Method and intermediate for synthesizing MRTX1133

Abstract

This invention relates to a novel synthetic route for synthesizing MRTX1133. The invention also provides intermediates used in the present synthetic route.

Description

[Technical Field]

[0001] (Field of invention) This invention relates to a novel and improved synthetic route for synthesizing MRTX1133. [Background technology]

[0002] (Background of the invention) The Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch that cycles between an inactive state (GDP-bound) and an active state (GTP-bound), transmitting upstream cellular signals received from multiple tyrosine kinases to downstream effectors that control various processes, including cell proliferation (see, for example, Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignant tumors was observed more than 30 years ago (see, e.g., Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Abnormal expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding, leading to constitutive activation of KRas and downstream signaling, have been reported in 25-30% of lung adenocarcinomas (see, e.g., Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942 doi:10.1038 / nrd428). Single nucleotide substitutions resulting in missense mutations at codons 12 and 13 of the primary amino acid sequence of KRas account for approximately 40% of these KRas driver mutations in lung adenocarcinomas. KRAS G12D mutations are found in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal cancer patients, 10.1% of all rectal cancer patients, 4.1% of all non-small cell lung cancer patients, and 1.7% of all small cell lung cancer patients (see, for example, The AACR Project GENIE Consortium, (2017) Cancer Discovery;7(8):818-831. Dataset Version 4).

[0004] The role of KRas in malignant tumors is well known, and mutations in KRas are frequently observed in various tumor types, making KRas an extremely attractive target for the pharmaceutical industry to treat cancer.

[0005] The KRas G12D inhibitor 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (also known as MRTX1133) has the following structure: [ka] It has.

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

[0007] Although a method for manufacturing MRTX1133 is described in WO 2021 / 041671, there is a need in the art for novel and improved synthetic routes for manufacturing MRTX1133. [Overview of the project] [Problems that the invention aims to solve]

[0008] In one embodiment, the present invention provides a novel and improved method for manufacturing MRTX1133. [Means for solving the problem]

[0009] In one embodiment, the present invention provides a method for synthesizing MRTX1133, the method comprising step (a): a) In the presence of a base and an aprotic solvent, [ka] of, [ka] When reacted with this, the following structure is formed: [ka] The process includes a step of producing the final compound of step (a) having the following characteristics.

[0010] In one embodiment, step (a) is carried out at a temperature of approximately -15°C to approximately -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), dimethyl sulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl ether.

[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 (Et3N), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

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

[0015] [[ID=十六]]In one embodiment, the inorganic base is selected from the group consisting of carbonate, bicarbonate, and phosphate. Any alkali such as lithium, sodium, potassium, and cesium can be used as the inorganic base. 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-tetramethylpiperidide (LiTMP).

[0016] In one embodiment, the method comprises step (b): b) In an aprotic solvent,

Chemical formula

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

[0018] The leaving group is determined by the activator used in the reaction.

[0019] In one embodiment, the activator may be, but is not limited to, a halogenated sulfonyl:R-SO2X (wherein R may be tolyl, mesityl, nosyl, methyl, ethyl, or propyl; X may be F, Cl, or Br, but is not limited to these), anhydrides (trifluoromethanesulfonic acid (triflic) anhydride and nonafluorobutanesulfonic acid anhydride), and organic triflate reagent:R 1 -N-Tf2 (where R 1 It contains one or more of the following (phenyl, 5-chloro-2-pyridine, and 2-pyridine).

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

[0021] In one embodiment, the organic base is selected from the group consisting of diisopropylethylamine (DIPEA), triethylamine (Et3N), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU).

[0022] In one embodiment, in step (b), the activator is trifluoromethanesulfonic anhydride.

[0023] 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 diethylene glycol dimethyl.

[0024] In one embodiment, the method involves step (c): c) In an aprotic solvent, the final compound from step (b) is reacted with the ligand and palladium catalyst to form the following structure: [ka] The process further includes a step of producing the final compound of step (c) having the above.

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

[0026] In one embodiment, the ligand is selected from the group consisting of bis(pinacolato)diborone 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)Cl2).

[0028] In yet another embodiment, the process may include additional bases and / or other additives, which may include, for example, triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine, but are not limited to those described below.

[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 diethylene glycol dimethyl.

[0030] In one embodiment, the method involves step (d): d) In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, the final compound from step (a) is reacted with the final compound from step (c) to obtain the following structure: [ka] The process further includes a step of producing the compound.

[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, dichloromethane, dimethylformamide, dimethylacetamide, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, NMP, DMSO, 1,4-dioxane, and diethylene glycol dimethyl.

[0034] In one embodiment, the method comprises step (e): e) The final compound from step (d) is reacted with a fluoride salt, a quaternary ammonium salt, and an aprotic solvent to obtain the following structure: [ka] The process further includes a step of producing the final compound of step (e) having the above.

[0035] In one embodiment, step (e) is carried out at a temperature of approximately 45°C to approximately 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 diethylene glycol dimethyl.

[0038] In one embodiment, the method involves step (f): f) The final compound from step (e) is reacted with an acid, an organic base, and an aprotic solvent to form the following structure: [ka] The process further includes a step of producing the final compound of step (f) having the above.

