57 (br d, J = 17.0 Hz, 1H), 3.94 (d, J = 17.5 Hz, 1H), 7.27 - 7.36 (m, 1H), 7.39 - 7.48 (m, IB), 7.53 (t, J - 7.9 Hz, 1H), 7.59 (dd, J - 7.4, 1.4 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.85 - 796 (m 1H) 11 68 - 1250 (br s 1H) [00243] ¹³ C NMR (126 MHz, DMSO-ds) 5 ppm 21.6, 49.7, 53.5, 109.8, 119.7, 125.5, 126.5, 127.3, 129.1, 129.3, 130.1, 137.5, 148.3, 150.1, 161.9, 172.9, 174.9.

[00244] HRMS (ESI) calculated for C17H15CIN3OS: 344.0624 [M+HJ ¹ ", Found: 344.0779,

EXAMPLE S

Step (b’)

7-(8-chloronaphthalen-l-yl)-2-thioxo-23,5,6,7,8-hexahydro pyrido[3,4-d]pyrimidin-4(lH)-one (10 g, 29.0 mmol, 1.0 equiv.) was charged into a 250 mL 3-necked round bottom flask. MeOH (100 mL) was then added. Sodium hydroxide IN aqueous solution (77 mL, 77.0 mmol, 2.66 equiv.) was then added. Stirring continued until an homogenous solution was obtained. 2- lodopropane (5.2 mL, 50.0 mmol, 1.7 equiv.) was then added to the solution. Following this, the reaction was allowed to react at 40 °C until starting material area was <3.0 area% (co. 36 h). The reaction mixture was cooled to 5°C and 2N aqueous HC1 (45 mL, 90 mmol, 3 equiv.) was slowly added. The solid formed upon addition was then collected by filtration and washed with water (100 mL). Solid was dried until constant mass affording 7-(8-chloronaphthalen-l-yl)-2- (isopropylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3 H)-one as an off-white solid (9.6 g, 24.7 mmol, 85% yield). ,

[00245] M.p.: 225.8 -225.9 °C.

[00246] *H NMR (400 MHz, DMSO-d ₆ ) 5 12.62 (s, 1H), 7.91 (dd, J= 8.2, 1.3 Hz, 1H),

7.73 (dd, J- 8.2, 1.1 Hz, 1H), 7.58 (dd, J= 7.5, 1.3 Hz, 1H), 7.52 (t, J= 7.8 Hz, 1H), 7.44 (t, J=

7.8 Hz, 1H), 7.36 (dd, J= 7.6, 1.2 Hz, 1H), 3.96 (d, J= 17.1 Hz, 1H), 3.86 (hept, J= 6.9 Hz, 1H), 3.73 (dt, J= 17.1, 2.1 Hz, 1H), 3.45 (dd, J= 12.5, 5.5 Hz, 1H), 3.06 (ddd, J= 11.8, 10.0, 4.1 Hz, 1H), 2.72 (dt, J= 15.7, 7.3 Hz, 1H), 2.46 (d, J= 16.7 Hz, 1H), 1.43 - 1.25 (m, 6H).

[00247] ^,3 C NMR (101 MHz, DMSO-d ₆ ) 5 162.3, 158.0, 155.3, 148.5, 137.5, 130.0,

129.4, 129.0, 127.3, 126.3, 125.4, 125.1, 119.2, 115.2, 57.4, 50.1, 36.1, 23.1, 23.0, 22.2.

[00248] HUMS (ESI) calculated for C20H21CIN3OS: 386.1094 [M+H]*, Found: 386.1092.

