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 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(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. 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-fluorotetrahydro-lH-pyrrolizin-7a(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 (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) reactingtriisopropyl silyl chloride (TIPSC1) and a base in an aprotic solvent to produce a final compound of step (a) with the following structure:

[0010] In one embodiment, step (a) is carried out at a temperature from about 0 °C to about 25 °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, di ethylene glycol dimethyl ether, dimethylformamide (DMF), 1,4-dioxane, dimethyl sulfoxide (DMSO), and N-Methyl-2-pyrrolidone (NMP).

[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), tri ethylenediamine (DABCO), and 1,8- 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 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).

[0016] In one embodiment, the method further comprises step (b):b) reactingactivating agent and a 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] In one embodiment, 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 of about 0°C.

[0021] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

[0022] In one embodiment, the base is an inorganic base.

[0023] In another embodiment, the base is an organic base.

[0024] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0025] 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).

[0026] In one embodiment, in step (b), the activating agent is triflic anhydride.

[0027] 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:

[0028] In one embodiment, step (c) is carried out at a temperature of between about 75 °C and about 80°C.

[0029] In one embodiment, the ligand is selected from the group consisting of bis(pinacolato)diboron and pinacolborane.

[0030] 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)Cb).

[0031] In yet another embodiment, the step can comprise additional bases and other additives, including but not limited to triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine.

[0032] 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, di ethylene glycol dimethyl ether, DMF, 1,4-dioxane, DMSO, and NMP.

[0033] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

[0034] In one embodiment, the method further comprises step (d):the presence of a base and aprotic solvent to produce a final compound of step (d) with the following structure:Boe

[0035] In one embodiment, step (d) is carried out at a temperature from about -15 °C to about 12 °C.

[0036] 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, di ethylene glycol dimethyl ether, , DMF, 1,4-di oxane, DMSO, and NMP .

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

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

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

[0040] In one embodiment, the inorganic base is selected from the group consisting of 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 LiHMDS, NaHMDS, KHMDS, LDA, and LiTMP.

[0041] In one embodiment, the method further comprises step (e): e) reacting the final compound of step (d) with the final compound of step (c) in the presence of a palladium catalyst, tris potassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)-hydrochloride, and an aprotic solvent to produce a compound of the following structure:

[0042] In one embodiment, step (e) is carried out at a temperature from about 60 °C to about 80 °C.

[0043] 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, di ethylene glycol dimethyl ether, DMF, 1,4-dioxane, DMSO, and NMP.

[0044] In one embodiment, the method further comprises step (f):f) reacting the final compound of step (e) with a fluoride salt in an aprotic solvent to produce a final compound of step (f) with the following structure:

[0045] In one embodiment, step (f) is carried out at a temperature from about 25 °C to about 45 °C.

[0046] In one embodiment, the fluoride salt is selected from the group consisting of ammonium fluoride, cesium fluoride, sodium fluoride and calcium fluoride.

[0047] 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, di ethylene glycol dimethyl ether, DMF, 1,4-dioxane, DMSO, and NMP.

[0048] In one embodiment, the method further comprises step (g): g) reacting the final compound of step (f) with boron trifluoride acetonitrile in an aprotic solvent to produce a final compound of step (g) with the following structure:

[0049] In one embodiment, step (g) is carried out at a temperature from about 25 °C to about 45 or

[0050] 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, diethylene glycol dimethyl ether, DMF, 1 ,4-dioxane, DMSO, and NMP.

[0051] In one embodiment, the invention provides a method of synthesizing MRTX1133, comprising reactingwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0052] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:-reactingwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0053] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:with boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0054] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:Boc iwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0055] 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 produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:Boc-reactingwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0056] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:-reactingactivating agent, an organic base in an aprotic solvent to produce:, wherein R is a leaving group;-reacting, wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:BocBocwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0057] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:triisopropyl silyl chloride (TIPSC1), a base, in an aprotic solvent to produce:p , g g p-reacting, wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:with boron trifluoride acetonitrile and an aprotic solvent to produce MRTX1133

[0058] 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),

[0059] The invention also provides a method of synthesizing MRTX1133 comprising,-a first reaction, whereinreacted in a vessel with triisopropyl silyl chloride (TIPSC1), a base in an aprotic solvent to produce:-a second reaction, wherein an activating agent, an aprotic solvent and an organic base are addedwherein R is a leaving group.

[0060] The invention also provides novel compounds of the following structures:DETAILED DESCRIPTION OF THE INVENTION

[0061] The present invention relates to new synthetic routes for synthesizing MRTX1133, as well as to a novel intermediate used in the provided route.

[0062] 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.

[0063] The new method provided in this application was found to be more efficient, affording overall yield of 29% over 6 steps, which is significantly netter than prior art methods.DEFINITIONS

[0064] 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.

[0065] 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.Gly 12Cys.

[0066] 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.

[0067] 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-fluoro-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:

[0068] MRTX1133 is described, for example, in Example 252 of PCT Application WO 2021 / 041671.

[0069] The term “MRTX1133” encompasses all chiral (enantiomeric and diastereomeric) and racemic forms of the compound.

[0070] 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, sulfuricacid, 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, 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).

[0071] 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.

[0072] “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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] The term “carbocycle” as employed herein is intended to mean a cycloalkyl or aryl moiety.

[0079] 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.

[0080] 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. 1

[0081] 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.

[0082] 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”.

[0083] 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, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0084] 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.

[0085] 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 define above), 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

[0086] The present invention, in one embodiment, provides new and improved methods of making MRTX1133.

[0087] In one embodiment, the invention provides 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) reactingtriisopropyl silyl chloride (TIPSC1) and a base in an aprotic solvent to produce a final compound of step (a) with the following structure:

[0088] In one embodiment, step (a) is carried out at a temperature from about 0 °C to about 25 °C.

