WO2023205074A1 - Processes and intermediates for synthesis of adagrasib - Google Patents

Processes and intermediates for synthesis of adagrasib Download PDF

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Publication number
WO2023205074A1
WO2023205074A1 PCT/US2023/018809 US2023018809W WO2023205074A1 WO 2023205074 A1 WO2023205074 A1 WO 2023205074A1 US 2023018809 W US2023018809 W US 2023018809W WO 2023205074 A1 WO2023205074 A1 WO 2023205074A1
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Prior art keywords
base
produce
reacting
polar aprotic
group
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PCT/US2023/018809
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French (fr)
Inventor
Thomas SCATTOLIN
Yonghong Gan
Cheng Chen
Chengsheng Chen
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Mirati Therapeutics, Inc.
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Publication of WO2023205074A1 publication Critical patent/WO2023205074A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to new and improved synthetic routes for synthesis of adagrasib.
  • KRas Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • GDP-bound inactive
  • GTP-bound active
  • cellular proliferation e.g., see Alamgeer et al., (2013) Current Opin Pbarmcol. 13:39*401.
  • KRas 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).
  • 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).
  • 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
  • Adagrasib is described, for example, in Example 478 of PCT Application WO 2019/099524.
  • the present invention in one embodiment, provides new and improved methods of making adagrasib.
  • the invention provides a method of synthesizing adagrasib, comprising the step of a) reacting a compound of the following structure;
  • step (a) in the presence of a base and a polar solvent to produce a final compound of step (a) with the following structure:
  • step (a) is carried out at a temperature from about 20 °C to about 120 °C.
  • 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:
  • step (b) is carried out at a temperature from about 0 °C to about 120 °C.
  • 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:
  • step (c) is carried out at a temperature from about 0 °C to about 120 °C.
  • 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.
  • step (d) is carried out at a temperature from about -20 °C to about 70 °C.
  • 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]
  • 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.
  • step (f) is carried out at a temperature from about -10 °C to about 50 °C,
  • the invention provides a method of synthesizing adagrasib, comprising
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • LG is a leaving group
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • fluoroacryiic acid or corresponding alkah or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • fluoroacrylic acid or corresponding alkali or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • the invention provides an alternative route of synthesizing adagrasib.
  • the invention provides a method of synthesizing adagrasib, comprising the step of:
  • step (a') reacting in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure:
  • step (a') is carried out at a temperature from about 0 °C to about 100 °C.
  • 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:
  • R is methyl, ethyl, isopropyl, or benzyl
  • step (b*) is carried out at a temperature from about 20 °C to about 120 °C.
  • 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.
  • step (c') is carried out at a temperature from about 0 °C to about 120 °C.
  • 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:
  • step (d*) is earned out at a temperature flora about -20 °C to about 50 °C.
  • 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.
  • step (e*) is earned out at a temperature from about -20 °C to about 70 °C.
  • 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:
  • step (f ) is carried out at a temperature from about 20 °C to about 120 °C.
  • 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.
  • step (g*) is carried out at a temperature from about -10 °C to about 50 °C.
  • the invention provides a method of synthesizing adagrasib comprising reacting
  • 2-fluoroacrylic acid or corresponding alkali or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • 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
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • 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;
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • LG is a leaving group
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • the invention provides a method of synthesizing adagrasib comprising flic steps of:
  • R is methyl, ethyl, isopropyl, or benzyl
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • step (a') 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
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • the invention provides novel intermediate compounds, such as:
  • the present invention relates to new synthetic routes for synthesizing adagrasib, as well as to novel intermediates used in the provided routes.
  • 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.
  • KRas G12C-associated disease or disorder 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.
  • 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)piperazin-2-ylJacetonitrile (also known as MRTX849) and which has fee following structure:
  • Adagrasib is described, for example, in Example 478 of PCT Application WO 2019/099524.
  • adagrasib encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.
  • 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, sul
  • 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
  • R refers to a group such as alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, carbocycle, cycloalkyl, heteroalkyl, heterocycle, aryl , aralkyl, or arylalkyl.
  • 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.
  • 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.
  • alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.
  • 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.
  • alkynyl groups include, without limitation, cthynyl, propynyl, butynyl, pentynyl, and hexynyl.
  • alkylene alkenylene
  • alkynylene alkynylene
  • 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.
  • the cycloalkyl group is fused to an aryl, heteroaryl or heterocyclic group.
  • 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.
  • 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.
  • 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.
  • the aryl group is a C6-C10aryl group, alternatively a C6aryl group.
  • aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl.
  • 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.
  • arylalkyl 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”.
  • 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.
  • inorganic acids for example, hydrochloric add, hydrobromic add, sulfuric acid, phosphoric acid, nitric acid, and the like
  • organic acids such as acetic acid, oxalic 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).
  • R is hydrogen, alkyl, or benzyl
  • Z is a counterion, including chloride, bromide, iodide, — O-alkyl, toluenesulfonate, methylsul
  • mineral add refers to any acid derived from an inorganic compound that dissociates to produce hydrogen ions (H+) in water.
  • 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.
  • organic add refers to any organic compound with acidic properties.
  • 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.
  • the invention provides a method of synthesizing adagrasib, comprising the step of: a) reacting a compound of the following structure;
  • step (a) in the presence of a base and a polar solvent to produce a final compound of step (a) with the following structure:
  • step (a) is carried out at a temperature from about 20 °C to about 120 °C.
  • 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:
  • step (b) is carried out at a temperature from about 0 °C to about 120 °C.
  • 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:
  • step (c) is carried out at a temperature from about 0 °C to about 120 °C.
  • 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.
  • step (d) is carried out at a temperature from about -20 °C to about 70 °C.
  • 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]
  • 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.
  • step (f) is carried out at a temperature from about -10 °C to about 50 °C.