EXAMPLE 9

Step (c’)

[00249] 7-(8-chloronaphthalen-l-yl)-2-(isopropylthio)-5,6,7,8-tetrah ydropyrido[3,4- d]pyrimidin-4(3H)-one (12 g, 31 mmol, 1.0 equiv.) was charged into a 250 mL 3-necked round bottom flask MeOH (60 mL) was then added. The reaction mixture was cooled to 0 °C and a sodium methoxide solution (7 mL, 34 mmol, 1.1 equiv., 4.5M in MeOH) was slowly added. Then sodium tungstate (1.0 g, 3.1 mmol, 0.1 equiv.) was added to the reaction mixture followed by slow addition of hydrogen peroxide (32 mL, 310 mmol, 10 equiv., 30% in water). Following this, the reaction was allowed to react at 20 °C until starting material area was <1.0 area% (co. 16 h). To the reaction mixture was added water (120 mL) and 2-MeTHF (120 mL). The mixture was cooled to 5 °C and 20% w/v aqueous acetic acid (120 mL) was added slowly. After completion of tire addition sodium carbanate was slowly added until pH = 8 (gas evolution). The aqueous phase was discarded and the organic phase was washed with brine. The organic phase was concentrated under reduced pressure and 2-MeTHF (36 mL) were added. Followed by the slow addition of heptane (120 mL) to afford after filtration and drying 7-(8-chloronaphthalen-l- yl)-2-(isopropylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyr iniidin-4(3H)-one as an off-white solid (12.5 g, 28.2 mmol, 91% yield).

[00250] M.p.: 195.5 - 195.6 °C. [00251] *H NMR (400 MHz, DMSO-4?) 6 13.66 (s, 1H), 7.92 (dd, J= 8.2, 1.3 Hz, 1H), 7.76 (dd, J= 8.3, 1.1 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.45 (t, J= 7.8 Hz, 1H), 7.39 (dd, J= 7.6, 1.2 Hz, 1H), 4.19 (d, J= 17.2 Hz, 1H), 3.99 (dt, J= 17.4, 1.8 Hz, 1H), 3.90 - 3.75 (m, J- 6.8 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.20 (ddd, J= 12.0, 10.1, 4.1 Hz, 1H), 2.97 (ddd, J= 16.7, 10.3, 6.3 Hz, 1H), 2.74 - 2.65 (m, 1H), 1.26 (d, J= 6.9 Hz, 6H).

[00252] ¹³ C NMR (101 MHz, DMSO-d ₆ ) 5 168.6, 163.7, 160.4, 148.2, 137.5, 130.1, 129.3, 129.1, 127.3, 126.4, 125.4, 125.4, 119.4, 117.8, 57.5, 51.0, 49.8, 22.8, 15.1, 15.0.

[00253] HUMS (ESI) calculated for C20H21CIN3O3S: 418.0992 [M+Hf, Foun* 418.099L

EXAMPLE 10

[00254] (^)-(l-methylpyrrolidin-2-yl)meithanol (230 mg, 2.0 mmol, 2.0 equiv.) was charged into a 20 mL vial. THF (2.4 mL) was then added. Reaction was cooled to 0 °C. Potassium tert-butoxide (450 mg, 4 mmol, 4.0 equiv.) was than added at the same temperature. 7-(8-chloronaphthalen-l-yl)-2-(isopropylsulfonyl)-5,6,7,8-te trahydropyrido[3,4-d]pyrimidin- 4(3H)-one (418 mg, 1.0 mmol, 1.0 equiv.) dissolved in THF (2.4 mL) was slowly added at 0 °C. Following this, the reaction was allowed to react at 20 °C until starting material area was <1.0 area% (ca 16 h). The reaction mixture was cooled to 0 °C and a 10 w/w% AcOH in THF (4 mL) was slowly added. Methanol (4 mL) was then added and the insoluble material was filtered off. The filtrate was concentrated to remove most solvent and ethyl acetate (10 mL) was added. Organic phase was washed with brine, dried over MgSO< and filtered-VoIatiles were removed and the crude product (400 mg) was stirred in n-heptane (8 mL) for 16 h at 20 °C. The solid product was filtered off to afford (S)7^8-chloronaphthalen-l-yl)-2-((l-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrinudin-4(3H)-o ne as an off-white solid (310 mg, 0.72 mmol, 72% yield).