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

[0040] In one embodiment, the organic base is selected from the group consisting of diisopropylethylamine (DIPEA), triethylamine (Et3N), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU).

[0041] In one embodiment, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic 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 diethylene glycol dimethyl.

[0043] In one embodiment, the present invention is [ka] The present invention provides a method for synthesizing MRTX1133, comprising the step of reacting with an acid, an organic base, and an aprotic solvent to produce MRTX1133.

[0044] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -Fluoride salts, quaternary ammonium salts and aprotic solvents, [ka] Reacting them, [ka] A process for generating; - Acids, organic bases, and aprotic solvents, [ka] A process to generate MRTX1133 by reacting the two substances.

[0045] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, [ka] of, [ka] And it will react, [ka] A process for generating; -In aprotic solvents, [ka] It is reacted with fluoride salts and quaternary ammonium salts, [ka] The process of generating; and -In an aprotic solvent, [ka] A process to produce MRTX1133 by reacting it with an acid and an organic base.

[0046] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -In an aprotic solvent, [ka] (In the formula, R is a leaving group.) This is reacted with a ligand and a palladium catalyst, [ka] A process for generating; -In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, [ka] of, [ka] And it will react, [ka] A process for generating; -Fluoride salts, quaternary ammonium salts and aprotic solvents, [ka] Reacting them, [ka] A process for generating; -In an aprotic solvent, [ka] A process to produce MRTX1133 by reacting it with an acid and an organic base.

[0047] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -Activating agent, aprotic solvent and organic base, [ka] Reacting them, [ka] (In the formula, R is a leaving group.) A process for generating; -In an aprotic solvent, [ka] (In the formula, R is a leaving group.) This is reacted with a ligand and a palladium catalyst, [ka] A process for generating; -In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, [ka] of, [ka] And it will react, [ka] A process for generating; -In an aprotic solvent, [ka] This is reacted with fluoride salts and quaternary ammonium salts, [ka] A process for generating; -In an aprotic solvent, [ka] A process to produce MRTX1133 by reacting it with an acid and an organic base.

[0048] The present invention encompasses each of the above steps themselves (i.e., embodiments relating to step (a); embodiments relating to step (b); embodiments relating to step (c), etc.) and combinations of each step (i.e., embodiments relating to steps (a) and (b); embodiments relating to steps (a), (b), and (c), etc.).

[0049] The present invention has the following structure: [ka] The invention also provides novel compounds. Detailed description of the invention

[0050] This invention relates to a novel synthetic route for synthesizing MRTX1133 and a novel intermediate used in the provided route.

[0051] While methods for synthesizing MRTX1133 are publicly known (see WO 2021 / 041671), the synthesis method provided by the present invention is a significant improvement in terms of higher isolation yield and overall higher or equivalent purity.

[0052] Furthermore, the provided method is scalable and minimizes the use of silica gel columns or reversed-phase column purification.

[0053] (definition) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains. All patents, patent applications, and publications referenced herein are incorporated by attribution.

[0054] As used herein, "KRas G12D" refers to a mutant of the mammalian KRas protein that contains an amino acid substitution from glycine to aspartic acid at amino acid position 12. The arrangement of amino acid codons and residue positions in human KRas is based on the amino acid sequence: mutant p.Gly12Cys. identified by UniProtKB / Swiss-Prot PO116.

[0055] As used herein, “KRas G12D-related disease or disorder” refers to a disease or disorder that is associated with, mediated by, or has a KRas G12D mutation. A non-exclusive example of a KRas G12D-related disease or disorder is KRas G12D-related cancer.

[0056] As used herein, the term "MRTX1133" refers to 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1Hpyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol), with the following structure: [ka] This refers to compounds that possess [a certain characteristic].

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

[0058] The term "MRTX1133" encompasses all chiral (enantiomer and diastereomer) and racemic forms of the compound.

[0059] In one embodiment, the term "MRTX1133" refers to salts of the above-mentioned compounds, for example, salts formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid; salts formed using 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 the formula: -NR+Z-[wherein R is hydrogen, alkyl, or benzyl Z is a counterion, e.g., chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, citrate, tartrate, ascorbate, cinnamate, mandelate, benzilate and diphenylacetate) and includes salts formed from quaternary ammonium salts represented by [Z is a counterion, e.g., chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, maleate, citrate, tartrate, ascorbate, cinnamate, mandelate, benzilate and diphenylacetate)].

[0060] Where this application refers to a compound, unless otherwise specified, the compound includes all chiral forms (enantiomers and diastereomers) and racemic forms of that compound, as well as its tautomers and any mixtures thereof.

[0061] "LG" refers to a leaving group and has a meaning conventionally associated with the term "leaving group" in organic synthesis chemistry; that is, it refers to an atom or group that can be substituted under alkylation or nucleophilic aromatic substitution conditions. The term "leaving group" includes, but is not limited to, halogens (e.g., chlorine and bromine); alkanesulfonyloxys (e.g., methanesulfonyloxys and ethanesulfonyloxys); arenesulfonyloxys (e.g., benzylsulfonyloxys and tosyloxys); thienyloxys; dihalophosphinoloxys; tetrahalophosphaoxys; and perfluoroalkanesulfonyloxys (e.g., trifluoromethanesulfonyloxys). The leaving group should be selected to be chemically less reactive than the reactant group, bromine, in order to ensure a proper reaction (unless, of course, the leaving group is bromine and has equivalent reactivity).