[0089] In one embodiment, the aprotic solvent is selected from the group consisting of toluene, anisole, xylene, dioxane, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, and diethylene glycol dimethyl, diethylene glycol dimethyl, DMF, 1,4-dioxane, DMSO, and NMP .

[0090] In one embodiment, the base is an organic base.

[0091] In one embodiment, the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), tri ethylenediamine (DABCO), and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0092] In another embodiment, the base is an inorganic base.

[0093] 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).

[0094] In one embodiment, the method further comprises step (b):b) reactingactivating agent and a base in an aprotic solvent to produce a final compound of step (b) with the following structure:wherein R is a leaving group.

[0095] In one embodiment, the leaving group is CF3.

[0096] In one embodiment, the leaving group is determined by the activating agent that is used in the reaction.

[0097] 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).

[0098] In one embodiment, in step (b), the activating agent is triflic anhydride.

[0099] In one embodiment, step (b) is carried out at a temperature of about 0°C.

[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 tert-butyl ether, and diethylene glycol dimethyl, diethylene glycol dimethyl, DMF, 1,4-dioxane, DMSO, and NMP.

[0101] In one embodiment, the base is an inorganic base.

[0102] In another embodiment, the base is an organic base.

[0103] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et?N, DABCO, and DBU.

[0104] 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:

[0105] In one embodiment, step (c) is carried out at a temperature of between about 75 °C and about 80°C.

[0106] In one embodiment, the ligand is selected from the group consisting of bis(pinacolato)diboron and pinacolborane.

[0107] 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).

[0108] In yet another embodiment, the step can comprise additional bases and other additives, including but not limited to triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine.

[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, di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

[0110] In one embodiment, the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.[0011 1] In one embodiment, the method further comprises step (d):the presence of a base and aprotic solvent to produce a final compound of step (d) with the following structure:Boe

[0112] In one embodiment, step (d) is carried out at a temperature from about -15 °C to about 12 °C.

[0113] 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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

[0114] In one embodiment, the base is an organic base.

[0115] In one embodiment, the organic base is selected from the group consisting ofDIPEA, Et3N, DABCO, and DBU.

[0116] In another embodiment, the base is an inorganic base.

[0117] 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 aslithium, sodium and potassium. In one embodiment, the inorganic base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS, LDA, and LiTMP.

[0118] In one embodiment, the method further comprises step (e): e) reacting the final compound of step (d) with the final compound of step (c) in the presence of a palladium catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)-hydrochloride, and an aprotic solvent to produce a compound of the following structure:

[0119] In one embodiment, step (e) is carried out at a temperature from about 60 °C to about 80 °C.

[0120] 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, di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

[0121] In one embodiment, the method further comprises step (f): f) reacting the final compound of step (e) with a fluoride salt in an aprotic solvent to produce a final compound of step (f) with the following structure:

[0122] In one embodiment, step (f) is carried out at a temperature from about 25 °C to about 55 °C.

[0123] In one embodiment, the fluoride salt is selected from the group consisting of ammonium fluoride, cesium fluoride, sodium fluoride and calcium fluoride.

[0124] 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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

[0125] In one embodiment, the method further comprises step (g): g) reacting the final compound of step (f) with boron trifluoride acetonitrile and an aprotic solvent to produce a final compound of step (g) with the following structure:

[0126] In one embodiment, step (g) is carried out at a temperature from about 25 °C to about 45 °C.

[0127] 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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

[0128] In one embodiment, the invention provides a method of synthesizing MRTX1133, comprising reactingwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0129] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:Boe-reactingwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0130] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:Boewith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0131] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:BocBoewith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0132] 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 produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:-reactingBoc iwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0133] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:-reactingactivating agent, an organic base in an aprotic solvent to produce:, wherein R is a leaving group;-reacting, wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:with boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

[0134] In one embodiment, the invention provides a method of synthesizing MRTX1133 comprising:-reactingtriisopropylsilyl chloride (TIPSC1), a base, in an aprotic solvent to produce:activating agent, an organic base in an aprotic solvent to produce:, wherein R is a leaving group;-reacting, wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:with boron trifluoride acetonitrile and an aprotic solvent to produce MRTX1133

[0135] 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),

[0136] The invention also provides a method of synthesizing MRTX1133 comprising,-a first reaction, whereinreacted in a vessel with triisopropyl silyl chloride (TIPSC1), a basein an aprotic solvent to produce:-a second reaction, wherein an activating agent, an aprotic solvent and an organic base are addedwherein R is a leaving group.

[0137]

[0138] The invention also provides novel compounds of the following structures:

[0140] 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 1APreparation of 7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen- 1-yl trifluoromethane sulfonate (MR113341) (2kg scale)

[0141] Dichloromethane (68.7 L) is charged to a reactor with 7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (MR113312, 6.9 kg, 19.25 mol, 1 eq.) at 20- 25°C. To the vessel is added Triisopropylsilyl chloride (4.49 kg, 23.29 mol, 1.20 eq.) at 0-5°C followed by slow addition of A(A-Diisopropylethylamine (DIPEA, 4.95 kg, 38.30 mol, 2 eq.) at 0-5°C . The batch is agitated at 15-20°C for 12h. The reaction mass is cooled to 0-5°C then diluted with purified water (13.8 L) at 15-25°C and stirred for 10-30 minutes. The phases are separated, the organic phase is washed with purified water (2x27.6 L), aqueous 20% sodium chloride (19.9 L) and filtered thru sodium sulfate (5.93 kg). The cake is rinsed by DCM (6.9 L) and the filtrate containing 7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-l-ol (MR113340) is charged in the reactor.A, A-Di isopropyl ethyl amine (DIPEA, 7.45 kg, 57.64 mol, 3 eq.) is charged at '5-5°C followed by triflic anhydride (8.14 kg, 28.85 mol, 1.5 eq.) at ’5-5°C. The batch is agitated at 0-5°C for Ih, the reaction mass is then diluted with purified water (13.8 L) at 0-5°C. The phases are separated, the organic phase is washed with purified water (19.9 L) at 15-25°C and aqueous 20% sodium chloride (19.0 L). The organic solvent is removed and the reactor is charged with heptane (104 L) and methanol (69 L). After stirring for 10-30min. at 15-25°C, the heptane layer is collected and washed with methanol (34.5 L). The combined methanol layers are extracted back by heptane (34.5 L). The combined heptane layers are washed by water (19.9 L), aqueous 20% sodium chloride (19.0 L) at 15-25°C and dried over MgSC (5.93 kg) . The solvent is partially removed and the desired material 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl) oxy)naphthalen-l-yl trifluoromethane sulfonate (MR113341) is isolated as a solution in heptane (30.35 kg, assay: 33.6%, IY: 81.9%, purity 97.8%, KF:0.02%).

