Processes and intermediates for synthesis of mrtx1133

Abstract

The present invention relates to new synthetic routes of synthesizing MRTX1133. The invention also provides intermediates used in the provided synthetic routes.

Description

PROCESSES AND INTERMEDIATES FOR SYNTHESIS OF MRTX1133FIELD OF THE INVENTION

[0001] The present invention relates to new and improved synthetic routes for synthesis of MRTX1133.BACKGROUND OF THE INVENTION

[0002] 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 Pharmcol. 13:394-401).

[0003] 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(l l):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. KRAS G12D mutation is present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal carcinoma patients, 10.1% of all rectal carcinoma patients, 4.1% of all non-small cell lung carcinoma patients and 1.7% of all small cell lung carcinoma patients (e.g., see The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8): 818-831. Dataset Version 4).

[0004] 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.

[0005] KRas G12D inhibitor compound 4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahy dro- 1 Hpyrrolizin-7 a(5H)-yl)methoxy)pyrido[4, 3 -d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (also known as MRTX1133) has the following structure:

[0006] MRTX1133 is described, for example, in Example 252 of PCT Application WO 2021 / 041671.

[0007] While WO 2021 / 041671 describes methods of making MRTX1133, there is a need in the art for new and improved synthetic routes of making MRTX1133.SUMMARY OF THE INVENTION

[0008] The present invention, in one embodiment, provides new and improved methods of making MRTX1133.

[0009] In one embodiment, the invention provides a method of synthesizing MRTX1133, comprising step (a): a) reactingBocin the presence of a base and aprotic solvent to produce a final compound of step (a) with the following structure:Boe i

[0010] In one embodiment, step (a) is carried out at a temperature from about -15 °C to about -8 °C.

[0011] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, N- Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

[0012] In one embodiment, the base is an organic base.

[0013] In one embodiment, the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0014] In another embodiment, the base is an inorganic base.

[0015] In one embodiment, the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. An inorganic base can be used with any alkali such as lithium, sodium, potassium, and cesium. In one embodiment, the inorganic base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium 2,2,6,6-tetramethylpiperidinide (LiTMP).

[0016] In one embodiment, the method further comprises step (b): b) reactingactivating agent and an organic base in an aprotic solvent to produce a final compound of step (b) with the following structure:wherein R is a leaving group.

[0017] In one embodiment, the leaving group is CF3.

[0018] The leaving group is determined by the activating agent that is used in the reaction.

[0019] In one embodiment, the activating agent comprises, but is not limited to, one or more of the following: sulfonyl halide R-SO2X (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 (triflic) anhydride and nonafluorobutanesulfonic anhydride) and organic triflate reagent R'-N-Tfz (where R1is phenyl, 5-chloro-2-pyridine, 2-pyridine).

[0020] In one embodiment, step (b) is carried out at a temperature from about -35 °C to about - 20 °C.

[0021] In one embodiment, the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0022] In one embodiment, in step (b), the activating agent is triflic anhydride.

[0023] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, di chloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-di oxane, and di ethylene glycol dimethyl.

[0024] In one embodiment, the method further comprises step (c): c) reacting the final compound of step (b) with a ligand and a palladium catalyst in an aprotic solvent to produce a final compound of step (c) with the following structure:

[0025] In one embodiment, step (c) is carried out at a temperature of between 80 °C and about 100 °C, preferably at about 90°C.

[0026] In one embodiment, the ligand is selected from the group consisting of bis(pinacolato)diboron and pinacolborane.

[0027] In one embodiment, the palladium catalyst is selected from the group consisting of palladium (II) acetate (Pd(OAc)2) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)C12).

[0028] In yet another embodiment, the step can comprise additional bases and / or other additives, including but not limited to triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine.

[0029] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-dioxane, and di ethylene glycol dimethyl.

[0030] In one embodiment, the method further comprises step (d): d) reacting the final compound of step (a) with a final compound of step (c) in the presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce a compound of the following structure:

[0031] In one embodiment, step (d) is carried out at a temperature of about 55°C to about 60°C, preferably about 60 °C.

[0032] In one embodiment, the catalyst is a palladium catalyst.

[0033] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, di chloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-di oxane, and di ethylene glycol dimethyl.

[0034] In one embodiment, the method further comprises step (e): e) reacting the final compound of step (d) with a fluoride salt, a quaternary ammonium salt and an aprotic solvent to produce a final compound of step (e) with the following structure:

[0035] In one embodiment, step (e) is carried out at a temperature from about 45 °C to about 55 °C.