  • the invention provides a method of synthesizing adagrasib, comprising
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • LG is a leaving group
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • the invention provides a method of synthesizing adagrasih, comprising the steps of:
  • fluoroacrylic acid or corresponding alkali or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • fluoroacrylic acid or corresponding alkali or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib, comprising the steps of:
  • the invention provides an alternative route of synthesizing adagrasib
  • the invention provides a method of synthesizing adagrasib, comprising the step of:
  • step (a') reacting in the presence of a base and apolar solvent to produce a final compound of step (a') with the following structure:
  • step (a') is carried out at a temperature from about 0 °C to about 100 °C.
  • 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:
  • R is methyl, ethyl, isopropyl, or benzyl.
  • step (b’) is carried out at a temperature from about 20 °C to about 120 °C.
  • 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.
  • step (c') is carried out at a temperature from about 0 °C to about 120 °C.
  • 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:
  • step (d’) is carried out at a temperature from about -20 °C to about 50 °C.
  • 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:
  • LG is a leaving group
  • step (e‘) is carried out at a temperature from about -20 °C to about 70 °C.
  • the invention provides a method of synthesizing adagrasib, further comprising step (P):
  • step (e’) 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:
  • step (P) is carried out at a temperature from about 20 °C to about 120 °C.
  • 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.
  • step (g*) is carried out at a temperature from about -10 °C to about 50 °C.
  • the invention provides a method of synthesizing adagrasib comprising reacting
  • 2-fluoroacrylic acid or corresponding alkali or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • LG is a leaving group
  • a base (5)-2-(piperazm-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • fluoroacrylic acid or corresponding alkali or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • 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
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagmsih comprising the steps of:
  • fluoroacrylic acid or corresponding alkali or metal salts
  • a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • R is methyl, ethyl, isopropyl, or benzyl
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • step (a') 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
  • LG is a leaving group
  • the invention provides a method of synthesizing adagrasib comprising the steps of:
  • 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.
  • DMAc dimethylacetamide
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • 2-MeTHF 2-methyltetrahydrofiiran
  • MeCN acetonitrile
  • DMSO dimethyl sulfoxide
  • NMP N-methylpyrrolidone
  • R-OH an alcohol with a formula R-OH, wherein R is alkyl, allyl or aryl.
  • 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.
  • the polar solvent is methanol (MeOH).
  • a base is selected from the group consisting of methoxide, ethoxide, iso-propoxidtee,rt- butoxide and tert-amylate.
  • the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iro-propoxide, Zert-butoxide and rert-amylate.
  • the base is sodium methoxide
  • the phosgene derivative is selected from the group consisting of phosgene, disphosgene, triphosgene, thiophosgene and l.P-carbonyldiimidazole.
  • the phosgene derivative comprises, but is not limited to, one or more of the following: phosgene, disphosgene, triphosgene, thiophosgene and 1 ,1 ’-carbonyldiimidazole.
  • step (b) the phosgene derivative is triphosgene.
  • the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, andNMP.
  • 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.
  • step (b) the polar aprotic solvent is 2-MeTHF.
  • the mineral acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
  • 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.
  • step (b) the mineral acid is hydrogen chloride.
  • the base in step (c), is a bulky alkoxide selected from the group consisting of iso-propoxide, tert-butoxide and rert-amylate.
  • the base in step (c), is a bulky alkoxide which comprises, but is not limited to, one or more of the following: iso-propoxide, tert-butoxide andtert- amylate.
  • step (c) the base is sodium tert-amylate ⁇
  • the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
  • 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.
  • step (c) the polar aprotic solvent is 2-MeTHF.
  • 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).
  • 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).
  • R-SOzX sulfonyl halide
  • R can be, but is not limited tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br
  • anhydride trifluoromethanesulfonic anhydride and non
  • the activating agent is bis(trifluoromethanesulfonyl)aniline.
  • the base in steps (d) and (e), is an inorganic base.
  • the inorganic base is selected fromthe group consisting of carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).
  • 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).
  • the inorganic base is used with an alkali salt selected from the group consisting of lithium, sodium, and potassium.
  • 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.
  • the base in step (d), is potassium phosphate tribasic and dibasic.
  • the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
  • 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.
  • step (d) the polar aprotic solvent is MeCN.
  • step (e) the polar aprotic solvent is MeCN.
  • 2-fluoroacrylic acid in step (f), can be used in the neutral form, free acid, or ionic form (as a metal or alkali salt).
  • 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 -tetramethylur
  • T3P® propylphosphonic an
  • the base is an organic base
  • the organic base is selected from the group consisting of
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
  • the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP,
  • 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.
  • 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.
  • 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.
  • step (a') the polar solvent is MeOH.
  • a base is selected from the group consisting of methoxide, ethoxide, iso-propoxide, tert-butoxide andtert- amylate.
  • the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iso-propoxide, /ert-butoxide and /ert-amylate.
  • the base is sodium methoxide.
  • 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.
  • R-X where R is methyl, ethyl, isopropyl, or benzyl and X is Cl, Rr, 1, alkyl sulfonate, aryl sulfonate, triflate or nonaflate
  • 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.
  • the alkylating agent is 2-iodopropane.
  • the base in step (b*), is an inorganic base*
  • fee inorganic base is selected from the group consisting of hydroxide, carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).
  • 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).
  • fee inorganic base is used wife an alkali salt selected from the group consisting of lithium, sodium, and potassium.
  • the base is sodium hydroxide.
  • the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide and urea hydrogen peroxide.
  • 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.
  • the catalyst in step (c’), is selected from the group consisting of sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogensulfete.
  • the catalyst comprises, but is not limited to, one or more of the following: sodium tungstate, phenylphosphonic acid, and methyltrioctylammonium hydrogensulfete.
  • step (c‘) the catalyst is sodium tungstate.
