Methods for preparing PRMT5 inhibitors and intermediates for their preparation

Abstract

Disclosed are methods for preparing protein arginine N-methyltransferase 5 (PRMT5) inhibitors and intermediates useful for their preparation.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 573,021, filed April 2, 2024, the entire contents of which are incorporated herein by reference.

[0003] field

[0004] This disclosure generally relates to methods for preparing protein arginine N-methyltransferase 5 (PRMT5) inhibitors and intermediates for their preparation.

[0005] background

[0006] Protein arginine N-methyltransferase (PRMT5) is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the guanidino functional group of an L-arginine residue in a protein. -nitrogen( (monomethylation), and catalyzes the transfer of the second methyl group to another. -Nitrogen, producing symmetrical dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylsomal protein 50), which is required for substrate recognition and orientation, and is also required for the histone 2A and histone 4 methyltransferase activities catalyzed by PRMT5. See, for example, Ho et al. (2013) PLOS ONE 8(8): 10.1371 / annotation / e6b5348e-9052-44ab-8f06-90d01dc88fc2.

[0007] Homozygous deletions of p16 / CDKN2a are prevalent in cancers, and these mutations often involve the co-deletion of adjacent genes, including the gene encoding methylthioadenosine phosphatase (MTAP). It is estimated that approximately 15% of all cancers have homozygous deletions of the MTAP gene. See, for example, Firestone & Schramm (2017). J. Am. Chem Soc. 139(39):13754-13760. doi: 10.1021 / jacs.7b05803. Electronic version, September 20, 2017.

[0008] Cells lacking MTAP activity exhibit elevated levels of the MTAP substrate methionine (MTA), a potent inhibitor of PRMT5. Inhibition of PRMT5 activity leads to decreased methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Therefore, loss of MTAP activity reduces PRMT5 methylation activity, making cells selectively dependent on PRMT5 activity.

[0009] Therefore, MTA-synergistic inhibition of PRMT5 activity in MTAP-deficient cancers could provide therapeutic benefits for a variety of cancers. The compounds of this invention provide this therapeutic benefit as MTA-synergistic inhibitors of PRMT5, negatively regulating the activity of MTA-bound PRMT5 in cells, particularly MTAP-deficient cells, or for the treatment of various forms of MTAP-related cancers.

[0010] In particular, 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile (MRTX-1719) is a potent and selective inhibitor of PRMT5 and has been found to possess pharmacological activity. Therefore, there is a need for synthetic methods for its and similar compounds to be used on a commercial scale.

[0011] Overview

[0012] A synthetic method is disclosed that can be used to prepare various 2-(4-(1-oxo-1,2-dihydrophthalazin-6-yl)-1H-pyrazol-5-yl)benzyl nitrile, including MRTX-1719, which is 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile and has the following structure: .

[0013] In one aspect, this disclosure provides a method for preparing compounds of formula (I), (I) in: R 1 It is halogen, aryl, or heteroaryl; R 2 and R 3 Each is an independent halogen; and R 4 Halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or OR 5 , where R 5 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl. This method involves treating compounds of formula (IA) with an electrophile. (IA) The electrophile is I2, Br2, Cl2, an aryl compound, or a heteroaryl compound. in: M represents a divalent metal in a divalent alkali; and X 1It represents the counter ion of a divalent metal alkali.

[0014] In another aspect, this disclosure provides a method for preparing compounds of formula (II). (II) in: R 2 R 3 and R 11 Each is an independent halogen; R 4 Halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or OR 5 , where R 5 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or a halo-C1-C6 alkyl; R 9 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; and R 10 It is hydrogen. The method includes: (a) Make the compound of formula (I) (I) It reacts with an amine to give a compound of formula (IIA). (IIA) Where R 1 It is halogen, aryl, or heteroaryl; (b) Dehydrating compound (IIA) to obtain compound (IIB), (IIB); (c) Couple the compound of formula (IIB) with an organoboron compound or an organozinc compound to obtain the compound of formula (IIC). (IIC); and (d) Halogenated (IIC) compounds yield compounds of formula (II).