[0036] In one embodiment, the fluoride salt is selected from the group consisting of ammonium fluoride, cesium fluoride, sodium fluoride and calcium fluoride.

[0037] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-dioxane, and di ethylene glycol dimethyl.

[0038] In one embodiment, the method further comprises step (f): f) reacting the final compound of step (e) with an acid, an organic base and an aprotic solvent to produce a final compound of step (f) with the following structure:

[0039] In one embodiment, step (f) is carried out at about 0°C to about 22°C, preferably 0 °C.

[0040] In one embodiment, the organic base selected from the group consisting ofDiisopropyl ethyl amine (DIPEA), triethylamine (EtsN), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0041] In one embodiment, the acid is selected from the group consisting of hydrochi orid acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, triflic acid, and methanesulfonic acid.

[0042] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-dioxane, and di ethylene glycol dimethyl.

[0043] In one embodiment, the invention provides a method of synthesizing MRTX1133, comprising the step of reactingwith an acid, an organic base and an aprotic solvent to produce MRTX1133.

[0044] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:Boe i-reactingfluoride salt, a quaternary ammonium salt and an aprotic solvent to produce:Boe-reactingwith an acid, an organic base and an aprotic solvent to produce MRTX1133.

[0045] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:-reactingfluoride salt, a quaternary ammonium salt in an aprotic solvent to produce:with an acid, an organic base in an aprotic solvent to produce MRTX1133.

[0046] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:wherein R is a leaving group, with a ligand and a palladium catalyst in an aprotic solvent to producethe presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:-reactingfluoride salt, a quaternary ammonium salt and an aprotic solvent to produce:with an acid and an organic base in an aprotic solvent to produce MRTX1133.

[0047] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:palladium catalyst in an aprotic solvent to producethe presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:-fluoride salt, a quaternary ammonium salt in an aprotic solvent to produce:with an acid, an organic base in an aprotic solvent to produce MRTX1133.

[0048] The invention also encompasses each of the above steps by themselves (i.e., an embodiment that is directed to step (a); an embodiment that is directed to step (b); an embodiment that is directed to step (c), etc.), as well to combinations of the steps (i.e., an embodiment that is directed to step (a) and step (b); an embodiment that is directed to steps (a), (b), and (c), etc).

[0049] The invention also provides a novel compound of the following structure:DETAILED DESCRIPTION OF THE INVENTION

[0050] The present invention relates to new synthetic routes for synthesizing MRTX1133, as well as to a novel intermediate used in the provided route.

[0051] Although there is a known method of synthesizing MRTX1133 (see WO 2021 / 041671), the synthesis provided by the present invention is much improved, in that it provides a higher isolated yield and a higher or similar purity overall.

[0052] Furthermore, the provided process is scalable and allows to minimize the use of silica gel column and reverse phase column purification.DEFINITIONS

[0053] 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.

[0054] As used herein, “KRas G12D” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of an aspartic acid 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.

[0055] A "KRas G12D-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.

[0056] As used herein, the term “MRTX1133” refers to the compound which has the name: 4-(4- ((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fhioro-2-(((2R,7aS)-2-fluorohexahydro- lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol) and has the following structure:

[0057] MRTX1133 is described, for example, in Example 252 of PCT Application WO 2021 / 041671.

[0058] The term “MRTX1133” encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0059] In one embodiment, the term “MRTX1133” 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 acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, andpolygalacturonic 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).

[0060] 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, as well as its tautomers, and any mixtures thereof.

[0061] “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; dihalophosphinoyloxy; tetrahalophosphaoxy; perfluoroalkanesulfonyloxys, 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.

[0062] 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.

[0063] 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.

[0064] 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 carbonatoms, alternatively 2-8 carbon atoms, and alternatively 2-6 carbon atoms. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0065] 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, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0066] 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. Eamples of alkylene groups include, without 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.

[0067] The term “carbocycle” as employed herein is intended to mean a cycloalkyl or aryl moiety.

[0068] 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, cyclopenten-2- enone, cyclopenten-2-enol, cyclohex-2-enone, cyclohex-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.

[0069] 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.

[0070] 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.

[0071] 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 un substituted. 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”.

[0072] 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 acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds 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).

[0073] As used herein, the term “mineral acid” (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 acid.

[0074] As used herein, the term “organic acid” refers to any organic compound with acidic properties. Nonlimiting examples of organic acids include sulfonic acids of the general formula RSO3H (where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl and are defineabove), carboxylic acids (with one or several carboxylic acid sites) of the general formula RCO2H (where R can be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, aryl and are define above). Nonlimiting examples of organic acids are lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.SYNTHETIC SCHEMES

[0075] The present invention, in one embodiment, provides new and improved methods of making MRTX1133.