  • a base is selected from fee group consisting of methoxide, ethoxide, iro-propoxide, tert- butoxide and tert-amylate.
  • the base comprises, but is not limited to, one or more of the following: methoxide, ethoxide, iso-propoxide, tert-butoxide and tert-amylate.
  • the ammonium or alkali salt is selected from the group consisting of lithium, sodium, and potassium.
  • the ammonium or alkali salt comprises, but is not limited to, one or more of the following: lithium, sodium, and potassium.
  • step (c’) the base is sodium methoxide ⁇
  • 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.
  • 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.
  • the base in step (d’), is a bulky alkoxide selected fromthe group consisting of iro-propoxide, ter/-butoxide andtert- amylate.
  • the base in step (d’), is a bulky alkoxide which comprises, but is not limited to, one or more of the following: iro-propoxide, tert-butoxide and rerf-amylate.
  • step (d’) the base is potassium tert-butoxide.
  • the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1 ,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
  • 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.
  • step (d*) the polar aprotic solvent is THF.
  • 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).
  • 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).
  • R-SChX sulfonyl halide
  • R can be, but is not limited tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X can be, but is not limited to, F, Cl or Br
  • anhydride trifluoromethanesulfonic anhydride and nona
  • the activating agent in steps (e*) and/or (f ) is bis(trifluoromethanesulfonyl)aniline.
  • the base in steps (e’) and (f ), is an inorganic base.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate (including mono-, di- and tribasic phosphate).
  • 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).
  • the inorganic base is used with an alkali salt selected from the group consisting of lithium, sodium, and potassium.
  • 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.
  • the inorganic base is potassium phosphate tribasic and dibasic.
  • the polar aprotic solvent in steps (e*) and (f ), is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
  • 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.
  • the polar aprotic solvent is MeCN.
  • 2-fluoroacrylic acid in step (g*), can be used in the neutral form, free acid, or ionic form (as a metal or alkali salt).
  • the coupling agent is selected from the group consisting of T3P®, GDI, the carbodiimide (e.g. DCC, DIG, EDC.HC1), BOP, PyBOP, HBTU, HATU .
  • the base is an organic base.
  • the organic base is selected from the group consisting of DIPEA, EtaN, DABCO, and DBU.
  • the base is an inorganic base.
  • the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
  • the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.
  • 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.
  • 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%.
  • Step (f) 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.
  • P ⁇ -0.06 MPa reduced pressure
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • Acetonitrile (1093.0 kg) was added into a 3000 L glass-lined reactor.
  • MR84916 (81.6 kg, 68.1 kg corrected by HPLC assay wt%, 128.0 mol, 1.0 equiv.) was 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).
  • 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.
  • 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.
  • 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).

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Abstract

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

Description

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:
Figure imgf000003_0001
[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;
Figure imgf000004_0001
with a compound of the following structure:
Figure imgf000004_0002
in the presence of a base and a polar solvent to produce a final compound of step (a) with the following structure:
Figure imgf000004_0003
[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:
Figure imgf000005_0001
[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
Figure imgf000005_0002
base and a polar aprotic solvent to produce a final compound of step (c) with the following structure:
Figure imgf000005_0003
[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:
Figure imgf000006_0002
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:
Figure imgf000006_0001
[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
Figure imgf000007_0001
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
Figure imgf000008_0002
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:
Figure imgf000008_0001
, reacting
Figure imgf000009_0001
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
Figure imgf000009_0002
activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce:
Figure imgf000010_0001
wherein LG is a leaving group;
- reacting
Figure imgf000010_0002
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:
Figure imgf000010_0003
- reacting
Figure imgf000011_0001
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
Figure imgf000011_0002
the presence of a base and a polar aprotic solvent to produce::
Figure imgf000012_0001
g activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce:
Figure imgf000012_0002
, wherein LG is a leaving group;
'^reacting
Figure imgf000013_0001
* 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
Figure imgf000013_0002
- reacting
Figure imgf000014_0001
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
Figure imgf000014_0002
with a derivative of phosgene in the presence of an acid and a polar solvent to produce:
Figure imgf000015_0001
-reacting
Figure imgf000016_0002
with an activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce:
Figure imgf000016_0003
wherein LG is a leaving group;
- reacting
Figure imgf000016_0001
, 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:
Figure imgf000017_0001
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
Figure imgf000018_0001
in the presence of a base and a polar solvent to produce:
Figure imgf000018_0002
derivative of phosgene in the presence of an acid and a polar solvent to produce: O
Figure imgf000019_0001
Figure imgf000019_0002
-reacting
Figure imgf000020_0003
activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce:
Figure imgf000020_0002
, wherein LG is a leaving group;
- reacting
Figure imgf000020_0001
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:
Figure imgf000021_0001
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
Figure imgf000022_0001
hydrogen chloride and 2-McTHF to produce:
Figure imgf000023_0002
the presence of sodium terr-amylate and 2-MeTHF to produce:
Figure imgf000023_0001
-reacting
Figure imgf000024_0002
with bis(trifluoromcthanesulfonyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce:
Figure imgf000024_0001
phnsphate tribasic in the presence of (S)-2(-piperazin-2-yl)acetonitrile dihydrochlonde, 2- MeTHF and MeCN to produce:
*
Figure imgf000025_0001
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
Figure imgf000026_0001
in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure:
Figure imgf000026_0002
[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 (a1) 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:
Figure imgf000027_0002
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:
Figure imgf000027_0001
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:
Figure imgf000028_0001
[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:
Figure imgf000028_0002
, 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:
Figure imgf000029_0001
[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
Figure imgf000030_0002
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
Figure imgf000030_0001
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:
Figure imgf000031_0001
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:
Figure imgf000032_0001
-reacting activating agent in the presence of a base, an additive and a polar aprotic solvent to produce.