[0062] In this application, unless otherwise specified, "R" refers to groups 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 linear or branched aliphatic group having 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms. Other examples of alkyl groups have 2 to 12 carbon atoms, or 2 to 8 carbon atoms and 2 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. "C0" alkyl groups (as in "C0-C3 alkyl") are covalently bonded.

[0064] The term "alkenyl" is intended to mean an unsaturated linear or branched aliphatic group having one or more carbon-carbon double bonds with 2 to 12 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms. Examples of alkenyl groups, but not limited to these, include ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0065] The term "alkynyl" refers to an unsaturated linear or branched aliphatic group having one or more carbon-carbon triple bonds, with 2 to 12 carbon atoms, alternatively 2 to 8 carbon atoms, or alternatively 2 to 6 carbon atoms. Examples of alkynyl groups, though not limited to these, include ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0066] As used herein, the terms “alkylene,” “alkenylene,” or “alkynylene” refer to an alkyl group, alkenyl group, or alkynyl group, respectively, that is located between two other chemical groups and serves to link them together, as defined above. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, but are not limited to, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0067] As used herein, the term "carbocycle" is intended to mean a cycloalkyl or aryl moiety.

[0068] The term "cycloalkyl" is intended to mean a saturated or unsaturated monocyclic, dicyclic, tricyclic, or polycyclic hydrocarbon group having approximately 3 to 15 carbon atoms, or 3 to 12 carbon atoms, or 3 to 8 carbon atoms, or 3 to 6 carbon atoms, or 5 or 6 carbon atoms. In certain embodiments, cycloalkyl groups are condensed with aryl, heteroaryl, or heterocyclic groups. Examples of cycloalkyl groups, but not limited to these, include cyclopentene-2-enone, cyclopentene-2-enol, cyclohexane-2-enone, cyclohexane-2-enol, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0069] The term "heteroalkyl" means a saturated or unsaturated linear or branched aliphatic group in which one or more carbon atoms are independently substituted by heteroatoms selected from the group consisting of O, S, and N.

[0070] The term "aryl" refers to a monocyclic, dicyclic, tricyclic, or polycyclic aromatic moiety (e.g., a C6-C14 aromatic moiety) containing, for example, one to three aromatic rings. Alternatively, an aryl group may be a C6-C10 aryl group or a C6 aryl group. Examples of aryl groups, but not limited to these, include phenyl, naphthyl, anthracenyl, and fluorenyl.

[0071] The terms "aralkyl" or "arylalkyl" refer to a group containing an aryl group covalently bonded to an alkyl group. Where it is stated that the aralkyl group "may be optionally substituted," it is intended that either or both of the aryl and alkyl moieties may, independently and optionally, be substituted or unsubstituted. Alternatively, the aralkyl group may be a (C1-C6)alkyl(C6-C10)aryl group, such as, but not limited to, benzyl, phenethyl, and naphthylmethyl. For simplicity, when written as "arylalkyl," this term and related terms are intended to indicate the order of the groups in the compound as "aryl-alkyl." Similarly, "alkylaryl" is intended to indicate the order of the groups in the compound as "alkyl-aryl."

[0072] As used herein, the term “pharmaceutically acceptable salt” means a salt that retains the desired biological activity of the compound described above and exhibits minimal or no undesirable toxic effects. Examples of such salts include acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid), and salts formed with organic acids (e.g., 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 compound may also be administered as a pharmaceutically acceptable quaternary salt known to those skilled in the art, specifically a quaternary ammonium salt represented by the formula:-NR+Z-[wherein R is hydrogen, alkyl or benzyl, and Z is a counterion comprising, for example, chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, citrate, tartrate, ascorbate, cinnamate, mandelate, benzylate and diphenylacetate)].

[0073] In this specification, the term "mineral acid" (or "inorganic acid") refers to an acid that dissociates in water to form hydrogen ions (H) + Mineral acids are any acids derived from inorganic compounds that produce ) (a type of mineral acid). Non-limiting examples of mineral acids include hydrogen halides of the general formula: HX (wherein 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 having acidic properties. Non-limiting examples of organic acids include sulfonic acids of the general formula: RSO3H (wherein R may be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, or aryl, as defined above) and carboxylic acids (having one or more carboxylic acid moieties) of the general formula: RCO2H (wherein R may be alkyl, alkenyl, alkynyl, carbocycle, heterocycle, or aryl, as defined above). Non-limiting examples of organic acids include lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, and tartaric acid.

[0075] Synthesis scheme In one embodiment, the present invention provides a novel and improved method for manufacturing MRTX1133.

[0076] In one embodiment, the present invention relates to step (a): a) In the presence of a base and an aprotic solvent, [ka] of, [ka] When reacted with this, the following structure is formed: [ka] A step (a) that produces the final compound, This provides a method for synthesizing MRTX1133, including [the specified element].