[0076] In one embodiment, the invention provides a method of synthesizing MRTX1133, comprising step (a): a) reactingin the presence of a base and aprotic solvent to produce a final compound of step (a) with the following structure:

[0077] In one embodiment, step (a) is carried out at a temperature from about -15 °C to about -8 or

[0078] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, N- Methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and di ethylene glycol dimethyl.

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

[0080] In one embodiment, the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

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

[0082] In one embodiment, the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. An inorganic base can be used with any alkali such as lithium, sodium and potassium. In one embodiment, the inorganic base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).

[0083] In one embodiment, the method further comprises step (b): b) reactingactivating agent and an organic base in an aprotic solvent to produce a final compound of step (b) with the following structure:

[0084] In one embodiment, the leaving group is CF3.

[0085] In one embodiment, the leaving group is determined by the activating agent that is used in the reaction.

[0086] In one embodiment, the activating agent comprises, but is not limited to, one or more of the following: sulfonyl halide R-SO2X (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 (triflic) anhydride and nonafluorobutanesulfonic anhydride) and organic triflate reagent R^N-Tfz (where R1is phenyl, 5-chloro-2-pyridine, 2-pyridine).

[0087] In one embodiment, step (b) is carried out at a temperature from about -35 °C to about - 20 °C.

[0088] In one embodiment, the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), l,4-diazabicyclo[2.2.2]octane (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0089] In one embodiment, in step (b), the activating agent is triflic anhydride.

[0090] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-dioxane, and di ethylene glycol dimethyl.

[0091] In one embodiment, the method further comprises step (c): c) reacting the final compound of step (b) with a ligand and a palladium catalyst in an aprotic solvent to produce a final compound of step (c) with the following structure:

[0092] In one embodiment, step (c) is carried out at a temperature of between 80 °C and about 100 °C, preferably at about 90°C.

[0093] In one embodiment, the ligand is selected from the group consisting of bis(pinacolato)diboron and pinacolborane.

[0094] In one embodiment, the palladium catalyst is selected from the group consisting of palladium (II) acetate (Pd(OAc)2) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)C12).

[0095] In yet another embodiment, the step can comprise additional bases and / or other additives, including but not limited to triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine.

[0096] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-di oxane, and di ethylene glycol dimethyl.

[0097] In one embodiment, the method further comprises step (d): d) reacting the final compound of step (a) with a final compound of step (c) in the presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce a compound of the following structure:Boc

[0098] In one embodiment, step (d) is carried out at a temperature of about 55°C to about 60°C, preferably about 60 °C.

[0099] In one embodiment, the catalyst is a palladium catalyst.

[0100] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, NMP, DMSO, 1,4-di oxane, and di ethylene glycol dimethyl.

[0101] In one embodiment, the method further comprises step (e): e) reacting the final compound of step (d) with a fluoride salt, a quaternary ammonium salt in an aprotic solvent to produce a final compound of step (e) with the following structure:

[0102] In one embodiment, step (e) is carried out at a temperature from about 45 °C to about 55 °C.

[0103] In one embodiment, the fluoride salt is selected from the group consisting of ammonium fluoride, cesium fluoride, sodium fluoride and calcium fluoride.

[0104] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, NMP, DMSO, 1,4-di oxane, and di ethylene glycol dimethyl.

[0105] In one embodiment, the method further comprises step (f): f) reacting the final compound of step (e) with an acid, an organic base in an aprotic solvent to produce a final compound of step (f) with the following structure:

[0106] In one embodiment, step (f) is carried out at about 0°C to about 22°C, preferably 0 °C.

[0107] In one embodiment, the organic base selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), tri ethylenediamine (DABCO), and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0108] In one embodiment, the acid is selected from the group consisting of hydrochi orid acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, triflic acid, and methanesulfonic acid

[0109] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, NMP, DMSO, 1,4-di oxane, and di ethylene glycol dimethyl.

[0110] In one embodiment, the invention provides a method of synthesizing MRTX1133, comprising the step of reactingwith an acid, an organic base and an aprotic solvent to produce MRTX1133.[0011 1] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:Boe-reactingfluoride salt, a quaternary ammonium salt in an aprotic solvent to produce:with an acid, an organic base in an aprotic solvent to produce MRTX1133.

[0112] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:fluoride salt, a quaternary ammonium salt in an aprotic solvent to produce:-reacting 1with an acid, an organic base and an aprotic solvent to produce MRTX1133.