[0015] In another aspect, this disclosure provides a method for preparing compounds of formula (III). (III) The method includes: (a) Treatment of 4-chloro-2,5-difluorobenzoic acid with a divalent metal base yields a mixture; (b) Treating the mixture with iodine yields 4-chloro-3,6-difluoro-2-iodobenzoic acid; (c) React 4-chloro-3,6-difluoro-2-iodobenzoic acid with an amine to give 4-chloro-3,6-difluoro-2-iodobenzoamide; (d) Dehydrate 4-chloro-3,6-difluoro-2-iodobenzamide to give 4-chloro-3,6-difluoro-2-iodobenzylnitrile; (e) Couple 4-chloro-3,6-difluoro-2-iodobenzyl nitrile with an organoboron compound to give 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile; (f) Iodide-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile to give 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile; and (g) 4-Chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile is reacted with cyclopropanol to give 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile.

[0016] In another aspect, this disclosure provides compounds of formula (IV), (IV) in: R 1 It is iodine, aryl, or heteroaryl; R 3 It is bromine or chlorine; and R 12 For -OR 13 or -NR 14 R 15 , where R 13 R 14 and R 15 Each is independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.

[0017] In another aspect, this disclosure provides compositions comprising a mixture of 4-chloro-2,5-difluorobenzoic acid and 4-chloro-3,6-difluoro-2-iodobenzoic acid.

[0018] Other aspects and embodiments of this disclosure will be apparent from the detailed description provided herein. Invention Details

[0020] This invention relates to methods for preparing PRMT5 inhibitors and intermediates for preparing them.

[0021] definition

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, patent applications, and publications cited herein are incorporated herein by reference to the extent consistent with this disclosure. Unless otherwise expressly stated, terms and scope have their usual definitions.

[0023] For simplicity, chemical moieties are defined and are referred to throughout as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms can also be used to convey corresponding polyvalent moieties in suitable structural cases that are obvious to those skilled in the art. For example, while the "alkyl" moieties generally refer to monovalent groups (e.g., CH3-CH2-), in some cases the divalent linking moieties can be "alkyl," in which case those skilled in the art will understand that alkyl refers to divalent groups (e.g., -CH2-CH2-), which is equivalent to the term "alkylene". Similarly, where a divalent moieties are required and described as "aryl," those skilled in the art will understand that the term "aryl" refers to the corresponding divalent arylene moieties. All atoms should be understood to have the normal valence for bond formation (i.e., carbon 4, N 3, O 2, and S 2, 4, or 6, depending on the oxidation state of S).

[0024] The term "amino" refers to -NH2.

[0025] The term "acetyl" refers to -C(O)CH3.

[0026] As used herein, the term "acyl" refers to an alkyl carbonyl or aryl carbonyl substituent, wherein the alkyl and aryl moieties are as defined herein.

[0027] As used herein, the term "alkyl" refers to a saturated straight-chain and branched aliphatic group having 1-12 carbon atoms. Therefore, "alkyl" includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C1 ...1, C1, C1, C1, C1, C1, C1, 10 C 11 and C 12 Group. Alkyl groups can be branched or unbranched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0028] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched aliphatic group having 2-12 carbon atoms and one or more carbon-carbon double bonds. Therefore, "alkenyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C16, C19, C10, C11, C12, C13, C14, C15, C16, C17, C18 ... 10 C 11 and C 12 Groups. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0029] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched aliphatic group having 2-12 carbon atoms and one or more carbon-carbon triple bonds. Therefore, "alkynyl" includes C2, C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C16, C19, C10, C11, C12, C13, C14, C15, C16, C17, C18 ... 10 C 11 and C 12 Groups. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, and hexynyl.

[0030] "alkylene," "alkenylene," or "yntynyl" refers to an alkyl, alkenyl, or yntyl group as defined above, which is located between and serves to connect the other two chemical groups. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. Examples of alkenyl groups include, but are not limited to, vinylene, propenyl, and butenylene. Examples of yntynyl groups include, but are not limited to, ethynylene, propynylene, and butynylene.