[0142] MR113312:XH NMR (400 MHz, CDCh) 8 ppm 1.19 - 1.21 (d, J=5.04, 21H),5.13 (s, IH), 6.68 - 6.69 (d, J=2.12, IH), 6.7527 - 6.7587 (d, J=2.4, IH), 7.16 - 7.20 (t, IH), 7.58 - 7.62 (m, IH), 9.19 (s, IH). LCMS m / z 359.1 [M+H]+.

[0143] MR113341: 'H NMR (400 MHz, CDC13) 5 ppm 1.13 - 1.37 (m, 42H), 7.24 -7.54 (m, 3H), 7.64 - 7.68 (q, IH).EXAMPLE IBPreparation of 7-fluoro-8-((triisopropylsiIyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen- 1-yl trifluoromethane sulfonate (MR113341) (12kg scale)

[0144] Dichloromethane (376.10 L) is charged to a reactor with 7-fluoro-8- ((triisopropylsilyl)ethynyl)naphthalene-l,3-diol (MR113312, 37.79 kg, 105.40 mol, leq.) at 20- 25°C. To the vessel is added Triisopropylsilyl chloride (24.55 kg, 126.48 mol, 1.2 eq.) at 0-5°C followed by slow addition of A,A-Diisopropylethylamine (DIPEA, 27.20 kg, 210.80 mol, 2 eq.) at 0-5°C . The batch is agitated at 15-20°C for 12h. The reaction mass is cooled to 0-5°C then diluted with purified water (75.5 L) at 15-25°C. The phases are separated, the organic phase is washed with purified water (2x109.7 kg) and brine (2x108.7 kg) at 10-25°C and filtered thru magnesium sulfate (16.23 kg). The cake is washed by DCM (280.0 L) and the filtrate containing 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-ol (MR113340) is cooled to 0-5°C. A,A-Diisopropylethylamine (DIPEA, 40.80 kg, 316.20 mol, 3 eq.) is charged at ’5-0°C and followed by triflic anhydride (44.60 kg, 158.10 mol, 1.5 eq.) at ’5-5°C. The batch is agitated at 0-5°C for Ih, the reaction mass is then diluted with purified water (75.5 k g) at ’5-5°C. The phases are separated, the organic phase is washed with purified water (108.72 kg) at 10- 25°C. The solvent is removed and the reactor is charged with heptane (569.03 L) and methanol (377.5 L). After stirring for 10-30min. atlO-25°C, the heptane layer is collected and washed with methanol (188.77 L). The combined methanol layers are washed back by heptane (188.77 L). The combined heptane layers are washed by water (109.48 kg). The solvent is partially removed and the desired material 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)naphthalen-l-yl trifluoromethane sulfonate (MR113341) is isolated as a solution in heptane (147.7 kg, assay: 39.3%, IY: 85.13%, purity 97.8%, KF:0.04%).

[0145] MR113312: 'H NMR (400 MHz, CDCh) 5 ppm 1.19 - 1.21 (d, J=5.04, 21H),5.13 (s, 1H), 6.68 - 6.69 (d, J=2.12, 1H), 6.7527 - 6.7587 (d, J=2.4, 1H), 7.16 - 7.20 (t, 1H), 7.58 - 7.62 (m, 1H), 9.19 (s, 1H). LCMS m / z 359.1 [M+H]+.

[0146] MR113341:XH NMR (400 MHz, CDCh) 8 ppm 1.13 - 1.37 (m, 42H), 7.24 -7.54 (m, 3H), 7.64 - 7.68 (q, 1H).EXAMPLE 2APreparation of ((6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (MR113342) (2 kg scale)

[0147] A solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-l-yl trifluoromethane sulfonate (MR113341) in heptane (30.35 kg, assay: 33.6%, 15.77 mol, 1 eq.), is added to a reactor and the solvent is distilled off under reduced vacuum. Acetonitrile (40.29 kg) is added in the reactor, followed by triethylamine (TEA, 4.79 kg, 47.34 mol, 3 eq.). After stirring for 30 min. at 15-25°C, the catalyst Pd(dppf)Ch (0.347 kg, 0.47 mol, 0.03 eq.) andHBpin (4.08 kg, 31.88 mol, 2 eq.) are added. The resulting mixture is heated to 75-80°C and stirred for 7h. The crude material is cooled to 5-15°C, stirred for 2h, filtered and the cake is rinsed with acetonitrile (20.4 kg). The cake is charged into second reactor followed by acetonitrile (20.4L) and stirred at 15-25°C for 2h. The crude material is filtered, the solid is rinsed with acetonitrile (20.4 L) and dried to afford the desired material ((6- fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (MR113342) as yellow solid (8.35 kg, IY: 84.8%, purity 99.2%,KF: 0.06%).