[0113] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:, wherein R is a leaving group, with a ligand and a palladium catalyst in an aprotic solventthe presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:fluoride salt a quaternary ammonium salt and an aprotic solvent to produce:with an acid, an organic base and an aprotic solvent to produce MRTX1133.

[0114] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:activating agent and an organic base in an aprotic solvent to produce:, wherein R is a leaving group;the presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:ammonium fluoride, a quaternary ammonium salt and an aprotic solvent to produce:with an acid, an organic base and an aprotic solvent to produce MRTX1133.

[0115] The invention also encompasses each of the above steps by themselves (i.e., an embodiment that is directed to step (a); an embodiment that is directed to step (b); an embodiment that is directed to step (c), etc.), as well to combinations of the steps (i.e., an embodiment that is directed to step (a) and step (b); an embodiment that is directed to steps (a), (b), and (c), etc).

[0116] The invention also provides a novel compound of the following structure:

[0117] The following Examples are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention.EXAMPLE 1Preparation of tert-butyl (lR,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lFT- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (MR113319).

[0118] THF (55 L) is charged to a reactor with ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol (MR113318, 2.86 kg, 17.96 mol, 1 eq.) and / c 7-butyl (lR,5S)-3- (2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113317, 8.1 kg, 18.91 mol, 1.05 eq.) at 10-20°C. The mixture is cooled to '15-'8°C and a solution of NaHMDS in THF (5.76 kg, 2M in THF, 1.25 eq.) was slowly added at ’15-’8°C. The batch is agitated for 4h and 20% AcOH THF solution (5.7 kg) is slowly added while maintaining the temperature at '15-'8°C to adjust pH to 6-7. The resulting suspension is stirred at 15-25°C for 30min. and concentrate to 5-6 vol. at atmosphere pressure at NMT 75 °C. The reactor is heated to 40-50 °C and MTBE (70 kg) is introduced dropwise over a period of 2 h. The reaction mass is stirred for 2h, cooled over 5 h to 5-15 °C and stirred for additional 8 h at 5-10 °C. The mixture is filtered, the cake is washed by MTBE (2x6 kg) and dried to lead / c / 7-butyl (lR,5S)-3-(7- chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113319) as solid (7.65 kg, IY: 77.2%, purity: 95.8%, KF: 0.3%).

[0119] MR113317:XH NMR (400 MHz, CDC13) 6 ppm 1.53 (s, 9H), 1.66 - 1.70 (t, 2H),1.98 - 2.02 (q, 2H), 3.74 (s, 2H), 4.44 - 4.54 (d, J=52.2, 4H), 8.8 (s, 1H). LCMS m z 428.1 [M+H]+.

[0120] MR113318:XH NMR (400 MHz, CDC13) 8 ppm 1.69 - 1.91 (m, 4H), 1.94 - 2.15(m, 2H), 2.86 - 2.92 (m, 1H), 2.95 - 3.11 (m, 2H), 3.15 - 3.18 (m, 1H), 3.25 (s, 2H), 4.25 (s, 1H), 5.09 - 5.25 (m, 1H). LCMS m / z 160.1 [M+H]+.

[0121] MR113319:XH NMR (400 MHz, CDCh) 5 ppm. 1.51 (s, 9H), 1.67 - 1.76 (t, 3H),1.84 - 1.95 (m, 5H), 2.09 - 2.31 (m, 3H), 2.94 - 3.00 (m, 1H), 3.10 - 3.27 (m, 3H), 3.64 (s, 2H), 4.12 - 4.14 (d, J=10.36, 1H), 4.22 - 4.25 (d, J=10.32, 1H), 4.36 (s, 1H), 4.45 - 4.50 (m, 2H), 5.20 - 5.34 (t, 1H), 8.71 (s, 1H). LCMS m / z 551.2 [M+H]+.EXAMPLE 27-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifl uoromethanesulfonate (MR113314)

[0122] Batch-1 : 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (MR113313, 5.3 kg, 13.17 mol, 1 eq.) is charged into the reactor followed by toluene (42 kg) and TEA (4 kg, 39.5 mol, 3 eq.). Internal temperature is adjusted to '35-'2O °C and triflic anhydride TfzO (5.6 kg, 19.85 mol, 1.5 eq.) is slowly introduced. After stirring at ’35-’2O °C for2-4 h, the reaction mass is diluted by aqueous 20% sodium chloride solution (5.5 kg) and agitated for 30-60 min. at ‘20-‘10 °C. Water (45 kg) is then charged at 15-25°C. the crude is agitated for 30-60min., then allow to stand for 60min. The layers are separated, the organic layer is washed by aqueous 5% Na2SO4 aq. solution (27 kg) and concentrate to 4-5 vol. at NMT 55°C. 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoro methane sulfonate (MR113314) is isolated as a solution in toluene (6.6 kg, assay: 34.4%, IY: 93.6%, purity: 96.6%)