Figure imgf000032_0002
, wherein LG is a leaving group;
-reacting
Figure imgf000032_0003
with a base, (S)-
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
-
Figure imgf000033_0001
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
Figure imgf000034_0002
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:
Figure imgf000034_0001
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
Figure imgf000035_0003
, wherein LG is a leaving group;
-reacting with a base, (S)-
Figure imgf000035_0001
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000035_0002
-reactin
Figure imgf000036_0001
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,
Figure imgf000036_0002
isopropyl, or benzyl, with an oxidizing agent in the presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce:
Figure imgf000037_0001
-reacting
Figure imgf000038_0001
with an activating agent in the presence of a base, an additive and a polar aprotic solvent to produce: wherein LG is a leaving
Figure imgf000038_0002
group; reacting with a base, (S)-
Figure imgf000038_0003
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce?
-
Figure imgf000039_0001
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
Figure imgf000040_0003
with an alkylating or arylating agent and a base in the presence of a polar solvent to produce:
Figure imgf000040_0001
wherein R is methyl, ethyl, isopropyl, or benzyl;
-reacting
Figure imgf000040_0002
presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce:
Figure imgf000041_0002
wherein R is methyl, ethyl, isopropyl, or benzyl;
-reacting
Figure imgf000041_0003
yl)methanol in the presence of a base and a polar aprotic solvent to produce;:
Figure imgf000041_0001
-reacting
Figure imgf000042_0002
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
Figure imgf000042_0001
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000043_0001
-reacting
Figure imgf000043_0002
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
Figure imgf000044_0001
in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure:
Figure imgf000044_0002
alkylating or arylating agent
-reacting
Figure imgf000044_0003
and a base in the presence of a polar solvent to produce:
Figure imgf000045_0001
-reacting with fS>-(l-methylpyrrolidin-2-
Figure imgf000046_0002
yl)methanol in the presence of a base and a polar aprotic solvent to produce*
-r
Figure imgf000046_0001
g activating agent in the presence of a base, an additive and a polar aprotic solvent to produce?-
Figure imgf000047_0001
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000047_0002
-reacting
Figure imgf000048_0001
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
Figure imgf000048_0002
in the presence of MeONa and MeOH to produce:
Figure imgf000049_0001
-reacting
Figure imgf000050_0003
with sodium methoxide, sodium tungstate and hydrogen peroxide in the presence of 2 -propanol to produce:
Figure imgf000050_0001
-reacting
Figure imgf000050_0002
yl)methanol in the presence of potassium tert-butoxide and THF to produce?
Figure imgf000051_0002
-reacting
Figure imgf000051_0003
bis(trifhioromethanesulfonyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce:
Figure imgf000051_0001
-reacting with potassium
Figure imgf000052_0001
phosphate tribasic, (S)-2-(piperazin-2-yl)acetomtrile dihydrochloride and MeCN to produce:
Figure imgf000052_0002
Figure imgf000053_0002
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:
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
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)piperazin-2-ylJacetonitrile (also known as MRTX849) and which has fee following structure:
Figure imgf000057_0001
[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;
Figure imgf000061_0003
with a compound of the following structure:
Figure imgf000061_0001
in the presence of a base and a polar solvent to produce a final compound of step (a) with the following structure:
Figure imgf000061_0002
[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:
Figure imgf000062_0003
[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
Figure imgf000062_0001
the presence of a base and a polar aprotic solvent to produce a final compound of step (c) with the following structure:
Figure imgf000062_0002
[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:
Figure imgf000063_0002
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:
Figure imgf000063_0001
[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
Figure imgf000064_0001
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
Figure imgf000065_0002
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:
Figure imgf000065_0001
- reacting
Figure imgf000066_0001
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
Figure imgf000066_0002
activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce?
Figure imgf000067_0003
, wherein LG is a leaving group;
- reacting
Figure imgf000067_0002
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
Figure imgf000067_0001
- reacting
Figure imgf000068_0002
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
Figure imgf000068_0001
presence of a base and a polar aprotic solvent to produce:
Figure imgf000069_0001
activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce-
Figure imgf000069_0002
, wherein LG is a leaving group;
-reacting with a base in
Figure imgf000070_0002
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:
Figure imgf000070_0001
-reacting with 2-
Figure imgf000071_0001
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
Figure imgf000071_0002
presence of an add and a polar solvent to produce:
Figure imgf000072_0001
-reacting
Figure imgf000073_0002
activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce; wherein LG is a leaving
Figure imgf000073_0001
group;
- reacting
Figure imgf000073_0003
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:
Figure imgf000074_0001
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
Figure imgf000075_0002
in the presence of a base and a polar solvent to produce;:
Figure imgf000075_0001
with a derivative of phosgene in the presence of an acid and a polar solvent to produce:
Figure imgf000076_0001
presence of a base and a polar aprotic solvent to produce:
Figure imgf000076_0002
-reacting
Figure imgf000077_0001
activating agent in the presence of an additive, a polar aprotic solvent and a base, to produce:
Figure imgf000077_0002
, wherein LG is a leaving group;
- reacting
Figure imgf000077_0003
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:
Figure imgf000078_0001
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
Figure imgf000079_0002
in the presence of MeONa and MeOH to produce:
Figure imgf000079_0001
with triphosgene in the presence of hydrogen chloride and 2-MeTHF to produce:
Figure imgf000080_0002
presence of sodium tert-amylate and 2-MeTHF to produce:
Figure imgf000080_0001
-reacting
Figure imgf000081_0002
bis(trifluoroniethanesulfbnyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce:
Figure imgf000081_0001
phosphate tribasic in the presence of (S)-2(-piperazin-2-yl)acetonitrile dihydrochloride, 2- MeTHF and MeCN to produce:
Figure imgf000082_0001
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
Figure imgf000083_0001
in the presence of a base and apolar solvent to produce a final compound of step (a') with the following structure:
Figure imgf000083_0002
[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 (a1) 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:
Figure imgf000084_0001
, 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:
Figure imgf000084_0002
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:
Figure imgf000085_0002
[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
Figure imgf000085_0001
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:
Figure imgf000086_0001
[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
Figure imgf000087_0001
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
Figure imgf000087_0002
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:
-
Figure imgf000088_0001
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
Figure imgf000089_0002
with an activating agent inthe presence of a base, an additive and a polar aprotic solvent to produce:
Figure imgf000089_0003
, wherein LG is a leaving group;
-reacting
Figure imgf000089_0001
abase, (S)-
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000090_0001
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
Figure imgf000091_0001
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:
Figure imgf000091_0002
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
Figure imgf000092_0001
Figure imgf000093_0002
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:
Figure imgf000093_0001
-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:
Figure imgf000094_0002
-reacting
Figure imgf000094_0003
yl)methanol in the presence of a base and a polar aprotic solvent to produce:
Figure imgf000094_0001
-reacting with an
Figure imgf000095_0002
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
Figure imgf000095_0001
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000096_0001
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
Figure imgf000097_0001
and a base in the presence of apolar solvent to producer
Figure imgf000097_0002
presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce;
wherein R is methyl, ethyl, isopropyl, or
Figure imgf000098_0001
benzyl;
-reacting
Figure imgf000098_0003
yl)methanol in the presence of a base and a polar aprotic solvent to produce:
Figure imgf000098_0002
-reacting
Figure imgf000099_0002
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce;
Figure imgf000099_0001
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000100_0001
-reacting
Figure imgf000100_0002
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
Figure imgf000101_0002
in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure:
Figure imgf000101_0001
Figure imgf000101_0003
with an alkylating or arylating agent and a base in the presence of a polar solvent to produces
Figure imgf000102_0001
-reacting -
Figure imgf000103_0002
yl)methanol in the presence of a base and a polar aprotic solvent to produce: :
Figure imgf000103_0001
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
wherein LG is a leaving
Figure imgf000104_0003
group;
-reacting
Figure imgf000104_0002
with a base, (S)-
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000104_0001
-reacting
Figure imgf000105_0002
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
Figure imgf000105_0001
inthe presence of MeONa and MeOH to produce:
Figure imgf000106_0001
with 2-iodopropane and sodium hydroxide in the presence of methanol to produce:
Figure imgf000106_0002
-reacting
Figure imgf000107_0002
tungstate and hydrogen peroxide in the presence of 2 -propanol to produce;
Figure imgf000107_0001
yl)methanol in the presence of potassium tert-butoxide and THF to produce;
Figure imgf000108_0001
bis(trifluorometha]iesulfbnyl)aniline in the presence of potassium phosphate tribasic K3PO4 and potassium phosphate dibasic K2HPO4 in MeCN, to produce:
Figure imgf000108_0002
-reactihg
Figure imgf000109_0002
phosphate tribasic, (S?-2-(piperazin-2-yl)acetonitrile dihydrochloride and MeCN to produce:
Figure imgf000109_0001
-reacting
Figure imgf000110_0001
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 R1 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 Rl-N-T6 (where R1 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 R1 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)
Figure imgf000119_0001
[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] JH 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] 13C NMR (126 MHz, DMSO-d6) 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)
Figure imgf000120_0001
[00218] 7-(8-Chloronaphthalen-l-yl)-2-thioxo-2,3,5,6,7,8-hexahydropyrido[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]pyrimidin-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]
Figure imgf000121_0002
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)
Figure imgf000121_0001
[00223] 2-Chloro-7-(8-chloronaphthalen- 1 -yl)-5s6,7,8-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-d6) 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] 13C 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
Figure imgf000122_0002
EXAMPLE 4
Steps (d) and (e)
Figure imgf000122_0001
[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-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrirmdin-4-yl)piperazin-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-d6) 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] UC 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)
Figure imgf000123_0001
[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] 1H NMR (400 MHz, DMSO-d6) 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] 13C NMR (101 MHz, DMSO-d6) 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] 19F 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
Figure imgf000128_0001
[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-d6) 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] 13C 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+HJ1", Found: 344.0779,
EXAMPLE S
Step (b’)
Figure imgf000129_0001
7-(8-chloronaphthalen-l-yl)-2-thioxo-23,5,6,7,8-hexahydropyrido[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(3H)-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-d6) 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] ,3C NMR (101 MHz, DMSO-d6) 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’)
Figure imgf000130_0001
[00249] 7-(8-chloronaphthalen-l-yl)-2-(isopropylthio)-5,6,7,8-tetrahydropyrido[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]pyriniidin-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] 13C NMR (101 MHz, DMSO-d6) 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
Figure imgf000131_0001
[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-tetrahydropyrido[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)-one 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] 13C NMR (126 MHz, DMSO-d6) 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)
Figure imgf000132_0001
[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-methylpyrrolidin-2- yI)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-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] 13C NMR (101 MHz, DMSO-d6) 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*)
Figure imgf000134_0001
[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
Figure imgf000136_0001
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] 13C 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] 19F 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.

Claims

WHAT IS CLAIMED IS:
•L A method of synthesizing adagrasib, comprising the step of: a) reacting a compound of the following structure:
Figure imgf000139_0002
with a compound of the following structure:
Figure imgf000139_0001
in tiie presence of a base and a polar solvent to produce a final compound of step (a) with the following structure:
Figure imgf000139_0003
2. The method of claim 1 , wherein the base is selected from the group consisting of methoxide, ethoxide, iro-propoxide, fert-butoxide and tert-amylate.
3. The method of claim 1, wherein the base is MeONa.
4. The method of claim 1, wherein the polar solvent is selected from the group consisting of dimethylacetamide (DMAc), dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THE), 2- methyltetrahydrofuran (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.