[00255] M.p.: 140.9 - 141.0 °C.

[00256] ’H NMR (500 MHz, DMSO-D6 ) 5 ppm 1.51 - 1.61 (m, 1H), 1.66 (br d, J = 8.21 Hz, 2H), 1.84 - 1.94 (m, 1H), 2.14 - 2.25 (m, 1H), 2.33 (s, 3H), 2.42 (m, 1H), 2.52 - 2.60 (m, 1H), 2.62 - 2.72 (m, 1H), 2.90 - 2.98 (m, 1H), 3.01 - 3.09 (m, 1H), 3.42 - 3.48 (m, 1H), 3.63 - 3.70 (m, 1H), 3.88 (d, J = 16.97 Hz, 1H), 4.16 - 4.27 (m, 2H), 7.34 (d, J = 7.12 Hz, 1H), 7.40 - 7.46 (m, 1 H), 7.51 (t, J = 7.94 Hz, 1 H), 7.57 (dd, J = 7.39, 137 Hz, 1 H), 7.72 (d, J - 7.67 Hz, 1H), 7.90 (dd, J = 821, 1.10 Hz, 1H), 12.2 (br s, 1H).

[00257] ¹³ C NMR (126 MHz, DMSO-d ₆ ) 8 ppm 163.6, 157.8, 156.0, 148.6, 137.6, 130.0, 129.4, 129.0, 127.3, 126.4, 125.5, 125.1, 1192, 112.4, 69.6, 63.7, 57.5, 57.3, 50.4, 41.6, 28.4, 23.1, 222.

[00258] HRMS (ESI) calculated for C23H26CIN4Q2: 425.1744 [M+H] ⁺ , Found: 425.1902.

EXAMPLE 11

Step (e*) and (P)

[00259] (S)-7-(8-chloronaphthalen-l-yl)-2-((l-methylpyiTolidin-2-yl) methoxy)-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (3.0 g, 7.06 mmol, 1 equiv.), potassium phosphate tribasic (3.0 g, 14.12 mmol, 2 equiv.) and potassium phosphate dibasic (1.2 g, 7.06 mmol, 1 equiv.) were charged into a 100 mL reactor followed by MeCN (30.0 mL). Reaction was stirred at 0 °C and bis(trifluoromethanesulfonyl)aniline (4.5 g, 12.71 mmol, 1.8 equiv.) was added slowly to the reaction mixture. Following this the reaction was allowed to react at 0 °C until starting material area was <5 area% (ca. 24 h). To the same mixture was then added potassium phosphate tribasic (1.5 g, 7.06 mmol, 1 equiv.) followed by (S)-2(-piperazin-2-yl)acetonitrile dihydrochloride (g, 8.47 mmol, 1.2 equiv.). Following this, the reaction was allowed to react at 20 °C until the Inflate intermediate area was <0.5 area% (ca. 16 h). To the mixture was added 30.0 mL of water. Phase cut was performed and the organic phase was concentrated to dryness and then diluted with 9.0 mL of DMAc. Then 3.0 mL of water was added and mixture was seeded with the final crystalline product (1% w/w). The mixture was stirred for 10 h, then 9.0 mL of water was slowly added over 3 h. The slurry was stirred at r.t until the assay of the supernatant was <1 area%. The crystalline solid was then filtered, washed with 6.0 mL of water and the solid was then dried under nitrogen flow and low vacuum at T <45 °C until constant mass and KF NMT 10%. 2-((^-4-(7-(8-chloronaphthalen-l-yl)-2-((f5p-l-methylpyrroli din-2- yI)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pi perazin-2-yl)acetonitrile was obtained as an off-white solid (2.6 g, 4.94 mmol, 70% yield).