[0123] Batch-2: 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen- l-ol (MR113313, 5.04 kg, 12.52 mol, 1 eq.) is charged into the reactor followed by toluene (42 kg) and TEA (4.18 kg, 41.3 mol, 3.3 eq.). Internal temperature is adjusted to ’35-’2O °C and triflic anhydride TfiO (6.5 kg, 23.04 mol, 1.8 eq.) is slowly introduced. After stirring at ’35-’20 °C for 2-4 h, the reaction mass is diluted by aqueous 20% sodium chloride solution (5.3 kg) andagitated for 30-60 min. at ’20-’10 °C. Water (40 kg) is then charged at 15-25°C. the crude is agitated for 30-60min., then allow to stand for 60min. The layers are separated, the organic layer is washed by aqueous 5% Na2SO4 aq. solution (26 kg) and concentrate to 4-5 vol. at NMT 55°C. 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoro methane sulfonate (MR113314) is isolated as a solution in toluene (6.5 kg, assay: 31.4%, IY: 98.2%, purity: 96.4%).

[0124] MR113313:JH NMR (400 MHz, CDCh-d) 8 = 9.13 (s, 1H), 7.68-7.64 (m, 1H),7.21-7.16 (m, 1H), 6.97-6.96 (m, 1H), 6.81-6.80 (m, 1H), 5.26 (s, 2H), 3.51 (s, 3H), 1.24-1.17 (m, 21H). LCMS [ESI, M+l]: 403.2.

[0125] MR113314:JH NMR (400 MHz, CDCh) 8 = 7.71-7.69 (m, 1H), 7.43 (d, J= 2.4Hz, 1H), 7.36-7.32 (m, 2H), 5.28 (s, 2H), 3.53 (s, 3H), 1.27-1.17 (m, 21H).EXAMPLE 3((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen- l-yl)ethynyl)triisopropylsilane (MR113315)

[0126] 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l-yl trifluoromethanesulfonate (MR113314, 12.2 kg, 22.8 mol, 1 eq.) toluene solution is charged into the reactor, followed by toluene (21 kg). Internal temperature is adjusted to 20-30 °C and the reactor is purged with nitrogen for 15-30 min. Pd(OAc)2 (0.27 kg, 1.2 mol, 0.05 eq.), Pl PCy (0.68 kg, 2.53 mol, 0.1 eq.), B2Pin2 (11.7 kg, 46.1 mol, 2 eq.) and KO Ac (6.8 kg, 69.3 mol, 3 eq.) are introduced. The reaction mass is stirred for Ih at 45-55°C, then 25 h at 90-95°C. After cooling to 20-30°C, aqueous 7% NaHCOs solution (39 kg) is slowly added. The crude reaction isstirred for 15min. and filtered through a pad of celite (7.3 kg). The cake is washed by toluene (3x17 kg) and the filtrate layers are separated. The organic layer is washed by twice aqueous 10% Na2SO4 aq. solution (40 kg and 38 kg), dried overNa2SC>4 (13 kg). The pad is rinsed with toluene (23 kg), the combined organic layers are poured into the reactor, followed by N-acetyl cysteine (6.8 kg) and celite (7.3 kg). The mixture is agitated for lOh at 45-55°C then cooled to 20-30°C and filtered through silica gel (6 kg 200-300 mush), the silica gel pad is rinsed twice by toluene (2x24-36 kg) and the resulting filtrate is concentrated to (12-36 L). Isopropanol (IP A, 50 kg) is added, the solution is concentrated to (12-36 L) atNMT 50°C and stirred for 2h. After a slow cooling over 4-6 h to ’10-0°C, the mixture is filtered, rinsed by isopropanol (6 kg) and dried at 45-55 °C for 20-30 h. ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)naphthalen-l-yl)ethynyl)triisopropylsilane (MR113315) is isolated (10 kg, IY: 85.5%, purity: 98.7%).