[0031] The term "alkoxy" refers to -O (C1-C6 alkyl).

[0032] As used herein, the term "cycloalkyl" refers to a saturated and partially unsaturated cyclic hydrocarbon group having 3–12 carbon atoms. Therefore, "cycloalkyl" includes C3, C4, C5, C6, C7, C8, C9, C16, C17, C18, C19, C19, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C1 10 C 11 and C 12 Cyclic hydrocarbon groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0033] The term "C3-C6 cycloalkoxy" refers to a group of the formula -O (C3-C6 cycloalkyl).

[0034] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more carbon atoms in the chain are independently bounded by O, S, or NR. x Replacement, where R x It is hydrogen or a C1-C3 alkyl group. Examples of heteroalkyl groups include methoxymethyl, methoxyethyl, and methoxypropyl.

[0035] "Aryl" is a C6-C group containing 1-3 aromatic rings. 14 The aromatic group. Therefore, "aryl" includes C6, C... 10 C 13 and C 14 Cyclic hydrocarbon group. A representative aryl group is C6-C. 10Aryl. Specific aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, and fluorenyl. "Aryl" also includes fused polycyclic (e.g., bicyclic) ring systems, wherein one or more of the fused rings are non-aromatic, provided that at least one ring is aromatic, such as indene.

[0036] "Arylalkyl" or "arylalkyl" contains an aryl group covalently linked to an alkyl group, wherein the aryl group is attached to another group via the alkyl moiety. Representative arylalkyl groups are -(C1-C6)alkyl (C6-C6)alkyl groups. 10 Aryl groups, including but not limited to benzyl, phenethyl, and naphthylmethyl. For example, aryl C1-C3 alkyl groups are aryl groups covalently linked to C1-C3 alkyl groups.

[0037] "Heterocyclic group" or "heterocyclic" or "heterocyclic alkyl" refers to a single or bicyclic (e.g., fused) ring structure having 3-12 atoms (3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms), such as 4-8 atoms, wherein one or more ring atoms are independently N, O, or S, and the remainder of the ring atoms is a quaternary carbon or carbonyl carbon. Examples of heterocyclic groups include, but are not limited to, epoxy, ethylene oxide, oxetane, azirne, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophene, pyrrolidinyl, piperidinyl, piperazine, imidazoalkyl, thiazoalkyl, thioheterocyclic butyl, dithiaalkyl, trithiaalkyl, azirnealkyl, oxazoalkyl, dioxopentane, oxazolidinyl, oxazolidinone, decahydroquinolinyl, piperidinone, 4-piperidinone, thiomorpholinyl, dimethylmorpholinyl, and morpholinyl. A heterocyclic group can be attached to a parent group (i.e., a linking point) via any ring atom (including one of the heteroatoms or one of the carbon atoms) on the heterocyclic group. Depending on chemical requirements, the heterocycle can be attached to one or more other groups, for example, acting as a bridging group. The term "heterocyclic group" also includes fused polycyclic (e.g., bicyclic) ring systems, wherein one or more of the fused rings are aromatic or non-aromatic, provided that at least one ring is non-aromatic and contains an N, O, or S ring atom. Examples of such fused polycyclic ring systems are dihydroindolyl, dihydroindol-2-yl, 2,3-dihydrobenzofuran-2-yl, and 2,3,4,5-tetrahydrobenzo[d]oxazol-2-yl. Each of these examples is a 9-membered heterocyclic group.

[0038] As used herein, the term "heteroaryl" refers to a group having 5-14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms; having 6, 10, or 14 π electrons shared in the ring array; and having 1-3 heteroatoms, each independently selected from N, O, or S, in addition to a carbon atom. "Heteroaryl" also includes fused polycyclic (e.g., bicyclic) ring systems, wherein one or more of the fused rings are non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. A heteroaryl can be attached to a parent group (i.e., a linking point) via any ring atom (including one of the heteroatoms or one of the carbon atoms) on the heteroaryl ring. Depending on chemical requirements, a heteroaryl can be attached to one or more other groups, for example, provided it operates as a bridging group.