[0148] MR113342:'H NMR (400 MHz, CDCh) 8 ppm 1.13 - 1.18 (m, 39H), 1.29 - 1.34(m, 3H), 1.44 (s, 12H), 7.18 - 7.23 (m, 2H), 7.4402 - 7.4465 (d, J=2.5, 1H), 7.59 - 7.63 (q, 1H). LCMS m,'z 543.3 [Boric Acid +H]+. m / z 625.4 [M+H]+.EXAMPLE 2BPreparation of ((6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (MR113342) (12 kg scale)

[0149] A solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)naphthalen-l-yl trifluoromethane sulfonate (MR113341) in heptane(147.7 kg, assay: 39.3%, 89.93 mol, 1 eq ), is added to a reactor and the solvent is distilled off under reduced vacuum. Acetonitrile (60.9 kg) is added in the reactor, the solvent is distilled off under reduced vacuum. The resulting mass is diluted by acetonitrile (229.4 kg) followed by triethylamine (TEA, 27.30 kg, 269.79 mol, 3 eq.) at 15-25°C. After stirring for 30 min. at 15- 25°C, the catalyst Pd(dppf)Ch (1.97 kg, 2.69 mol, 0.03 eq.) andHBpin (23.20 kg, 179.86 mol, 2 eq.) are added. The resulting mixture is heated to 75-80°C and stirred for 12h. The crude material is cooled to 5-15°C, stirred for 6-12h, filtered and the cake is washed with acetonitrile (91.80 kg). The solid (62.60 kg) is charged back into the reactor followed by acetonitrile (183.2 kg, 4 vol) and stirred at 75-80 °C for 2h. The crude material is cooled to 5-15°C, stirred for additional 6- 12h and filtered. The solid is rinsed with acetonitrile (91.80 kg) and dried to afford the desired material ((6-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)ethynyl)naphthalen-2-yl)oxy)triisopropylsilane (MR113342) as solid (46.91 kg, IY: 83.67%, purity 98.9%, KF:0.09%).

[0150] MR1 13342= *H NMR (400 MHz, CDCh) 5 ppm 1.13 - 1.18 (m, 39H), 1.29 - 1.34 (m, 3H), 1.44 (s, 12H), 7.18 - 7.23 (m, 2H), 7.4402 - 7.4465 (d, J=2.5, 1H), 7.59 - 7.63 (q, 1H). LCMS m,z 543.3 [Boric Acid +H]+. m / z 625.4 [M+H]+.EXAMPLE 3APreparation of tert-butyl (lR,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yI)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (MR113319) (2 kg scale)

[0151] THF (48 L) is charged to a reactor with ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol (MR113318, 1.78 kg, 11.18 mol, 1 eq.) and ter / -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, 4.81 kg, 11.21 mol, 1 eq.) at 10-20°C. The mixture is cooled to '15-'5°C and a solution of NaHMDS in THF (5.76 kg, 2M in THF, 1.2 eq.) is slowly added at ’15-’5°C . The batch is agitated for 2h at 5-12°C. The reaction mass is then added to an aqueous 20% ammonium chloride (9.60 kg) at '5-0°C and the organic solvent is removed via distillation under vacuum at 30-35°C. Dichloromethane (48 L) is charged in the reactor at 15-25°C. After stirring for 30 min., the phases are separated and the organic phase is collected. The aqueous layer is extracted with DCM (48 L) and the combined organic layers are washed with purified water (19.2 L) and dried over MgSO4 (1.92 kg). The cake is rinsed with DCM (14.4 L) at 15-25 °C. The organic solvent is removed via distillation under vacuum at <35°C to afford crude material (6 kg). Acetonitrile (45.8 L) is charged in the reactor, the reaction mass is heated to 75-80°C and agitated for 2h, then cooled to 15-25°C. The mixture is filtered, the solid is rinsed by acetonitrile (4.8 L) and dried to lead 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]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (MR113319) as solid (3.23 kg, IY: 52.3%, purity: 96.6%, KF: 0.1%).

[0152] MR113317:XH NMR (400 MHz, CDC13) 3 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]+.

[0153] 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]+.

[0154] MR113319:XH NMR (400 MHz, CDCh) 8 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 3BPreparation of tert-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[3.2.1Joctane-8- carboxylate (MR113319) (12 kg scale)

[0155] THF (240.70 kg) is charged to a reactor with ((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methanol (MR113318, 9 kg, 56.04 mol, 1 eq.) and / c77-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, 24 kg, 56.04 mol, 1 eq.) at 10-20°C. The mixture is cooled to '15-'5°C and a solution of NaHMDS in THF (30.21 kg, 2M in THF, 1.2 eq.) was slowly added. The batch is agitated for 2h at 5-12°C. The reaction mass is then added to an aqueous solution of ammonium chloride (288 kg, 20%) at '5-0°C and the organic solvent is removed via distillation undervacuum at 30-35°C. Dichloromethane (240 L) is charged in the reactor at 15-25°C; the phases are separated and the organic phase is collected. The aqueous layer is extracted with DCM (240.6 L) and the combined organic layers are washed with purified water (96 L). The organic solvent is removed via distillation under vacuum at <35°C and acetonitrile (149.6 kg) is charged in the reactor. Half of the volume of acetonitrile is distilled and the reaction mass is agitated for 2-3h at 75-80°C. The suspension is filtered at 15-20°C and the solid is rinsed by acetonitrile (19.96 kg). The cake (54.63 kg) is charged back into the reactor and acetonitrile (57.2 kg, 1 vol ) is added. After stirring for 4-5h at 15-25 °C; the solid is filtered, rinsed by acetonitrile (19.96 kg) and dried to lead tert-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 (23.03 kg, IY: 74.58%, purity: 98.9%).

[0156] MR113317:XH NMR (400 MHz, CDC13) 8 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]+

[0157] MR113318:JH 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]+.

[0158] MR113319:XH NMR (400 MHz, CDCh) 8 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 z 551.2 [M+H]1.EXAMPLE 4APreparation of tert-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)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 (MR113343) (2kg scale)

[0159] Batch-1. THF (10.53 kg) is charged to a reactor with tert-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, 3.2 kg, 5.81 mol, 1 eq.), ((6-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (MR113342, 4 kg, 6.40 mol, 1.2 eq.) and an aqueous solution of potassium phosphate (1.86 kg, 1.7M, 8.76 mol, 3 eq.) at 15-25 °C. Catalyst ataCXium A Pd G3 (0.64 kg, 0.88 mol) is added, the reaction mass is heated to 58-63°C and agitated for 6-10h. After cooling to 15- 30°C, n-heptane (2.4 L) is charged in the reactor and the layers are separated. The aqueous layer is extracted twice by n-heptane / THF (1 / 4, 2x4.8 L). The combined organic layers are washed by water (4.96 L) and aqueous 20% sodium chloride solution (4 L) at 15-25°C.