[0127] MR113315 'H NMR (400 MHz, CDCh-d) 8 = 7.69-7.65 (m, 1H), 7.51 (d, J =2.4 Hz, 1H), 7.38 (d, J= 2.4 Hz, 1H), 7.25 (t, J= 8.8 Hz, 1H), 5.28 (s, 2H), 3.50 (s, 3H), 1.44 (s, 12H), 1.18-1.16 (m, 21H); LCMS [ESI, M+l]: 513.4.EXAMPLE 4 tert-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (MR113320)

[0128] Water (35 kg) is charged into the reactor, followed by K3PO4 (8.3 kg, 39.1 mol, 3 eq.) at 20-25°C. After stirring for Ih, Ze / 7-butyl (lR,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrirnidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (MR113319, 7.1kg, 12.88 mol, 1 eq.) is introduced, followed by THF (30 kg). The reactor is purged with nitrogen for Ih then catalyst Ad2nBup-Pd- G3 (0.93 kg, 1.3 mol, 0.1 eq.). Internal temperature is adjusted to 55-60°C and a solution of ((2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-l- yl)ethynyl)triisopropylsilane (MR113315, 8.0 kg, 15.6 mol, 1.22 eq.) in THF (31 kg) is slowly added over 3h. The reaction mass is stirred for 8 h at 55-60°C. An excess of MR113315 (0.82kg, 1.6 mol) in THF (3 kg) is slowly added and the mixture is stirred for 1-3 h at 55-60°C, then cooled to 40-50°C. Toluene is charged (35 kg) and after stirring Ih at 35-40°C, the aqueous layer is decanted and the crude is concentrated to 1.5-2.5 vol. below 55°C under vacuum.Toluene (30 kg) is added and the crude is concentrated to 1.5-2.5 vol. Celite (6 kg) and N-acetyl cysteine (8.1 kg) are added, the resulting mixture is stirred at 50-55°C for 7 h and filtered at 25- 30°C. The cake is rinsed three times by toluene (13 kg, 2x31kg), the combined organic layers are poured into the reactor and followed by celite (3.5 kg) and SEM26 (3.5 kg). The reaction mass is stirred at 50-55°C for 6.5 h, cooled to 25-30°C and filtered. The cake is rinsed twice by toluene (2x14 kg), the filtrate is poured into the reactor and followed by CUNO (0.6 kg) and stirred at 25-30°C for 4 h. After filtration, CUNO is rinsed twice by toluene (2x12 kg). The organic layer is washed twice at 35-40°C with aqueous 7% NaHCCh solution (24 kg). Toluene is exchanged to IPA by charging IPA (2x31 kg) and concentrating to 1.5-2.5 vol. below 55°C under vacuum. IPA (44 kg) is added, followed by 30 g seeds of MR113320. The crude mixture is stirred for 8h at 40-45°C then diluted with water (55 kg) and stirred for an additional 3h. After cooling to 20- 25°C and stirring for 4h, the mixture is filtered. The cake is washed by n-heptane (27 kg) and transfer back into the reactor with n-heptane (28 kg). The suspension is heated for 5 h at 50- 55°C, cooled to 20-25°C for 4 h and filtered. The solid is rinsed by n-heptane (11 kg) and dried at 45-50°C for 24 h. tert-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113320) is isolated (4.56 kg, IY: 40%, purity: 98%).

[0129] MR1 13320: LCMS [ESI, M+l]: 901.4; IH NMR (400 MHz, methanol-d4) 8 8.99 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 5.7, 9.1 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.30 (t, J = 8.9 Hz, 1H), 7.22 (t, J = 2.3 Hz, 1H), 5.29-5.10 (m, 3H), 4.82 (br t, J = 11.2 Hz, 1H), 4.38-4.06 (m, 5H), 3.79 (br dd, J = 6.1, 11.9 Hz, 1H), 3.43-3.35 (m, 4H), 3.18-3.05 (m, 3H), 2.91 (dt, J = 5.6, 9.5 Hz, 1H), 2.23-2.00 (m, 3H), 1.91-1.56 (m, 7H), 1.43 (s, 9H), 0.85-0.74 (m, 18H), 0.44 (q, J = 7.5 Hz, 3H).EXAMPLE 5 tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113321)