[0039] Examples of heteroaryl groups include acridinel, aziridine octyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophene, benzooxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazole, phenylisooxazolyl, benzoisothiazolyl, benzimidazolylalkyl, carbazole, 4aH-carbazole, carbolinyl, chromanyl, chromenyl, terolinyl, furanyl, furanyl, and furanyl. Zanyl, imidazolinyl, imidazolyl, 1H-indazole, indoleenyl, dihydroindole, indazinyl, indole, 3H-indole, isobenzofuranyl, isochoryl, isoindazole, isodihydroindole, isoindole, isoquinolinyl, isothiazolyl, isoxazolyl, naphridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolylalkyl Pyrimidinyl, phenanthridine, phenanthrolinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, piperinyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinine Cycloyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthonyl.

[0040] Preferred heteroaryl groups have 5-10 members. Other preferred heteroaryl groups have 5-6 members.

[0041] "Arylidene", "heteroarylidene", or "heterocyclic" are divalent aryl, heteroaryl, or heterocyclic groups as defined above, which are located between two other chemical groups and are used to connect the two other chemical groups.

[0042] As used herein, when a part (e.g., cycloalkyl, aryl, heteroaryl, heterocyclic, urea, etc.) is described as “optionally substituted” without specifying the substituents, it means that the group optionally has a plurality of non-hydrogen substituents, for example, 1-5, or 1-4, or 1-3, or 1 or 2 non-hydrogen substituents.

[0043] As used in this article, the term "halogen" or "halogenated" refers to chlorine, bromine, fluorine, or iodine.

[0044] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms are replaced by halogens. Representative haloalkyl groups are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0045] The term "hydroxyalkyl" refers to -alkylene-OH.

[0046] It should be understood that each individual atom present in formula (I) and the compound in formula (I) can exist in the form of any naturally occurring isotope, with the most abundant isotope being preferred. Thus, by example, each individual hydrogen atom present in formula (I) or the formula shown below can be as… 1 H, 2 H (deuterium; D) or 3 The presence of H (tritium; T) atoms is preferred. 1 H. Similarly, as an example, each individual carbon atom present in formula (I) or the formula shown below can be considered as 12 C 13 C or 14 The presence of C atoms is preferred. 12 C.

[0047] As used in this article, the “effective amount” of a compound is an amount sufficient to treat inflammatory conditions.

[0048] As used herein, a "therapeuticly effective amount" of a compound is an amount sufficient to improve or alleviate symptoms in some way or to stop or reverse the progression of inflammatory conditions. This amount may be effective as a single dose or as prescribed.

[0049] As used in this article, “treatment” means any manner in which the symptoms or pathology of a patient’s condition, disorder, or disease are improved or otherwise beneficially altered.

[0050] As used herein, “improvement of symptoms of an inflammatory condition by application of a particular compound or pharmaceutical composition” means any relief that can be attributed to or associated with the application of the composition, whether permanent or temporary, lasting or transient.

[0051] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably and refer to any animal, including mammals, preferably humans.

[0052] Preparation method

[0053] In one aspect, this disclosure provides a method for preparing compounds of formula (I), (I) in: R 1 It is halogen, aryl, or heteroaryl; R 2 and R 3 Each is an independent halogen; and R 4 Halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or OR 5 , where R 5 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl. The method includes treating compound of formula (IA) with an electrophile. (IA) The electrophile is I2, Br2, Cl2, an aryl compound, or a heteroaryl compound. in: M represents a divalent metal in a divalent alkali; and X 1 It represents the counter ion of a divalent metal alkali.

[0054] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 1 It is a halogen.

[0055] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 1 It is iodine.

[0056] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 1 It is an aryl group.

[0057] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 1 For C6-C 10The aryl group is optionally substituted with one or more of a C1-C6 alkyl, a halo-C1-C6 alkyl, a C3-C6 cycloalkyl, or a C1-C6 alkoxy group.