The metiiod of claim 1, wherein the polar solvent is MeOH,
6. The method of claim 1, further comprising 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:
Figure imgf000140_0001
7. The method of claim 6, wherein the derivative of phosgene is selected from the group consisting of phosgene, disphosgene, triphosgene, thiophosgene and l.r-carbomyldiimidazole.
8. The method of claim 7, wherein the derivative of phosgene is triphosgeneu
9. The metiiod of claim 6, wherein the acid is selected from the group consisting of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric add.
10. The metiiod of claim 9, wherein the mineral acid is hydrogen chloride.
11. The method of claim 6, wherein the polar aprotic solvent is selected from the group consisting ofDMAc, DMF, 1,4-dioxane, THE, 2-MeTHF, MeCN, DMSO, and NMP.
12. The method of claim 11, wherein the polar aprotic solvent is 2-MeTHF,
13. The method of claim 6, further comprising step (c); c) reacting the final compound of step (b) with in the presence of a
Figure imgf000141_0002
base and a polar aprotic solvent to produce a final compound of step (c) with the following structure:
Figure imgf000141_0001
14. The method of claim 13, wherein the base is selected from the group consisting of iso- propoxide, tert-butoxide and tert-amylate.
15. The method of claim 14, wherein the base is tert-amylate.
16. The method of claim 13, wherein the base is sodium tert-amylate.
17. The method of claim 13, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
18. The method of claim 17, wherein the polar aprotic solvent is 2-MeTHF.
19. The method of claim 13, further comprising 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
Figure imgf000142_0001
leaving group.
20. The method of claim 19, wherein 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 triflate reagent R*-N-Tf2 (where R1 is phenyl, 5-chloro-2-pyridine, 2-pyridine).
21. The method of claim 20, wherein the activating agent is bis(trifluoromethanesulfonyl)aniline.
22. The method of claim 19, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-di oxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
23. The method of claim 19, wherein the polar aprotic solvent is MeCN,
24. The method of claim 19, wherein the base is an inorganic base.
25. The method of claim 24, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
26. The method of claim 25, wherein the inorganic base is potassium phosphate Iribasic or potassium phosphate dibasic.
27. The method of claim 19, further comprising step (e): e) reacting the final compound of step (d) with a base in file 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 a final compound of step (e) with the following structure:
Figure imgf000143_0001
28. The method of claim 27, wherein the base is an organic base.
29. The method of claim 28, wherein the organic base is selected from fixe group consisting of DIPEA, Et3N, DABCO, and DBU.
30. The method of claim 27, wherein the base is an inorganic base.
31. The method of claim 30, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
32. The method of claim 27, wherein the polar aprotic solvent is selected from the group consisting of DM Ac, DMT, 1,4-di oxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
33. The method of claim 33, wherein the polar aprotic solvent comprises MeCN.
34. The method of claim 27, further comprising 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.
35. The method of claim 34, wherein the coupling agent is selected from the group consisting of propylphosphonic anhydride (T3P®), carbonyldiirnidazole (CDI), the carbodiimide (e.g. dicyclohexylcarbodiimide (DCC), di isopropylcarbodiimide (DIC), ethyl-(Ar,.V’- dimcthylamino)propylcarbodiimide hydrochloride (EDC.HCI)), the phosphonium ((benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol- 1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)) and uranium (O-(benzotriazol- -tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-l-yl)-
Figure imgf000144_0002
Figure imgf000144_0001
36. The method of claim 34, wherein the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DCM, EtOAc, IPAc, and NMP.
37. The method of claim 34, wherein the base is an organic base.
38. 1’he method of claim 37, wherein the organic base is selected from the group consisting of DIPEA, EbN, DABCO, and DBU.
39. The method of claim 34, wherein the base is an inorganic base.
40. The method of claim 39, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
41. A method of synthesizing adagrasib, comprising
-reacting
Figure imgf000145_0002
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.
42. A method of synthesizing adagrasib, comprising the steps of:
- reacting with |
Figure imgf000145_0001
)ase 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:
- r
Figure imgf000146_0001
fluoroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in tiie presence of a solvent and, optionally, a base to produce adagrasib.
43. A method of synthesizing adagrasib, comprising the steps of:
-reacting with an
Figure imgf000147_0001
activating agent in the presence of an additive, a polar aprotic solvent and a base to produce:
Figure imgf000147_0002
wherein LG is a leaving group;
- reacting
Figure imgf000147_0003
with a base in the presence of (S)-2-(piperazm-2-yl)acetonitrilc or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:
Figure imgf000148_0001
fluoroaciylic acid (or corresponding alkali or metal salts) and a coupling agent in tire presence of a solvent and, optionally, a base to produce adagrasib.
44. A method of synthesizing adagrasib, comprising the steps of:
-reacting
Figure imgf000149_0001
the presence of a base and a polar aprotic solvent to produce:
Figure imgf000149_0002
activating agent in the presence of an additive, a polar aprotic solvent and a base to produce:
Figure imgf000150_0001
wherein LG is a leaving group;
Figure imgf000150_0003
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:
Figure imgf000150_0002
-reacting
Figure imgf000151_0002
fluoroacrylic add (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
45. A method of synthesizing adagrasib, comprising the steps of:
-reacting with a derivative of phosgene in the
Figure imgf000151_0001
presence of an acid and a polar solvent to produce:
Figure imgf000151_0003
-reacting in the
Figure imgf000152_0001
presence of a base and a polar aprotic solvent to produce:
Figure imgf000152_0002
activating agent in the presence of an additive, a polar aprotic solvent and a base to produce;
Figure imgf000153_0001
wherein LG is a leaving group;
- reacting
Figure imgf000153_0002
with a base in the presence of (S)-2(-pipcrazin-2-yl)acctonitrile or its inorganic or organic salt, and one or more of a polar aprotic solvent to produce:
Figure imgf000153_0003
- reacting with 2-
Figure imgf000154_0001
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.