[00260] M.p.: 60.3 - 60.4 °C,

[00261] *H NMR (400 MHz, DMSO-dQ 6 ppm 1.52 - 1.73 (m, 3H), 1.84 - 1.96 (m, 1H),

2.13 (q, J = 8.67 Hz, 1H), 2.32 (d, J - 1.77 Hz, 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 (hr s, 2H), 3.42 - 3.51 (m, 1H), 3.72 (s, 1H), 3.85 (br d, J- 12.38 Hz, 1H) 4.01 (ddd,J= 10.48, 6.69, 3.28 Hz, 1H), 4.17 (br d, J = 17.43 Hz, 1H), 4.24 (dd, J = 10.74, 4.93 Hz, 1H) 7.31 (ddd, J = 7.58, 3.41, 0.88 Hz, 1H), 7.43 (t, J= 7.83 Hz, 1H), 7.52 (t, J= 7.71 Hz, 1H), 7.57 (dd, J- 7.58, 1.26 Hz, 1H), 7.72 (d, J= 8.08 Hz, 1H), 7.87 - 7.95 (m, 1H).

[00262] ¹³ C NMR (101 MHz, DMSO-d ₆ ) 5 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.

[00263] HUMS (ESI) calculated for C29H35CIN7O: 532.2592 [M+H]*, Found: 532.2706.

EXAMPLE 12

Step (g*)