[0058] In some embodiments of the method for preparing compounds of formula (I) as described in other parts of this document, the aryl group is phenyl, naphthyl, anthraceneyl, fluorenyl, benzyl, phenethyl, or naphthylmethyl.

[0059] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 1 It is a heteroaryl group.

[0060] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 1 It is a 5- or 6-membered heteroaryl group, which may be optionally substituted by one or more C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy groups.

[0061] In some embodiments of the method for preparing compounds of formula (I) as described in other parts of this document, the heteroaryl group is furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrroleyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, or triazinyl.

[0062] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, the electrophile is a heteroaryl compound of formula (IB). (IB) in: X 2 It can be I, Br, or Cl; R 6 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; and R 7 and R 8 Each is independently hydrogen or a protecting group, or R 7 and R 8 Together with the N it combines, it forms a ring structure.

[0063] In some embodiments of the method for preparing heteroaryl compounds of formula (IB) as described in other parts of this document, R 6 It is a methyl group.

[0064] In some embodiments of the method for preparing heteroaryl compounds of formula (IB) as described in other parts of this document, R 7 and R 8 Each is independently hydrogen.

[0065] In some embodiments of the method for preparing heteroaryl compounds of formula (IB) as described in other parts of this document, R 7 and R 8 One is hydrogen, and the other is a protecting group.

[0066] In some embodiments of the method for preparing heteroaryl compounds of formula (IB) as described in other parts of this document, the protecting group is tert-butoxycarbonyl (Boc).

[0067] In some embodiments of the method for preparing heteroaryl compounds of formula (IB) as described in other parts of this document, the ring structure is an phthalimide group.

[0068] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 2 It is fluorine.

[0069] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 3 It is chlorine.

[0070] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 3 It is bromine.

[0071] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 4 It is fluorine.

[0072] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, R 4 OR 5 And R 5 It is cyclopropyl.

[0073] In some embodiments of the method for preparing a compound of formula (I) as described in other parts of this document, the compound of formula (IA) is provided in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether (MTBE), cyclopentylmethyl ether (CPME), toluene, or acetonitrile.

[0074] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, the compound of formula (IA) is provided in THF or 2-MeTHF.

[0075] In some embodiments, the method for preparing the compound of formula (I) is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0076] In some embodiments of the methods for preparing compound (I) as described in other parts of this document, compound (IA) is treated with an electrophile in THF or 2-MeTHF.

[0077] In some embodiments, the method for preparing compound (I) is carried out in an inert atmosphere. Suitable gases for generating an inert atmosphere include nitrogen and argon.

[0078] In some embodiments of the method for preparing compound (I) as described in other parts of this document, the compound (IA) is treated with an electrophile in a nitrogen atmosphere.

[0079] In some embodiments, the method for preparing compound (I) is carried out in an inert atmosphere at a temperature range of about -10 to about -30°C. Representative temperatures used for this reaction are about -10°C, about -15°C, about -20°C, about -25°C, and about -30°C.

[0080] In some embodiments of the method for preparing compound (I) as described in another part of this document, the electrophilic treatment of compound (IA) is carried out in a nitrogen atmosphere at a temperature of about -25°C.

[0081] In some embodiments, the method for preparing compound (I) is carried out for at least 0.5 hours. Representative times for completing the reaction are about 1 hour, about 1.5 hours, and about 2 hours.

[0082] In some embodiments of the method for preparing compound (I) as described in another part of this document, compound (IA) is treated with an electrophile for about 1 hour.

[0083] In some embodiments of the method for preparing compounds of formula (I) as described in other parts of this document, by using a divalent metal base MX 1 Processed (IC) compounds and prepared (IA) compounds, (IC).

[0084] In some embodiments, the preparation of the compound of formula (IA) is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0085] In some embodiments of the method for preparing the (IA) compound as described in other parts of this document, the (IC) compound is treated with a divalent metal base in THF or 2-MeTHF.

[0086] In some embodiments, the preparation of compound (IA) is carried out in an inert atmosphere. Suitable gases for generating an inert atmosphere include nitrogen and argon.