[0077] In one embodiment, step (a) is carried out at a temperature of approximately -15°C to approximately -8°C.

[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 diethylene 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 (Et3N), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undeca-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 carbonates, bicarbonates, and phosphates. Any alkali such as lithium, sodium, and potassium can be used as the inorganic base. 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 tetramethylpiperizide (LiTMP).

[0083] In one embodiment, the method comprises step (b): b) In an aprotic solvent, [ka] This is reacted with an activator and an organic base to produce the following structure: [ka] (In the formula, R is a leaving group.) The process further includes a step of producing the final compound of step (b) having the above.

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

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

[0086] In one embodiment, the activator includes, but is not limited to, one or more of the following: sulfonyl halogens: R-SO2X (wherein R may be, but is not limited to, tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X may be, but is not limited to, F, Cl, or Br), anhydrides (trifluoromethanesulfonic acid (triflic) anhydride and nonafluorobutanesulfonic acid anhydride), and organic triflate reagents: R 1 -N-Tf2 (where R 1 (These are phenyl, 5-chloro-2-pyridine, or 2-pyridine).

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

[0088] In one embodiment, the organic base is selected from the group consisting of diisopropylethylamine (DIPEA), triethylamine (Et3N), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU).

[0089] In one embodiment, in step (b), the activator is trifluoromethanesulfonic 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 diethylene glycol dimethyl.

[0091] In one embodiment, the method involves step (c): c) In an aprotic solvent, the final compound from step (b) is reacted with the ligand and palladium catalyst to form the following structure: [ka] The process further includes a step of producing the final compound of step (c) having the above.

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

[0093] In one embodiment, the ligand is selected from the group consisting of bis(pinacolato)diborone 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)Cl2).

[0095] In yet another embodiment, this step may include additional bases and / or other additives, which may include, for example, triethylamine (TEA), sodium bicarbonate, potassium acetate, and cyclohexyldiphenylphosphine, but are not limited to those described below.

[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-dioxane, and diethylene glycol dimethyl.

[0097] In one embodiment, the method involves step (d): d) In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, the final compound from step (a) is reacted with the final compound from step (c) to obtain the following structure: [ka] The process further includes a step of producing the compound.

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

[0101] In one embodiment, the method comprises step (e): e) In an aprotic solvent, the final compound from step (d) is reacted with a fluoride salt and a quaternary ammonium salt to obtain the following structure: [ka] The process further includes a step of producing the final compound of step (e) having the above.

[0102] In one embodiment, step (e) is carried out at a temperature of approximately 45°C to approximately 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 tert-butyl ether, NMP, DMSO, 1,4-dioxane, and diethylene glycol dimethyl.

[0105] In one embodiment, the method involves step (f): f) In an aprotic solvent, the final compound from step (e) is reacted with an acid and an organic base to form the following structure: [ka] The process further includes a step of producing the final compound of step (f) having the above.

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

[0107] In one embodiment, the organic base is selected from the group consisting of diisopropylethylamine (DIPEA), triethylamine (Et3N), triethylenediamine (DABCO), and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU).

[0108] In one embodiment, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic 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 tert-butyl ether, NMP, DMSO, 1,4-dioxane, and diethylene glycol dimethyl.

[0110] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: [ka] A step of reacting with an acid, an organic base, and an aprotic solvent to produce MRTX1133.

[0111] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -In an aprotic solvent, [ka] By reacting it with fluoride salts and quaternary ammonium salts, the following compounds are obtained: [ka] A process for generating; -In an aprotic solvent, [ka] A process to produce MRTX1133 by reacting it with an acid and an organic base.

[0112] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, [ka] of, [ka] And it will react, [ka] A process for generating; -In an aprotic solvent, [ka] This is reacted with fluoride salts and quaternary ammonium salts to form the following compounds: [ka] The process of generating; and - Acids, organic bases, and aprotic solvents, [ka] A process to generate MRTX1133 by reacting the two substances.

[0113] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -In an aprotic solvent, [ka] (In the formula, R is a leaving group.) This is reacted with a ligand and a palladium catalyst, [ka] A process for generating; -In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, [ka] of, [ka] And it will react, [ka] A process for generating; -Fluoride salts and quaternary ammonium salts and aprotic solvents, [ka] Reacting them, [ka] The process of generating; - Acids, organic bases, and aprotic solvents, [ka] A process to generate MRTX1133 by reacting the two substances.

[0114] In one embodiment, the present invention provides a method for synthesizing MRTX1133, comprising the following steps: -In an aprotic solvent, [ka] This is reacted with an activator and an organic base, [ka] (In the formula, R is a leaving group.) A process for generating; -In an aprotic solvent, [ka] (In the formula, R is a leaving group.) This is reacted with a ligand and a palladium catalyst, [ka] A process for generating; -In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, [ka] of, [ka] And it will react, [ka] A process for generating; - Ammonium fluoride, quaternary ammonium salts, and aprotic solvents, [ka] Reacting them, [ka] The process of generating; and - Acids, organic bases and aprotic solvents [ka] A process to generate MRTX1133 by reacting the two substances.