[00264] Acetonitrile (1093.0 kg) was added into a 3000 L glass-lined reactor. Next, MR84916 (81.6 kg, 68.1 kg corrected by HPLC assay wt%, 128.0 mol, 1.0 equiv.) was added to tiie reactor. The mixture was concentrated at a temperature below <45 °C under reduced pressure (P <-0.06 MPa) until (204~272 L) 3-4 vol remained. Acetonitrile (268.0 kg) was then added into the mixture at a temperature below 45 °C. The mixture was concentrated at a temperature below 45 °C under reduced pressure (P <-0.06 MPa) until (204-272 L) 3-4 vol remained. The mixture was sampled to confirm moisture content was below 0.3% as judged by Karl-Fischer analysis (0.1%, actual). The mixture was cooled to a temperature between 10-25 °C (16.5 °C, actual). Acetonitrile (163.9 kg) was added into a separate 3000 L hastelloy reactor. The mixture was sampled to confirm moisture content below 0.3% (0.02%, actual). Sodium 2- fluoroacrylate (25.0 kg, 218 mol, 1.7 equiv.) was added into the hastelloy reactor under the protection of nitrogen at a temperature between 10-20 °C. It was confirmed that the sodium 2- fluoroacrylate was a finely powdered state prior to addition. The reactor wall was rinsed with acetonitrile (13.7 kg). A 50 w/w% propylphosphosphonic anhydride solution in ethyl acetate (124.7 kg, 192 mol, 1.5 equiv.) was added into the sodium 2-fluoroacrylate solution in the hastelloy reactor at a temperature between 10-20 °C under the protection of nitrogen. The mixture was stirred for not less than 2 h at a temperature between 10-20 °C. The mixture containing MR84916 in the 3000 L glass-lined reactor was slowly added into the mixture containing the 2-fluoroacrylate in the 3000 L hastelloy reactor at a temperature between 10-20 °C. The 3000 L glass-lined reactor containing MR84916 was rinsed with acetonitrile (18.2 kg) which was transferred into the Hastelloy reactor with the acrylate. The reaction proceeded at 10- 20 °C (14.5-18.0 °C), and after 1 h, the mixture was sampled for HPLC purity analysis every 1-3 h until tire area% of MR84916 / (MR84916 + MRTX849) was less than 0.4% (0.3% observed at 5 h and 1 min). At a temperature between 10-30 °C, the mixture was adjusted to a pH of 8-9 with a potassium carbonate solution (348.3 kg) which was prepared from potassium carbonate (41.6 kg) and purified water (307.2 kg). The mixture continued to stir for another 0.5 h and was then pH was retested for confinnation (pH 8, actual). The mixture was adjusted to a temperature of 25-35 °C, stirring was stopped, and the layers were allowed to settle prior to separation. The aqueous phase was removed and kept. The phase was washed with a potassium phosphate tribasic solution which was prepared from potassium phosphate tribasic (50.1 kg) and purified water (204.4 kg) at a temperature of 25-35 °C. The mixture was stirred for an additional 0.5-3 h and allowed to settle prior to separation 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, and the layers were allowed to settle prior to separation at a temperature between 25-35 °C. The organic fractions were combined, and then the combined mixture was concentrated at a temperature <45°C under reduced pressure (P <-0.06 MPa) until (136~204 L) 2-3 vol remained. Isopropanol (429.2 kg) was added into the mixture at a temperature <45 °C. The mixture was concentrated at a temperature <45 °C under reduced pressure (P <-0.06 MPa) until (136-204 L) 2-3 vol remained. Isopropanol (320.1 kg) was added into the mixture at a temperature <45 °C. The mixture was circulated through a CUNO filtration system. Then isopropanol (106.9 kg) was used to rinse the CUNO filter and added into the reactor. The mixture was concentrated at a temperature of <45 °C under reduced pressure (P <- 0.06 MPa) until 4.5-5.S vol (306~374 L) remained. The mixture was sampled to confirm that residual acetonitrile residuals were less than 1.5% (0.05%, actual). The mixture was adjusted to a temperature of 33-38 °C (35.3 °C, actual). Purified water (170.0 kg) was added into the mixture at 33-38 °C. Form 2 seed crystal (0.2 kg) was added into the mixture at a temperature between 33-38 °C. The mixture was maintained at this temperature and stirred for 2-3 h. The mixture was slowly cooled to 15-20 °C. The mixture was maintained at this temperature and stirred for 6-10 h. Purified water (170.0 kg) was added into the reactor at a temperature between 15-20 °C. The mixture was cooled to -3 to 7 °C slowly (4.8 °C, actual). The mass was stirred at -3 to 7 °C for crystallization, and after 8 h, the mixture was sampled every 3-5 h 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 with a stainless-steel centrifuge. Purified water (102.6 kg) and isopropanol (16.4 kg) were added into a 3000 L hastelloy-lined reactor, and then transferred into a stainless-steel centrifuge to rinsethe filter cake. The wet filter cake was swept with nitrogen for 6-8 h, dried in a rotary corneal dryer at T <40 °C until the moisture content was not more than 1% as judged by Karl-Fischer analysis. After completion of drying, the solid was cooled to 20-30 °C. Isopropanol (368.4 kg) was added into a 1000 L glass-lined reactor, and then the stirrer was started. The solids from the filter cake were added to the 1000 L reactor, and the mixture was heated to a temperature between 55-60 °C (57.2 °C, actual). The mixture was maintained at this temperature and stirred until the solid dissolved completely as confirmed by a visual check The mixture was then filtered into a 1000 L hastelloy reactor (Preheated to through a filtration system heated to 55-60 °C. The mixture was held at 55-60 °C. n-Heptane (80.5 kg) was added into the reactor, first passing through the filter for rinsing. The mixture was stirred for 0.5 h in the reactor. After the solid dissolved completely, the mixture was cooled to a temperature of 43-47 °C. A seed slurry was prepared by addition of isopropanol (5.5 kg) and n-heptane (1.3 kg) into a 20 L four-neck flask through a capsule filter, followed by addition of Form 2 seed crystals (MRTX849 Form 2, 0.8kg) held at a temperature between 20-25 °C. The mixture was stirred until evenly mixed, and then it was recycled through a wet mill. Prior to addition of the slurry feed to the reactor, the reactor was checked to confirm full dissolution of MRTX849 and that precipitation had not occurred. After this, the Form 2 seed slurry was added into the 1000 L Hastelloy reactor at a temperature between 43-47 °C. The mixture was stirred for 3-4 h at 43-47 °C. The mixture was then cooled to a temperature of 28-32 °C and stirred for 4-5 h at that temperature (30.6 °C, actual). After this time, the mixture was cooled to 18-22 °C and stirred for 4-5 h (20.9 °C, actual). The mixture was then cooled to -3 to 7 °C (3.5 °C, actual) with stirring. After 12 h, the supernatant of the mixture was sampled every 3- 5 h to check the assay wt% of MRTX849 in the mother liquors, and to confirm when the level was not more than 1.2% or alternatively, when the difference between samples is equal to or less than 0.2%. During the crystallization, nitrogen was bubbled intermittently through the bottom port of the reactor. On checking the mother liquors, the assay wt% of MRTX849 was found to be 1.0%. The mixture was recycled through a wet mill at -3 to 10 °C, and the batch temperature can be expected to rise by 2-3 °C during this process. The solid was sampled for particle size until the D(90) was not more than 100 pm (22 pm, actual). The mixture was maintained at -3 to 7 °C for 0.5-1 h. The mixture was then filtered with a stainless steel Nutsche filter. The reactor wall was rinsed with a mixed solvent system of n-heptane (15.9 kg) and isopropanol (74.1 kg) through a liquid material filter. Then the wet mill was rinsed with these rinsing liquors, which were transferred into the reactor and then discharged into the filter to rinse the filter cake. The above operation was repeated once more with the mixed solvent of n-heptane (15.9 kg) and isopropanol (74.2 kg). The filtration was noted to be quite slow as a result of the small particle size from wet milling. The solid in the filter was swept with nitrogen at Tjeckct=20-30 °C for 8-10 h, and then dried at Tjtd*f=35-45 °C until the isopropanol residual was not more than 6300 ppm (3488 ppm, actual) and the n-heptane residual was not more than 3500 ppm (not detected, LOD 432 ppm) as measured by GC. After drying completed, the solid was cooled to a temperature between 20-30 °C. The solid was sieved until the appearance of the product was uniform and without blocking. The operation area RH% should be not more than 50%. The product (MRTX849) was obtained as an off-white solid (51.1 kg, 50.0 kg corrected for assay wt%, 100.4 assay wt%, 64.7% yield).