46. A method of synthesizing adagrasib, comprising the steps of!
-reacting
Figure imgf000154_0002
in the presence of a base and a polar solvent to produce:
Figure imgf000154_0003
-reacting
Figure imgf000155_0002
derivative of phosgene in the presence of an acid and a polar solvent to producer
Figure imgf000155_0001
the presence of an alkali salt of an alkoxide and apolar aprotic solvent to produce:
Figure imgf000156_0001
-reacting
Figure imgf000156_0002
activating agent in the presence of an additive, a polar aprotic solvent and a base to produce:
Figure imgf000156_0003
group;
- reacting with a base in the
Figure imgf000157_0002
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:
Figure imgf000157_0001
- reacting
Figure imgf000158_0003
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.
47. A method of synthesizing adagrasib, comprising the step of: a') reacting a compound of the following structure:
Figure imgf000158_0001
with a compound of the following structure:
Figure imgf000158_0002
in the presence of a base and a polar solvent to produce a final compound of step (a') with the following structure:
Figure imgf000159_0001
48. The method of claim 47, wherein the base is an inorganic base.
49. The method of claim 48, wherein the inorganic base is selected from the group consisting of methoxide, ethoxide, fco-propoxide, tert-butoxide and tert-amylate, or ammonium or alkali salts thereof.
50. The method of claim 49, wherein the ammonium or alkali salt is selected from the group consisting of lithium, sodium, and potassium.
51. The method of claim 49, wherein the inorganic base is sodium methoxide.
52. The method of claim 47, wherein the polar solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THE, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol with a formula R-OH, wherein R is alkyl, allyl or aryl.
53. The method of claim 52, wherein the polar solvent is MeOH.
54. The method of claim 47, further comprising step (b*)t b’) reacting the final compound of step (a') 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: O
Figure imgf000160_0001
, wherein R is methyl, ethyl, isopropyl, or benzyl.
55. The method of claim 54, wherein the alkylating or arylating agent is selected from the group consisting of aryl ahlides or alkyl halides R-X (where R is methyl, ethyl, isopropyl, or benzyl and X is Cl, Br, I, alkyl sulfonate, aryl sulfonate, triflate or nonaflate), di-alkyl sulfete and carbonate.
56. The method of claim 55, wherein fee alkylating agent is 2 -iodopropane.
57. The method of claim 54, wherein the polar solvent is selected from the group consisting of DMAc, DMF, 1 ,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, NMP, and an alcohol wife a formula R-OH, wherein R is alkyl, allyl or aryl.
58. The method of claim 57, wherein fee polar solvent is MeOH.
59. The method of claim 50, wherein fee base is an inorganic base.
60. The method of claim 59, wherein fee inorganic base is selected from fee group consisting of hydroxide, carbonate, bicarbonate, and phosphate, or mmonium or alkali salts thereof.
61. The method of claim 60, wherein the ammonium or alkali salt is selected from the group consisting of lithium, sodium, and potassium.
62. The method of claim 54, further comprising step (c')f c*) reacting the final compound of step (b’) with an oxidizing agent in fee presence of a polar aprotic solvent, and, optionally, a catalyst and a base, to produce a final compound of step (c') wife the following structure:
Figure imgf000161_0001
63. The method of claim 62, wherein the oxidizing agent is selected from the group consisting of peracid, oxone, bleach, hydrogen peroxide and urea hydrogen peroxide.
64. The method of claim 63, wherein the oxidizing agent is hydrogen peroxide.
65. The method of claim 62, wherein the catalyst is selected from the group consisting of sodium tungstate, phenylpbosphonic acid, and methyltrioctylammonium hydrogensulfete.
66. The method of claim 65, wherein the catalysts is sodium tungstate.
67. The method of claim 62, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4- dioxane, THF, 2-MeTHF, MeCN, DMSO, 2-propanol and NMP.
68. The method of claim 67, wherein the polar aprotic solvent is 2-propanol.
69. The method of claim 62, wherein the base is an inorganic baset
70. The method of claim 69, wherein the inorganic base is selected from the group consisting of methoxide, ethoxide, iso-propoxide, tert-butoxide and terZ-amylate, or ammonium or alkali salts thereof.
71. The method of claim 70, wherein the ammonium or alkali salt is selected from the group consisting of lithium, sodium, and potassium.
72. The method of claim 70, wherein the base is sodium methoxide.
73. The method of claim 63, further comprising step (d’); d’) reacting the final product of step (c’) with (S)-(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:
Figure imgf000162_0001
74. The method of claim 73, wherein the base is an alkoxide selected from the group consisting of fso-propoxide, rert-butoxidc and tert- amylate, or ammonium or alkali salts thereof,
75. The method of claim 74, wherein the alkali salt is selected from the group consisting of lithium, sodium, and potassium.
76. The method of claim 74, wherein the alkoxide is potassium terr-butoxide*
77. The method of claim 73, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
78. The method of claim 77, wherein the polar aprotic solvent is THF,
79. The method of claim 73, further comprising step (o’): 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:
Figure imgf000163_0001
, wherein LG is a leaving group.
80. The method of claim 79, wherein the activating agent is selected from the group consisting of sulfonyl halide R-SOzX (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 triflate reagent R*-N-T£2 (where R1 is phenyl, 5-chloro-2-pyridine, or 2 -pyridine).