[0115] The present invention also includes each of the above steps themselves (i.e., embodiments relating to step (a); embodiments relating to step (b); embodiments relating to step (c), etc.) and combinations of each step (i.e., embodiments relating to steps (a) and (b); embodiments relating to steps (a), (b), and (c), etc.).

[0116] The present invention has the following structure: [ka] We also provide novel compounds.

[0117] The following examples are intended to further illustrate specific embodiments of the present invention and are not intended to limit the scope of the invention.

[0118] Example 1 tert-butyl(1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(MR113319) [ka]

[0119] 55 L of THF was added to a reaction vessel containing ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methanol (MR113318, 2.86 kg, 17.96 mol, 1 eq) and tert-butyl(1R,5S)-3-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-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 was cooled to -15 to -8°C, and a THF solution of NaHMDS (5.76 kg, 2 M in THF, 1.25 eq) was slowly added at -15 to -8°C. The batch was stirred for 4 hours, and while maintaining the temperature at -15 to -8°C, 5.7 kg of 20% AcOH THF solution was slowly added to adjust the pH to 6 to 7. The resulting suspension was stirred at 15 to 25°C for 30 minutes and concentrated to 5 to 6 volumes at atmospheric pressure with an NMT of 75°C. The reaction vessel was heated to 40 to 50°C, and 70 kg of MTBE was added dropwise over 2 hours. The reactants were stirred for 2 hours, then cooled to 5 to 15°C over 5 hours, and further stirred at 5 to 10°C for 8 hours. The mixture was filtered, the cake was washed with MTBE (2 x 6 kg), and dried to obtain tert-butyl(1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113319) as a solid (7.65 kg, IY: 77.2%, purity: 95.8%, KF: 0.3%).

[0120] MR113317: 1 H NMR (400MHz, CDCl3)δppm 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] + . MR113318: 1 1H NMR (400 MHz, CDCl3) δ 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] + . MR113319: 1 1H NMR (400 MHz, CDCl3) δ 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] + .

[0121] Example 2 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (MR113314)

Chemical Structure

[0122] Batch - 2: 7 - Fluoro - 3 - (methoxymethoxy) - 8 - ((triisopropylsilyl)ethynyl)naphthalen - 1 - ol (MR113313, 5.04 kg, 12.52 mol, 1 eq) was placed in a reaction vessel, and then toluene (42 kg) and TEA (4.18 kg, 41.3 mol, 3.3 eq.) were added. The internal temperature was adjusted to - 35~ - 20 °C, and trifluoromethanesulfonic anhydride Tf2O (6.5 kg, 23.04 mol, 1.8 eq) was slowly added. After stirring at - 35~ - 20 °C for 2~4 hours, the reaction mass was diluted with a 20% aqueous sodium chloride solution (5.3 kg) and stirred at - 20~ - 10 °C for 30~60 minutes. Then, water (40 kg) was added at 15~25 °C. The crude product was stirred for 30~60 minutes and then allowed to stand for 60 minutes. The layers were separated, and the organic layer was washed with a 5% aqueous Na2SO4 solution (26 kg) and concentrated to 4~5 volumes at NMT 55 °C. 7 - Fluoro - 3 - (methoxymethoxy) - 8 - ((triisopropylsilyl)ethynyl)naphthalen - 1 - yl trifluoromethanesulfonate (MR113314) was isolated as a solution in toluene (6.5 kg, assay: 31.4%, IY: 98.2%, purity: 96.4%). MR113313: 1 H NMR (400MHz, CDCl3 - d) δ = 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 + 1]:403.2. MR113314: 1 H NMR (400 MHz, CDCl3) δ = 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).

[0123] Example 3 ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethinyl)triisopropylsilane (MR113315) [ka]

[0124] A toluene solution of 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yltrifluoromethanesulfonate (MR113314, 12.2 kg, 22.8 mol, 1 eq.) was placed in the reaction vessel, and then toluene (21 kg) was added. The internal temperature was adjusted to 20-30°C, and the reaction vessel was purged with nitrogen for 15-30 minutes. Pd(OAc)2 (0.27 kg, 1.2 mol, 0.05 eq.), Ph2PCy (0.68 kg, 2.53 mol, 0.1 eq.), B2Pin2 (11.7 kg, 46.1 mol, 2 eq.), and KOAc (6.8 kg, 69.3 mol, 3 eq.) were added. The reaction mixture was stirred at 45–55°C for 1 hour, then stirred at 90–95°C for 25 hours. After cooling to 20–30°C, 39 kg of 7% NaHCO3 aqueous solution was slowly added. The crude reaction mixture was stirred for 15 minutes and filtered through a Celite pad (7.3 kg). The cake was washed with toluene (3 x 17 kg) and the filtrate layer was separated. The organic layer was washed twice with 40 kg and 38 kg of 10% Na2SO4 aqueous solution and dried on Na2SO4 (13 kg). The pad was rinsed with toluene (23 kg), and the combined organic layer was poured into the reaction vessel, after which N-acetylcysteine ​​(6.8 kg) and Celite (7.3 kg) were added. The mixture was stirred at 45–55°C for 10 hours, cooled to 20–30°C, and filtered through silica gel (6 kg 200–300 mesh). The silica gel pads were rinsed twice with toluene (2 x 24-36 kg), and the resulting filtrate was concentrated to (12-36 L). Isopropanol (IPA, 50 kg) was added, and the solution was concentrated to (12-36 L) at NMT 55°C and stirred for 2 hours.After slowly cooling to -10 to 0°C over 4 to 6 hours, the mixture was filtered, rinsed with isopropanonol (6 kg), and dried at 45 to 55°C for 20 to 30 hours to isolate ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (MR113315) (10 kg, IY: 85.5%, purity: 98.7%). MR113315: 1 H NMR (400MHz, CDCl3-d)δ= 7.69-7.65 (m, 1H), 7.51 (d, J = 2.4Hz, 1H), 7.38 (d, J = 2.4Hz, 1H), 7.25 (t, J = 8.8Hz, 1H), 5.28 (s, 2H), 3.50 (s, 3H), 1.44 (s, 12H), 1.18-1.16 (m, 21H); LCMS [ESI, M+1]:513.4.