[0160] Batch-2. THF (10.53 kg L) is charged to a reactor with tert-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, 1.6 kg, 2.9 mol, 1 eq.), ((6-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (MR113342, 2 kg, 3.2 mol, 1.1 eq.) and an aqueous solution of potassium phosphate (1.86 kg, 1.7M, 8.76 mol, 3 eq.) at 15-25°C. The catalyst ataCXium A Pd G3 (0.32 kg, 0.44 mol, 0.15 eq.) is added, the reaction mass is heated to 58-63°C and agitated for 6-10h. After cooling to 15-30°C n-heptane (2.4 L) is added in the reactor and the layers are separated. The aqueous layer is extracted twice by n-heptane / THF (1 / 4, 2x4.8 L). The combined organic layers are washed by water (4.96 L) and aqueous 20% sodium chloride solution (4 L) at 15-25°C.

[0161] The combined organic layers (batch- 1 and batch-2) are concentrated and the residue is suspended in methanol / n-heptane (1 / 2, 9.6 L) at 30-40°C. After cooling to 0-5°C the reaction mass is stirred for additional 12h. The solid is filtered and the cake is rinsed by n-heptane (2x3.2 L).The solid is charged back into the reactor followed by toluene (44 L), 16.5 wt% Ethanethiol, 2-(dimethylamino)-, hydrochloride (0.53 Kg) and 33wt % silica gel (1 .06 Kg, 200 - 300 mesh) at 1 -25 °C. The mixture is heated to 48-53°C and agitated for 4h. After cooling the reaction mass to 15-25°C, the mixture is fdtered and the waste cake is rinsed by toluene (46.6 L). To the fdtrate is added 16.5 wt% Ethanethiol, 2-(dimethylamino)-hydrochloride (0.53 Kg) and 33wt % silica gel (1.06 Kg, 200 - 300 mesh) at 15-25 °C. The mixture is heated to 48-53°C and stirred for 4h. After cooling the reaction mass to 15-25°C, the mixture is filtered and the waste cake is rinsed by toluene (5.5 L). The filtrate is washed by water (5.3 L) followed by aqueous 10% sodium chloride solution (16 L). The organic solvent is removed and methanol (14 L) is added at 45°C. Methanol is partially reduced to 10 L, the reaction mass stirred at 0-5°C for 5h. The solid is filtered and dried to afford the desired material / c / 7-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3- ((triisopropylsilyl)oxy)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 (MR113343) as a light brown solid (4.44kg, IY: 75.4%, purity: 97.1%, KF:0.2%).

[0162] MR113343: 'H NMR (400 MHz, CDCh) 5 ppm 0.50 - 0.57 (m, 3H), 0.86 - 0.90 (t, 20H), 1.12 - 1.14 (d, J=7.4, 20H), 1.27 - 1.36 (m, 5H), 1.64 (s, 6H), 2.20 - 2.33 (q, 4H), 3.02 (s, 1H), 3.21 - 3.42 (t, 4H), 3.83 (s, 1H), 4.16 - 4.39 (q, 6H), 4.85 - 4.87 (d, J=9.56, 1H ), 5.24 - 5.37 (d, J=53.4, 1H), 7.22 - 7.32 (m, 5H), 7.72 - 7.75 (q, 1H), 9.06 (s, 1H). LCMS m z 1013.5 [M+H]+.EXAMPLE 4BPreparation of tert-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)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 (MR113343) (12kg scale)

[0163] Batch-1 . THF (85 L) is charged to a reactor with ter / -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, 11.50 kg, 20.87 mol, 1 eq.), ((6-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (MR113342, 16.96 kg, 25.04 mol, 1.2 eq.) and potassium carbonate (41.75 kg, 58.12 mol, 2.8 eq.) at 15-25 °C. Catalyst ataCXium A Pd G3 (0.46 kg, 0.62 mol, 0.03 eq.) is added and the reaction mass is heated to 58-63°C and agitated for 6-10h. After cooling to 15-30°C, n-heptane (16.9 L) is added in the reactor and the layers are separated. The organic layer is washed by water (32.8 L) at 15-25°C.

[0164] Batch-2. THF (85 L) is charged to a reactor with tert-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, 11.330 kg, 20.56 mol, 1 eq.), ((6-fluoro-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2- yl)oxy)triisopropylsilane (MR113342, 16.96 kg, 24.67 mol, 1.2 eq.) and potassium carbonate (41.75 kg, 58.12 mol, 2.8 eq.) at 15-25°C. The catalyst ataCXium A Pd G3 (0.46 kg, 0.62 mol, 0.03 eq.) is added, the reaction mass is heated to 58-63°C and agitated for 6-10h. After cooling to 15-30°C n- heptane (16.9 L) is added in the reactor and the layers are separated. The organic layer is washed by water (32.8 L).