[0130] tert-butyl (lR,5S)-3-(8-fhioro-7-(7-fhioro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-l-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113320, 4.5 kg, 5 mol, 1 eq.) and 2-Me-THF (41 kg) are charged into the reactor at 20-30°C. After stirring for Ih, aqueous solution of NHrF (6.6 kg in 8kg of water) is added followed by TBAF(0.3 kg, 0.31 mol, 0.06 eq.). The reaction mass is stirred for 20h at 45-55°C, cooled to 20- 30°C and the layers are separated. The organic layer is washed twice by aqueous 10% Na2SO4 solution (19 kg and 21kg) and concentrated to 2-3 V below 45°C. Additional 2-MeTHF (22 kg) is charged and the crude is concentrated to 2-3V below 45°C. 2-MeTHF (40 kg), SEM26 (4.5kg) are charged and the mixture is stirred for 1 Ih at 45-55°C. After cooling to 25-30°C, celite (4.6 kg) is introduced and the resulting mixture is filtered. The wet cake is rinsed twice by 2-MeTHF (2x20 kg), the filtrate is concentrated to 2-3V and the temperature is adjusted to 45-55°C. Seeds (20.2 g of MR113321) are added and the crude is stirred for 6 h at 45-55°C. n-heptane (32 kg) isintroduced dropwise over 8 h. After stirring for 4h, the mixture is cooled to 15-25°C over 8h and stirred for additional 4h. The mixture is fdtered, rinsed by n-heptane (4 kg) and the solid is dried at 40-50°C for 18-24 h. Tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113321) is obtained as a solid (3.36 kg, IY: 87.4%, purity: 98.8%).

[0131] MR113321: LCMS [ESI, M+l]: 745.3.EXAMPLE 64-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- lH-pyrrolizin-7a(5H)-yI)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fluoronaphthalen-2-ol (MRTX1133)

[0132] MTBE (24 kg) is charged in the reactor and the temperature is adjusted to 0-10°C. Sulfuric acid (6.4 kg, 65.25 mol, 15 eq.) is added dropwise and followed by tert-butyl (lR,5S)-3- (7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (MR113321, 3.1kg, 4.16 mol, 1 eq.). The crude mass is agitated for 27h at 0-10°C then filtered. The solid is rinsed by MTBE (5 kg) and charge back into the reactor containing 2-MeTHF (33 kg), aqueous 3% Na2SO4 solution (31 kg) and EtsN (8.8 kg). The resulting slurry is stirred for 30min. at 10-20°C then filtered. The solid is rinsed by 2- MeTHF (4 kg), suspended in water (30L) for 2 h at 15-25°C, filtered and dried for l-3h at 45°C. The wet cake (2.61kg) is charged back into the reactor containing DMSO (7.8 L) and the solution is stirred for l-2h at 40°C. Water (1.43 L) is slowly added and seeds of MRTX1133 areadded. The mixture is agitated for 10-15h, slowly diluted by water (22 L), stirring for 1 -2h and fdtered. The cake is washed by water (5 L) and charged back into the reactor with water (21 L). The slurry was stirred for 5h at 55°C and lOh at 15°C. The reaction mass is filtered, washed by water (2x2.6 L) and dried 40-50° C for 48 h. 4-(4-((lR,5S)-3,8-diazabicyclo [3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl) methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fhioronaphthalen-2-ol (MRTX1133) was isolated as a solid (2.157 kg, IY: 75%, purity: 97.7%).

[0133] MRTX1133 ’H NMR (400 MHz, METHANOL-d4) 8 = 9.02 (s, 1H), 7.87 (dd, J = 5.7, 9.2 Hz, 1H), 7.39-7.30 (m, 2H), 7.23 (d, J= 2.6 Hz, 1H), 5.42-5.23 (m, 1H), 4.62 (q, J= 11.9 Hz, 2H), 4.36-4.21 (m, 2H), 3.78-3.62 (m, 4H), 3.36 (dd, .7 = 0.8, 6.8 Hz, 1H), 3.31-3.14 (m, 3H), 3.03 (dt, J= 5.7, 9.4 Hz, 1H), 2.41-2.11 (m, 3H), 2.07-1.96 (m, 2H), 1.96-1.75 (m, 5H), 1.33 (s, 1H). LCMS [ESI, M+l]: 601.0..

[0134] 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:

1. A method of synthesizing MRTX1133 (4-(4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-lHpyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol), comprising step (a): a) reactingBoein the presence of a base and aprotic solvent to produce a final compound of step (a) with the following structure:Boe2. The method of claim 1, wherein step (a) is carried out at a temperature from about -15 °C to about -8 °C.

3. The method of claim 1, where in the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

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

5. The method of claim 4, wherein the the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), triethylenediamine (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

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

7. The method of claim 6, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. An inorganic base can be used with any alkali such as lithium, sodium and potassium.

8. The method of claim 6, wherein the inorganic base is selected from the group consisting of lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide (LDA), and lithium tetramethylpiperidide (LiTMP).