[0125] Example 4 tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(MR113320) [ka]

[0126] After adding water (35 kg) to the reaction vessel, K3PO4 (8.3 kg, 39.1 mol, 3 eq) was added at 20-25°C. After stirring for 1 hour, tert-butyl(1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113319, 7.1 kg, 12.88 mol, 1 eq) was added, followed by THF (30 kg). After purging the reaction vessel with nitrogen for 1 hour, the catalyst Ad2nBup-Pd-G3 (0.93 kg, 1.3 mol, 0.1 eq) was added. The internal temperature was adjusted to 55-60°C, and a solution of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (MR113315, 8.0 kg, 15.6 mol, 1.22 eq) in THF (31 kg) was slowly added over 3 hours. The reaction mixture was stirred at 55-60°C for 8 hours. An excess amount of MR113315 (0.82 kg, 1.6 mol) in THF (3 kg) solution was slowly added, and the mixture was stirred at 55-60°C for 1-3 hours, after which it was cooled to 40-50°C. Toluene (35 kg) was added and the mixture was stirred at 35-40°C for 1 hour. The aqueous layer was then decanted, and the crude product was concentrated to 1.5-2.5 volumes under vacuum at 55°C or below. Toluene (30 kg) was added, and the crude product was concentrated to 1.5-2.5 volumes. Celite (6 kg) and N-acetylcysteine ​​(8.1 kg) were added, and the resulting mixture was stirred at 50-55°C for 7 hours and filtered at 25-30°C. The cake was rinsed three times with toluene (13 kg, 2 x 31 kg), and the combined organic layers were poured into a reaction vessel and Celite (3.5 kg) and SEM26 (3.5 kg) were added. The reaction mixture was stirred at 50-55°C for 6.5 hours, cooled to 25-30°C, and filtered.The cake was rinsed twice with toluene (2 x 14 kg), and the filtrate was poured into the reaction vessel. CUNO (0.6 kg) was added, and the mixture was stirred at 25-30°C for 4 hours. After filtration, the CUNO was rinsed twice with toluene (2 x 12 kg). The organic layer was washed twice with 7% NaHCO3 aqueous solution (24 kg) at 35-40°C. Toluene was replaced with IPA by adding IPA (2 x 31 kg), and the mixture was concentrated to 1.5-2.5 volumes under vacuum at 55°C or below. After adding IPA (44 kg), MR113320 seeds (30 g) were added. The crude mixture was stirred at 40-45°C for 8 hours, diluted with water (55 kg), and stirred for a further 3 hours. After cooling to 20-25°C and stirring for 4 hours, the mixture was filtered. The cake was washed with n-heptane (27 kg) and returned to the reaction vessel containing n-heptane (28 kg). The suspension was heated at 50-55°C for 5 hours, cooled to 20-25°C for 4 hours, and then filtered. The solid was rinsed with n-heptane (11 kg) and dried at 45-50°C for 24 hours. tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113320) was isolated (4.56 kg, IY: 40%, purity: 98%). MR113320:LCMS [ESI, M+1]:901.4;1H NMR (400MHz, methanol-d4) δ 8.99 (d, J = 2.1Hz, 1H), 7.87 (dd, J = 5.7, 9.1Hz, 1H), 7.56 (d, J = 2.6Hz, 1H), 7.30 (t, J = 8.9Hz, 1H), 7.22 (t, J = 2.3Hz, 1H), 5.29-5.10 (m, 3H), 4.82 (br t, J = 11.2Hz, 1H), 4.38-4.06 (m, 5H), 3.79 (br dd, J = 6.1, 11.9Hz, 1H), 3.43-3.35 (m, 4H), 3.18-3.05 (m, 3H), 2.91 (dt, J = 5.6, 9.5Hz, 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 (d, J = 2.1Hz, 1H)0), (q, J = 7.5Hz, 3H).