[0165] The combined organic layers (batch-1 and batch-2) are concentrated, the residue is suspended in methanol (23.6 L) and n-heptane (46.3 L) at 15-20°C and stirred for 2h. The reaction mass is cooled to 0-5°C and stirred for additional 12h. The solid is filtered and the cake is rinsed by n-heptane (2x1 1 .5 L) and charged back in the reactor followed by toluene (366.6 L), 33 wt% Ethylenediamine (7.59 kg) and 33wt % silica gel (7.59 kg, 200 - 300 mesh) at 15-25 °C. The mixture is heated to 75-80°C and stirred for 4h. After cooling the reaction mass to 15-25°C, the solid waste is filtered and rinsed by toluene (46.6 L). The filtrate is washed by water (69.2 L) followed by aqueous 10% sodium chloride (77 kg). The solvent is removed and methanol (92.6 L) is added at 45°C. Methanol is partially reduced to 69.4 L and the solid is suspended and stirred at 0-5°C for 5h. The solid is filtered, rinsed with methanol (40.1 L) and dried to afford the desired material tert-butyl ( 1 R, 5 S)-3 -(8-fluoro-7-(7-fluoro-8-((trii sopropy Isily l)ethyny l)-3 -((trii sopropy 1 silyl)oxy)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 (MR113343) as a solid (33.91 kg, IY: 80.16%, purity: 98.3%).

[0166] MR113343: 'H NMR (400 MHz, CDCh) 5 ppm 0.50 - 0.57 (m, 3H), 0.86 - 0.90 (t,20H), 1.12 - 1.14 (d, J=7.4, 20H), 1.27 - 1.36 (m, 5H), 1.64 (s, 6H), 2.20 - 2.33 (q, 4H), 3.02 (s, 1H), 3.21 - 3.42 (t, 4H), 3.83 (s, 1H), 4.16 - 4.39 (q, 6H), 4.85 - 4.87 (d, J=9.56, 1H ), 5.24 - 5.37 (d, J=53.4, 1H), 7.22 - 7.32 (m, 5H), 7.72 - 7.75 (q, 1H), 9.06 (s, 1H). LCMS m z 1013.5 [M+H]+EXAMPLE 5A preparation of tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyirolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113344) (2kg scale)

[0167] DMF (20.29 kg) and te / 7-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)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 (MR113343, 4.41 kg, 4.34 mol, 1 eq.), are charged to a reactor. The mixture is stirred at 45-55°C until clear solution, then cooled to 8-15°C. Cesium fluoride (1.63 kg, 10.73 mol, 2.5 eq.) is charged and the reaction mass is agitated for 7h at 20- 25°C. Additional cesium fluoride (2.28 kg, 15 mol, 3.5 eq.) is introduced and the crude mass is stirred till complete conversion to desired product. Water (66 L) is introduced and after stirring for 12h at 15-25°C, the mixture is fdtered. The cake is washed by water (8.8 L), the aqueous layer is extracted by MTBE (44 L) and the organic layer is concentrated. The residue and the cake are dissolved in DCM (71 L), washed by water (35.2 L) and aqueous 20% sodium chloride solution (14L). DCM is removed and exchanged by acetonitrile (10.1 L). The reaction is agitated for 12h at 5-10°C and filtered. The solid is rinsed by acetonitrile (8.8 L) and suspended in n-heptane (29.7 L) for 2h at 55-65°C. After filtration and rinse by n-heptane (14.8 L), / c / V-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-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 (MR113344) is isolated as a light brown solid (2.63 kg IY: 86%, purity: 99.7%, KF: 0.1%).

[0168] MR1 13344: 'H NMR (400 MHz, CDCh) 8 ppm 1.47 (s, 9H), 1.74 - 1.86 (m, 7H), 1.99 - 2.14 (m, 4H), 2.80 - 2.86 (q, 1H), 3.02 - 3.14 (m, 3H), 3.58 - 3.68 (m, 2H), 3.93 (s, 1H), 4.11 - 4.14 (q, 1H), 4.31 (s, 2H), 4.38 - 4.41 (d, J=12.08, 1H ), 4.55 - 4.58 (d, J=12.32, 1H), 5.21 - 5.35 (d, J=54.04, 1H), 7.18 - 7.19 (d, J=2.32, 1H), 7.39 - 7.40 (d, J=2.52, 1H), 7.44 - 7.49 (t, 1H), 7.96 - 8.00 (m, 1H), 9.08 (s, 1H), 10.18 (s, 1H). LCMS m / z 701.3 [M+H]+.EXAMPLE 5B preparation of tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-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 (MR113344) (12kg scale)

[0169] Ethyl acetate (272.1 L) and tert-butyl (lR,5S)-3-(8-fluoro-7-(7-fluoro-8- ((triisopropylsilyl)ethynyl)-3-((triisopropylsilyl)oxy)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 (MR113343, 33.85 kg, 33.40 mol, 1 eq.) are charged to a reactor followed by tetrabutylammonium fluoride (26.40 kg, 83.50 mol, 2.5 eq.). After 2h at 15-25°C, the reaction mass is diluted with water (135.8 kg) and THF (135.6 L) at 15-25°C. The organic layer is collected, the aqueous layer is extracted back by a solvent mixture THF (33.9 L) and ethyl acetate (67.8L). The combined organic layers are washed by aqueous 13% sodium chloride (117.0 kg) and concentrated to 67.8 L. n-Heptane (406.6 L) is added and the crude mass is concentrated by distillation to 220.4 L. The resulting crude is heated to 55-65°C for 2-4h,cooled to 10-20°C and stirred for an additional 12h. The solid is fdtered and the wet cake is rinsed by n-heptane( 33.9 L) and charged back into the reactor, followed by acetonitrile (133.4 kg). The suspension is stirred for 12h at 10-20°C, the suspension is filtered, the solid is rinsed by acetonitrile (27 kg) and dried to afford tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen- 1 -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 (MR113344) as solid (22 kg, IY: 94%, purity: 99.7%).