9. The method of claim 1, wherein the method further comprises step (b): b) reactingactivating agent and an organic base in an aprotic solvent to produce a final compound of step (b) with the following structure:, wherein R is a leaving group.

10. The method of claim 9, wherein R is CF3.

11. The method of claim 9, wherein step (b) is carried out at a temperature from about -35 °C to about -20 °C.

12. The method of claim 9, wherein the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide,acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tertbutyl ether, N-Methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and di ethylene glycol dimethyl.

13. The method of claim 9, wherein the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

14. The method of claim 9, wherein the activating agent is selected from the group consisting of sulfonyl halide R-SO2X (wherein R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl and X is F, Cl, Br, Oms, or OTs), anhydride, and organic triflate reagent R1-N-Tf2 (where R1is phenyl, 5- chloro-2-pyridine, or 2-pyridine).

15. The method of claim 13, wherein the activating agent is triflic anhydride.

16. The method of claim 1, wherein the method further comprises step (c): c) reacting the final compound of step (b) with a ligand and a palladium catalyst in an aprotic solvent to produce a final compound of step (c) with the following structure:

17. The method of claim 16, wherein step (c) is carried out at a temperature of between 80 °C and about 100 °C.

18. The method of claim 16, wherein the ligand is selected from the group consisting of bis(pinacolato)diboron and pinacolborane.

19. The method of claim 16, wherein the aprotic solvent is selected from the group consisting of of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), 1,4- dioxane, and diethylene glycol dimethyl.

20. The method of claim 16, wherein step (c) further comprises additional bases and / or other additives.

21. The method of claim 16, wherein the method further further comprises step (d): d) reacting the final compound of step (a) with the final compound of step (c) in the presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce a compound of the following structure:

22. The method of claim 21, wherein step (d) is carried out at a temperature of between 55 °C and about 60 °C.

23. The method of claim 21, wherein the catalyst is a palladium catalyst.

24. The method of claim 21, wherein the aprotic solvent is selected from the group consisting of of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, di methyl acetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), 1,4- di oxane, and di ethylene glycol dimethyl.

25. The method of claim 21, wherein the method further comprises step (e): e) reacting the final compound of step (d) with a fluoride salt, a quaternary ammonium salt and an aprotic solvent to produce a final compound of step (e) with the following structure:

26. The method of claim 25, wherein step (e) is carried out at a temperature from about 45 °C to about 55 °C.

27. The method of claim 25, wherein the aprotic solvent is selected from the group consisting of of toluene, anisole, xylene, dioxane, di chloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), 1,4- di oxane, and di ethylene glycol dimethyl.

28. The method of claim 25, wherein the fluoride salt is selected from the group consisting of ammonium fluoride, cesium fluoride, sodium fluoride and calcium fluoride.

29. The method of claim 25, wherein the method further comprises step (f): f) reacting the final compound of step (e) with an acid, an organic base and an aprotic solvent to produce a final compound of step (f) with the following structure:

30. The method of claim 29, wherein step (f) is carried out at about 0°C to about 22°C.31 . The method of claim 29, wherein the acid is selected from the group consisting of hydrochlorid acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, triflic acid, and methanesulfonic acid.

32. The method of claim 29, wherein the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), triethylenediamine (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

33. The method of claim 29, wherein the aprotic solvent is selected from the group consisting of of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, N-Methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), 1,4- di oxane, and diethylene glycol dimethyl.

34. A method of synthesizing MRTX1133, comprising the step of reactingwith an acid, an organic base and an aprotic solvent to produce MRTX1133.

35. A method of synthesizing MRTX1133 comprising:-reactingfluoride salt, a quaternary ammonium salt and an aprotic solvent to produce:with an acid, an organic base and an aprotic solvent to produce MRTX1133.

36. A method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:fluoride salt, a quaternary ammonium salt and an aprotic solvent to produce:with an acid, an organic base and an aprotic solvent to produce MRTX1133.

37. A method of synthesizing MRTX1133 comprising:-reacting, wherein R is a leaving group, with a ligand and a palladium catalyst in an aprotic solventthe presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:fluoride salt, a quaternary ammonium salt and an aprotic solvent to produce:with an acid, an organic base and an aprotic solvent to produce MRTX1 133.

38. A method of synthesizing MRTX1133 comprising:palladium catalyst in an aprotic solventthe presence of a catalyst, tripotassium phosphate and an aprotic solvent to produce:fluoride salt, a quaternary ammonium salt and an aprotic solvent to produce:with an acid, an organic base and an aprotic solvent to produce MRTX1133.

39. A compound of the following structure:

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