[0127] Example 5 tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(MR113321) [ka]

[0128] tert-butyl(1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-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) were placed in a reaction vessel at 20-30°C. After stirring for 1 hour, an aqueous solution of NH4F (6.6 kg in 8 kg of water) was added, followed by TBAF (0.3 kg, 0.31 mol, 0.06 eq). The reactants were stirred at 45-55°C for 20 hours, cooled to 20-30°C, and the layers were separated. The organic layer was washed twice with 10% Na2SO4 aqueous solution (19 kg and 21 kg) and concentrated to 2-3V below 45°C. Additional 2-MeTHF (22 kg) was added and concentrated to 2-3V below 45°C. 2-MeTHF (40 kg) and SEM26 (4.5 kg) were added, and the mixture was stirred at 45-55°C for 11 hours. After cooling to 25-30°C, Celite (4.6 kg) was added, and the resulting mixture was filtered. The wet cake was rinsed twice with 2-MeTHF (2 x 20 kg), the filtrate was concentrated to 2-3V, and the temperature was adjusted to 45-55°C. Seed (MR113321, 20.2 g) was added, and the crude product was stirred at 45-55°C for 6 hours. n-heptane (32 kg) was added dropwise over 8 hours. After stirring for 4 hours, the mixture was cooled to 15-25°C over 8 hours, and stirred for a further 4 hours. The mixture was filtered, rinsed with n-heptane (4 kg), and the solid was dried at 40-50°C for 18-24 hours.tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113321) was obtained as a solid (3.36 kg, IY: 87.4%, purity: 98.8%). MR113321:LCMS [ESI, M+1]:745.3.

[0129] Example 6 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (MRTX1133) [ka]

[0130] MTBE (24 kg) was placed in the reaction vessel and the temperature was adjusted to 0-10°C. After adding sulfuric acid (6.4 kg, 65.25 mol, 15 eq.) dropwise, tert-butyl(1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (MR113321, 3.1 kg, 4.16 mol, 1 eq.) was added. The crude product was stirred at 0-10°C for 27 hours and then filtered. The solid was rinsed with MTBE (5 kg) and returned to the reaction vessel containing 2-MeTHF (33 kg), 3% Na2SO4 aqueous solution (31 kg), and Et3N (8.8 kg). The resulting slurry was stirred at 10-20°C for 30 minutes and filtered. The solid was rinsed with 2-MeTHF (4 kg), suspended in water (30 L) at 15-25°C for 2 hours, filtered, and dried at 45°C for 1-3 hours. The wet cake (2.61 kg) was returned to the reaction vessel containing DMSO (7.8 L), and the solution was stirred at 40°C for 1-2 hours. Water (1.43 L) was slowly added to add the MRTX1133 seed. The mixture was stirred for 10-15 hours, slowly diluted with water (22 L), stirred for 1-2 hours, and filtered. The cake was washed with water (5 L) and returned to the reaction vessel containing water (21 L). The slurry was stirred at 55°C for 5 hours and at 15°C for 10 hours. The reaction mixture was filtered, washed with water (2 x 2.6 L), and dried at 40-50°C for 48 hours. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (MRTX1133) was isolated as a solid (2.157 kg, IY: 75%, purity: 97.7%).

[0131] MRTX1133: 1H NMR (400MHz, methanol-d4)δ= 9.02 (s, 1H), 7.87 (dd, J = 5.7, 9.2Hz, 1H), 7.39-7.30 (m, 2H), 7.23 (d, J = 2.6Hz, 1H), 5.42-5.23 (m, 1H), 4.62 (q, J = 11.9Hz, 2H), 4.36-4.21 (m, 2H), 3.78-3.62 (m, 4H), 3.36 (dd, J = 0.8, 6.8Hz, 1H), 3.31-3.14 (m, 3H), 3.03 (dt, J = 5.7, 9.4Hz, 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+1]: 601.0.

[0132] While the present invention has been described in relation to its specific embodiments, it will be understood that the present invention is subject to further modification, and this application is generally intended to cover modifications, uses, or adaptations of the present invention in accordance with the appended claims, including deviations from the disclosure that are applicable to the essential features set forth herein, within the scope of prior art or common practice in which the present invention belongs, in accordance with the principles of the present invention.

Claims

1. A method for synthesizing MRTX1133 (4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1Hpyrrolidine-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol), comprising the following steps (a): a) In the presence of a base and an aprotic solvent, 【Chemistry 1】 of, 【Chemistry 2】 When reacted with this, the following structure is formed: 【Transformation 3】 A method comprising the step of producing a final compound of step (a) having the above.

2. The method according to claim 1, wherein step (a) is carried out at a temperature of approximately -15°C to approximately -8°C.

3. The method according to claim 1, 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 tert-butyl ether, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

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

5. The organic bases are diisopropylethylamine (DIPEA) and triethylamine (Et 3 N) The method according to claim 4, selected from the group consisting of triethylenediamine (DABCO) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU).

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

7. The method according to claim 6, wherein the inorganic base is selected from the group consisting of carbonates, bicarbonates, and phosphates, and the inorganic base can be any alkali such as lithium, sodium, and potassium.