[00265] M.p.: 128.3 - 128.4 °C.

[00266] ’H NMR (400 MHz, DMSO-dk) 5 ppm 1.56 - 1.77 (m, 3H), 1.96 (hr dd, J=

11.87. 7.58 Hz, 1H), 2.20 (dd, J = 8.21 , 2.40 Hz, 1H), 2.37 (d, J = 3.54 Hz, 3H), 2.72 (hr d, J = 1.77 Hz, 1H), 2.91 - 3.03 (m, 2H), 3.04 - 3.23 (m, 4H), 328 (hr dd, J= 13.77, 3.66 Hz, 1H), 333 - 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), 522 - 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 =

7.58 Hz, 1H), 7.63 (dt, J - 7.45, 1.07 Hz, 1H), 7.75 - 7.83 (m, 1H), 7.93 - 8.00 (m, 1H).

[00267] ¹³ C NMR (101 MHz, DMSO-dQ 8 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 = 266.39 Hz), 161.0 (d, J= 11.71 Hz), 162.0, 164.3, 165.9.

[00268] ¹⁹ F NMR (376 MHz, DMSO-dQ 5 ppm -106.4.

[00269] HRMS (ESI) calculated for C32H36CIFN7O2: 604.2603 [M+H] ⁺ , Found; 6042690.

Optional isolation of MRTX849 as tartrate salt:

[00270] 3.5 L of ethanol was added to a reactor charged with MRTX849 (875 g) and stirred until fully dissolved. In a separate reactor IM 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 45-50 °C and precipitate formation was slowly observed. The slurry was stirred at 45-50 °C for at least 1 h before being filtered, washed with cold ethanol, and dried in a vacuum over at 40 °C for 24 hours.

[00271] While the invention has been described in connection with specific 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 following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.