[0170] MR113344: 'H NMR (400 MHz, CDCh) 5 ppm 1.47 (s, 9H), 1.74 - 1.86 (m,7H), 1.99 - 2.14 (m, 4H), 2.80 - 2.86 (q, IH), 3.02 - 3.14 (m, 3H), 3.58 - 3.68 (m, 2H), 3.93 (s, IH), 4.11 - 4.14 (q, IH), 4.31 (s, 2H), 4.38 - 4.41 (d, J=12.08, IH ), 4.55 - 4.58 (d, J=12.32, IH), 5.21 - 5.35 (d, J=54.04, IH), 7.18 - 7.19 (d, J=2.32, IH), 7.39 - 7.40 (d, J=2.52, IH), 7.44 - 7.49 (t, IH), 7.96 - 8.00 (m, IH), 9.08 (s, IH), 10.18 (s, IH). LCMS m.z 701.3 [M+H]+.EXAMPLE 6APreparation of 4-(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) (2 kg scale)

[0171] Dichloromethane (47.22 kg) is charged to a reactor with tert-butyl (lR,5S)-3-(7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-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 (MR113344, 3.54 kg, 5.05 mol, 1 eq.). The mass is heated to 35-40°C, when materials are dissolved, acetonitrile (28.09 kg) is introduced, followed by boron trifluoride acetonitrile solution (19wt%, 5.80 kg, 10.10 mol, 2 eq.). The batch was agitated at 35-40°C for Ih. The reaction mixture is cooled to 15-25°C, diluted with water (1.78 kg) and ethanol (18.21kg). After stirring at 15-25°C for 2-5h, aqueous solution of sodium bicarbonate (6%, 35.5 kg) is slowly added and the resulting crude is stirred for 0.5h at 15-25 °C. The layers are separated, the aqueous layer is extracted by DCM (23.43 kg) and the combined organic layers are concentrated to 7.1 L. The residue is diluted by ethanol (11.22 kg) and concentrated to 7.01 L. To the reaction mass are added DCM (70.84 kg) and ethanol (13.99 kg), followed by aqueous solution of sodium bicarbonate (6%, 35.5 kg). The resulting mixture is filtered thru a pad of celite (3.55 kg, 150 mesh) and the waste cake is rinsed by DCM (2.85 kg) and ethanol (0.95 kg). The filtrate layers are separated, the organic layer is washed twice by aqueous solution of sodium bicarbonate (6%, 2x35.5 kg) and aqueous solution of sodium chloride (10%, 35.5 kg). After concentration of the organic layer, the residue is dissolved in DCM (80.26 kg) and slowly diluted by MTBE (26.27 kg). Seeds (MRTX1133, 18g) are introduced, followed by additional MTBE (13.14 L) and the reaction mass is concentrated to 14-21 L. MTBE (13.14 L) is added and the crude is concentrated to 14-21 L second time. Final charge of MTBE is (65.70 kg) is slowly added and stirred for 12- 24h at 48-53°C. After cooling to 15-25°C, the mixture is filtered. The cake is washed by MTBE (7.88 kg) and dried. The solid is dissolved in THF (53.40 kg) , filtered through silica pad (3.60 kg, 200-300 mesh) and the pad is rinsed by THF (172.41 kg). THF is removed and switch to DCM (47.91 kg). MTBE (17.76 kg) is added to DCM solution, followed by seeds (MRTX1133, 12 g). The reaction mass is concentrated to 24 L then MTBE (44.4 kg) is added over a period of 0.5h. After stirring at 40-50°C for 12-24h, the mixture is filtered at 15-25°C, the solid is rinsed by MTBE (5.33 kg) and dried to afford 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-fluoronaphthalen-2-ol (MRTX1133) as a solid (1.716 kg, IY: 56.63%, purity: 98.8, KF: 0.94%).

[0172] MRTX1133 'HNMR (400 MHz, DMSO-de) 5 = 9.05 (s, 1H), 7.97 (dd, J= 5.6, 9.2 Hz, 1H), 7.47 (t, .7= 9.2 Hz, 1H), 7.40 (d, ,7= 2.4 Hz, 1H), 7.18 (d, .7= 2.4 Hz, 1H), 5.38- 5.19 (m, 1H), 4.51 (br d, J - 11.8 Hz, 1H), 4.35 (br d, J- 12.0 Hz, 1H), 4.11 (dd, J= 2.8, 10.4 Hz, 1H), 4.02 (br dd, J= 2.0, 10.4 Hz, 2H), 3.94-3.91 (m, 2H), 3.65-3.61 (m, 2H), 3.14-2.98 (m, 2H), 3.03 (s, 1H), 2.89-2.80 (m, 1H), 2.16-1.98 (m, 3H), 1.88-1.71 (m, 7H); LCMS [ESI, M+l]: 601.3.EXAMPLE 6BPreparation of 4-(4-((l R,5S)-3,8-diazabicyclo [3.2. l]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-fluoronaphthalen-2-ol (MRTX1133) (12 kg scale)

[0173] Dichloromethane (200 L) is charged to a reactor with rt-butyl (lR,5S)-3-(7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-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 (MR113344, 20 kg, 28.54 mol, 1 eq.). The mass is heated to 35-40°C, when all material is dissolved, acetonitrile (158.4 kg) is introduced, followed by boron trifluoride acetonitrile solution (19wt%, 36 kg, 62.79 mol, 2.2 eq.). The batch was agitated at 36-43°C for 1- 3h. The reaction mixture is cooled to 15-25°C, diluted with ethanol (120 L) and stirred at 15- 25°C for 2-5h. Aqueous solution of potassium hydrogen carbonate (6%, 300 kg) is slowly added and the resulting crude is stirred for 2-3h at 15-25°C. The reaction mass is filtered thru a pad of diatomite (150 mesh, lOKg) and the waste cake is washed by DCM (40 L). The filtrate layers were separated, the aqueous layer is extracted by DCM (100 L) and the combined organic layers are diluted by potassium hydrogen carbonate (6%, 200 L) at 15-25°C. After stirring for 2-3 h, the layers are separated. The bottom layer is washed with 10% aqueous NaCl (100.0 L) and dried over magnesium sulfate (4 kg). The waste cake is rinsed by DCM (40.2 L) and the combined DCM layers are filtrated thru silica gel (30 kg, 75wt% with THF). The silica pad is rinse by THF (1200 L). The solvents are partially removed (80-100 L remained in the reactor) and the resulting solution is added to a suspension of seeds MRTX1133 (0.1 kg) in MTBE (500L). The mixture is heated to 40-50°C for 12h, cooled to 15-25°C and stirred for additional l-2h. The suspension is filtered, the solid is rinsed with MTBE (60 L) and dried to afford a yellow solid (14.16 kg). The latter is charged back in the reactor, dissolved in DCM (85 L) and added at to a suspension of seeds MRTX1133 (71.5 g, 0.5wt%) in MTBE (354.1 L) at 40-50°C. After 24h, the suspension is cooled to 15-25°C, stirred for 2h then filtered. The cake is rinsed by MTBE (43.2 L) and dried to afford 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- fluoronaphthalen-2-ol (MRTX1133) as a solid (12.7 kg, IY: 74.1%, purity: 98.2, KF: 0.61%).