8. The method according to 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. Process (b): b) In an aprotic solvent, 【Chemistry 4】 This is reacted with an activator and an organic base to form the following structure: 【Transformation 5】 (In the formula, R is a leaving group.) A step to produce the final compound of step (b), The method according to claim 1, further comprising:

10. R, CF 3 The method according to claim 9.

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

12. The method according to 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 tert-butyl ether, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

13. Organic bases are DIPEA, Et 3 The method according to claim 9, selected from the group consisting of N, DABCO, and DBU.

14. The activator is sulfonyl halogen: R-SO 2 X (wherein R is tolyl, mesityl, nosyl, methyl, ethyl, or propyl, and X is F, Cl, Br, Oms, or OT), anhydrous and organic triflate reagent: R 1 -N-Tf2 (where R 1 The method according to claim 9, wherein is selected from the group consisting of phenyl, 5-chloro-2-pyridine, or 2-pyridine.

15. The method according to claim 13, wherein the activator is trifluoromethanesulfonic acid anhydride.

16. Process (c): c) In an aprotic solvent, the final compound from step (b) is reacted with the ligand and palladium catalyst to form the following structure: 【Transformation 6】 A step (c) that produces the final compound, The method according to claim 1, further comprising:

17. The method according to claim 16, wherein step (c) is carried out at a temperature of 80°C to approximately 100°C.

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

19. The method according to claim 16, 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 tert-butyl ether, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

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

21. Step (d): d) In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, the final compound from step (a) is reacted with the final compound from step (c) to obtain the following structure: 【Transformation 7】 A process for producing the compound, The method according to claim 16, further comprising:

22. The method according to claim 21, wherein step (d) is carried out at a temperature of 55°C to approximately 60°C.

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

24. The method according to claim 21, 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 tert-butyl ether, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

25. Process (e): e) The final compound from step (d) is reacted with a fluoride salt, a quaternary ammonium salt, and an aprotic solvent to obtain the following structure: 【Transformation 8】 A step (e) that produces the final compound, The method according to claim 21, further comprising:

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

27. The method according to claim 25, 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 tert-butyl ether, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

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

29. Process (f): f) The final compound from step (e) is reacted with an acid, an organic base, and an aprotic solvent to form the following structure: 【Chemistry 9】 A step to produce the final compound of step (f) having the following: The method according to claim 25, further comprising:

30. The method according to claim 29, wherein step (f) is carried out at a temperature of approximately 0°C to approximately 22°C.

31. The method according to claim 29, wherein the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid.

32. The organic bases are diisopropylethylamine (DIPEA) and triethylamine (Et 3 N) The method according to claim 29, selected from the group consisting of triethylenediamine (DABCO) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU).

33. The method according to claim 29, 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 tert-butyl ether, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), 1,4-dioxane, and diethylene glycol dimethyl.

34. A method for synthesizing MRTX1133, including the following steps: - Acids, organic bases and aprotic solvents, 【Chemistry 10】 A process to generate MRTX1133 by reacting the two substances.

35. A method for synthesizing MRTX1133, including the following steps: - Fluoride salts, quaternary ammonium salts and aprotic solvents, 【Chemistry 11】 Reacting them, 【Chemistry 12】 The process of generating; and - Acids, organic bases and aprotic solvents, 【Chemistry 13】 A process to produce MRTX1133 by reacting the following.

36. A method for synthesizing MRTX1133, including the following steps: - In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, 【Chemistry 14】 of, 【Chemistry 15】 And it will react, 【Chemistry 16】 The process of generating; - Fluoride salts, quaternary ammonium salts and aprotic solvents, 【Chemistry 17】 Reacting them, [Chemistry 18] The process of generating; and - Acids, organic bases and aprotic solvents, 【Chemistry 19】 A process to generate MRTX1133 by reacting the two substances.

37. A method for synthesizing MRTX1133, including the following steps: - In an aprotic solvent, 【Chemistry 20】 (In the formula, R is a leaving group.) This is reacted with a ligand and a palladium catalyst, 【Chemistry 21】 The process of generating; - In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, 【Chemistry 22】 of, 【Chemistry 23】 And it will react, 【Chemistry 24】 The process of generating; - Fluoride salts, quaternary ammonium salts and aprotic solvents, 【Chemistry 25】 Reacting them, 【Chemistry 26】 The process of generating; and - Acids, organic bases and aprotic solvents 【Chemistry 27】 A process to produce MRTX1133 by reacting the following.

38. A method for synthesizing MRTX1133, including the following steps: - In an aprotic solvent, 【Chemistry 28】 This is reacted with an activator and an organic base, 【Chemistry 29】 (In the formula, R is a leaving group.) The process of generating; - In an aprotic solvent, 【Transformation 30】 (In the formula, R is a leaving group.) This is reacted with a ligand and a palladium catalyst, 【Chemistry 31】 The process of generating; - In the presence of a catalyst, tripotassium phosphate, and an aprotic solvent, 【Chemistry 32】 of, 【Transformation 33】 And it will react, 【Transformation 34】 The process of generating; - Fluoride salts, quaternary ammonium salts and aprotic solvents, 【Chemistry 35】 Reacting them, 【Transformation 36】 The process of generating; and - Acids, organic bases and aprotic solvents, 【Chemistry 37】 A process to produce MRTX1133 by reacting the following.

39. The following structure: 【Transformation 38】 A compound of [unclear].

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