81. The method of claim 80, wherein the activating agent is bis(trifluoromethanesulfonyl)aniline.
82. The method of claim 81, wherein the base is an inorganic base.
83. The method of claim 82, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate or ammonium or alkali salts thereof.
84. The method of claim 83, wherein the inorganic base is potassium phosphate tribasic or potassium phosphate dibasic.
85. The method of claim 81, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, and NMP.
86. The method of claim 85, wherein the polar aprotic solvent is MeCN.
87. The method of claim 79, further comprising step (f ): f ) reacting the final product of step (e*) with a base, fS>)-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:
Figure imgf000164_0001
88. The method of claim 87, wherein the base is an organic base.
89. The method of claim 88, 'wherein the organic base is selected from the group consisting of DIPEA, EtsN, DABCO, and DBU.
90. The method of claim 87, wherein the base is an inorganic base.
91. The method of claim 90, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate or ammonium or alkali salts thereof.
92. The method of claim 91 , wherein the inorganic base is potassium phosphate tribasic or potassium phosphate dibasic.
93. The method of claim 87, wherein the polar aprotic solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, andNMP.
94; The method of claim 93, wherein the polar aprotic solvent is MeCN.
95. The method of claim 87, further comprising step (g’): g’) reacting the final compound of step (f ) with sodium 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.
96. The method of claim 95, wherein the coupling agent is selected from the group consisting of propylphosphonic anhydride (T3P®), carbonyldiimidazole (CDI), the carbodiimide (e.g. dicyclohexylcarbodiimide (DCQ, diisopropylcarbodiimide (DIG), ethyl-(
Figure imgf000165_0003
dimethylamino)propylcarbodiimide hydrochloride (EDC.HC1)), the phosphonium ((benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)) and uranium (O-(benzotriaz»l-
Figure imgf000165_0001
tctramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-l-yl)-
Figure imgf000165_0002
hexafluorophosphate (HATU)).
97. The method of claim 95, wherein the solvent is selected from the group consisting of DMAc, DMF, 1,4-dioxane, THF, 2-MeTHF, MeCN, DMSO, DOM, EtOAc, IP Ac, andNMP.
98. The method of claim 95, wherein the base is an organic base.
99. The method of claim 98, wherein the organic base is selected from the group consisting of DIPEA, EtsN, DABCO, and DBU.
100. The method of claim 95, wherein the base is an inorganic base.
101. The method of claim 100, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.
102. A method of synthesizing adagrasib comprising reacting
Figure imgf000166_0002
(or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
103. A method of synthesizing adagrasib comprising the steps of:
-reacting
Figure imgf000166_0001
, wherein LG is a leaving group, with a base, (S)-2-(-piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000167_0001
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.
104. A method of synthesizing adagrasib comprising the steps of:
-reacting
Figure imgf000168_0001
with an activating agent in the presence of a base, an additive and a polar aprotic solvent to produce!
Figure imgf000168_0002
, wherein LG is a leaving group;
-reacting
Figure imgf000168_0003
with a base, (S)-
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000169_0001
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.
105. A method of synthesizing adagrasib comprising the steps ofi
-reacting
Figure imgf000170_0002
, wherein R is methyl, ethyl, isopropyl, or benzyl, with $)-(l -methylpyrrolidin-2-yl)mcthanol in the presence of a base and a polar aprotic solvent to produce:
Figure imgf000170_0001
-reacting
Figure imgf000170_0003
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
Figure imgf000171_0003
wherein LG is a leaving group; S>-
Figure imgf000171_0001
2-(piperazin-2-yl)acetanitrile or its inorganic or organic salt, and a polar qnotic solvent to produce:
Figure imgf000171_0002
-reacting
Figure imgf000172_0001
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.
106. A method of synthesizing adagrasib comprising the steps of?
-reacting wherein R is methyl, ethyl,
Figure imgf000172_0002
isopropyl, or benzyl, with an oxidizing agent in the presence of a polar aprotic solvent to produce:
Figure imgf000173_0003
-reacting
Figure imgf000173_0001
l-methylpynx)lidin-2- yl)methanol in the presence of a base and a polar aprotic solvent to produce:
Q
Figure imgf000173_0002
-reacting
Figure imgf000174_0003
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
Figure imgf000174_0001
, wherein LG is a leaving group;
Figure imgf000174_0002
-reacting .■>< with a base, (iy-
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000175_0001
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.
107. A method of synthesizing adagrasib comprising the steps of:
-reacting
Figure imgf000176_0002
with a base in the presence of a polar solvent to produce; :
Figure imgf000176_0003
, wherein R is methyl, ethyl, isopropyl, or benzyl;
-reacting with an oxidizing agent in the
Figure imgf000176_0001
presence of a polar aprotic solvent to produce:
Figure imgf000177_0001
yl)methanol in the presence of a base and a polar aprotic solvent to produce:
Figure imgf000177_0002
Figure imgf000178_0001
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000179_0001
fhioroacrylic acid (or corresponding alkali or metal salts) and a coupling agent in the presence of a solvent and, optionally, a base to produce adagrasib.
108. A method of synthesizing adagrasib comprising the steps of:
-reacting
Figure imgf000180_0001
in the presence of a base and a polar solvent to produce:
Figure imgf000180_0002
with an alkylating or arylating agent with a base in the presence of a polar solvent to produce:
Figure imgf000181_0003
, wherein R is methyl, ethyl, isopropyl, or benzyl;
-reacting
Figure imgf000181_0002
with an oxidizing agent in the presence of a polar aprotic solvent to produces
Figure imgf000181_0001
-reacting
Figure imgf000182_0002
yl)methanol in the presence of a base and a polar aprotic solvent to produce:
-
Figure imgf000182_0001
activating agent in the presence of a base, an additive and a polar aprotic solvent to produce:
wherein LG is a leaving
Figure imgf000183_0001
group;
-reacting
Figure imgf000183_0002
2-(piperazin-2-yl)acetonitrile or its inorganic or organic salt, and a polar aprotic solvent to produce:
Figure imgf000183_0003
-reacting
Figure imgf000184_0002
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.
109. A compound selected from the group consisting of:
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
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