[0174] MRTX1133 'H NMR (400 MHz, DMSO-de) 5 = 9.05 (s, 1H), 7.97 (dd, J= 5.6, 9.2 Hz, 1H), 7.47 (t, J= 9.2 Hz, 1H), 7.40 (d, J= 2.4 Hz, 1H), 7.18 (d, J= 2.4 Hz, 1H), 5.38- 5.19 (m, 1H), 4.51 (br d, J= 11.8 Hz, 1H), 4.35 (br d, J= 12.0 Hz, 1H), 4.11 (dd, J= 2.8, 10.4 Hz, 1H), 4.02 (br dd, J= 2.0, 10.4 Hz, 2H), 3.94-3.91 (tn, 2H), 3.65-3.61 (m, 2H), 3.14-2.98 (m, 2H), 3.03 (s, 1H), 2.89-2.80 (m, 1H), 2.16-1.98 (m, 3H), 1.88-1.71 (m, 7H); LCMS [ESI, M+l]: 601.3.

[0175] 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) reacting triisopropyl silyl chloride (TIPSC1) and a base in an aprotic solvent ound of step (a) with the following structure:

2. The method of claim 1, wherein step (a) is carried out at a temperature from about 0 °C to about 25 °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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

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): reactingactivating agent and a 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 of about 0 °C.

12. 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).

13. The method of claim 12, wherein the activating agent is triflic anhydride.

14. 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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

15. The method of claim 9, wherein the base is an inorganic base.

16. The method of claim 9, wherein the base is an organic base.

17. The method of claim 16, wherein the organic base is selected from the group consisting of DIPEA, Et3N, DABCO, and DBU.

18. 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:

19. The method of claim 18, wherein step (c) is carried out at a temperature of between about 75 °C and about 80 °C.

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

21. The method of claim 18, 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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

22. The method of claim 18, wherein step (c) further comprises additional bases and / or other additives.

23. The method of claim 18, wherein the method further further comprises step (d): d)the presence of a base and aprotic solvent to produce a final compound of step (d) with the following structure:Boe24. The method of claim 23, wherein step (d) is carried out at a temperature from about -15 °C to about 12 °C.

25. The method of claim 23, where in 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, di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

26. The method of claim 23, wherein the base is an organic base.

27. The method of claim 26, wherein the the organic base is selected from the group consisting of Diisopropylethylamine (DIPEA), triethylamine (EtsN), tri ethylenediamine (DABCO), and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

28. The method of claim 23, wherein the base is an inorganic base.

29. The method of claim 28, wherein the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate.

30. The method of claim 28, 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).

31. A method of claim 23, wherein the method further comprises step (e) : e) reacting the final compound of step (d) with the final compound of step (c) in the presence of a palladium catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2- (dimethylamino)-hydrochloride, and an aprotic solvent to produce a compound of the following structure:Boe32. The method of claim 31, wherein step (e) is carried out at a temperature of between about60 °C an about 80 °C.

33. The method of claim 31, 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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

34. The method of claim 31, wherein the method further comprises step (f): f) reacting the final compound of step (e) with a fluoride salt in an aprotic solvent to produce a final compound of step (f) with the following structure:

35. The method of claim 34, wherein step (f) is carried out at a temperature from about 25 °C to about 45 °C.

36. The method of claim 34, 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, di ethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

37. The method of claim 34, wherein the method further comprises step (g): g) reacting the final compound of step (f) with boron trifluoride acetonitrile and an aprotic solvent to produce a final compound of step (g) with the following structure:

38. The method of claim 37, wherein step (g) is carried out at between about 25°C and about 45 °C.

39. The method of claim 37, 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, diethylene glycol dimethyl ether, DMF, 1,4-di oxane, DMSO, and NMP.

40. A method of synthesizing MR.TX1 133, comprising the step of reactingwith boron trifluoride acetonitrile and an aprotic solvent to produce MRTX1133.

41. A method of synthesizing MRTX1133 comprising:-reactingwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

42. A method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:with boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

41. A method of synthesizing MRTX1133 comprising:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:BocBoewith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

42. A method of synthesizing MRTX1133 comprising:, wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:-reactingBoc iwith boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

43. A method of synthesizing MRTX1133 comprising-reactingactivating agent, an organic base in an aprotic solvent to produce:, wherein R is a leaving group;-reacting, wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:with boron trifluoride acetonitrile in an aprotic solvent to produce MRTX1133.

44. A method of synthesizing MRTX1 133 comprising<img src='' class="img-anchor img-center" img-id="IMGF000084_0004" / >-reactingproduce:-reacting, wherein R is a leaving group with a ligand and a palladium catalyst in an aprotic solvent to produce:the presence of a catalyst, tripotassium phosphate, silica gel, an organic base, ethanethiol, 2-(dimethylamino)- hydrochloride, and an aprotic solvent to produce:with boron trifluoride acetonitrile and an aprotic solvent to produce MRTX1133.

45. A method of synthesizing MR.TX1 133, comprising-a first reaction, whereinreacted in a vessel with triisopropyl silyl chloride (TIPSC1), a base, and an aprotic solvent to produce:-a second reaction, wherein an activating agent, an aprotic solvent and an organic base are added

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