[0087] In some embodiments of the method for preparing compound (IA) as described in other parts of this document, compound (IC) is treated with a divalent metal alkali in a nitrogen atmosphere.

[0088] In some embodiments, the preparation of the compound of formula (IA) is carried out at a temperature of about -30°C or above in an inert atmosphere. Representative temperatures used for this reaction are about -30°C, about -25°C, about -20°C, about -15°C, and about -10°C.

[0089] In some embodiments of the method for preparing compound (IA) as described in other parts of this document, compound (IC) is treated with a divalent metal alkali at a temperature of about -20°C in a nitrogen atmosphere.

[0090] In some embodiments, the preparation of compound (IA) is carried out for at least 1 hour. Representative times for completing the reaction are about 2 hours, about 3 hours, and about 4 hours.

[0091] In some embodiments of the method for preparing compound (IA) as described in another part of this document, compound (IC) is treated with a divalent metal base for about 3 hours.

[0092] In some embodiments, the preparation of the (IA) compound is carried out using the (IC) compound with a divalent metal base in a molar ratio of about 2.0:1.0, about 2.2:1.0, or about 2.5:1.0.

[0093] In some embodiments of the method for preparing the (IA) compound as described in another part of this document, the (IC) compound is treated with a divalent metal base using a molar ratio of about 2.2 to 1.0.

[0094] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, the divalent metal base is a magnesium base. In some embodiments, the magnesium base is a metal with R... G MgX-type alkyl Grignard reagents, where R G The form is C1-C6 alkyl, C3-C6 cycloalkyl, or NR1R2, wherein R1 and R2 are each independently C1-C6 alkyl, C3-C6 cycloalkyl, or together with the attached nitrogen to form a 3-8 membered monocyclic heterocyclic group, wherein the 3-8 membered monocyclic heterocyclic group is optionally substituted with a C1-C6 alkyl group, and wherein X is I, Br, or Cl. Suitable magnesium bases include TMPMgCl·LiCl, (TMP)2Mg·2LiCl, and i-PrMgCl·LiCl, wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

[0095] In some embodiments of the method for preparing compound (I) as described in a further section of this document, a magnesium base is provided to the reaction for treating compound (IC) in a solvent. Suitable solvents include dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, and acetonitrile. In some embodiments of the method for preparing compound (I) as described in a further section of this document, the divalent metal base is a zinc base. Suitable zinc bases include (TMP)₂Zn·₂LiCl and TMPZnCl·LiCl, wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

[0096] In some embodiments of the method for preparing compound (I) as described in another part of this document, the zinc base is a dialkylzinc or a dialkylzinc halide.

[0097] In some embodiments of the method for preparing compound (I) as described in another part of this document, the zinc base is Et2Zn or EtZnCl.

[0098] In some embodiments of the methods for preparing compounds of formula (I) as described in other parts of this document, the compound of formula (I) is 4-chloro-3,6-difluoro-2-iodobenzoic acid, which is prepared by: (a) Treatment of 4-chloro-2,5-difluorobenzoic acid with a divalent metal base yields a mixture; and (b) The mixture was treated with iodine to give 4-chloro-3,6-difluoro-2-iodobenzoic acid.

[0099] In one aspect, this disclosure provides a method for preparing compounds of formula (II), (II) in: R2 R 3 and R 11 Each is an independent halogen; R 4 Halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or OR 5 , where R 5 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or a halo-C1-C6 alkyl; R 9 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; and R 10 It is hydrogen. The method includes: (a) Make compound (I) (I) It reacts with an amine to give a compound of formula (IIA). (IIA) Where R 1 It is halogen, aryl, or heteroaryl; (b) Dehydrating compound (IIA) to obtain compound (IIB), (IIB); (c) Couple compound (IIB) with an organoboron compound to obtain compound (IIC). (IIC); and (d) Halogenated (IIC) compounds yield compounds of formula (II).

[0100] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 2 It is fluorine.

[0101] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 3 It is chlorine.

[0102] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 3 It is bromine.

[0103] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 4 It is fluorine.

[0104] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R4 OR 5 And R 5 It is cyclopropyl.

[0105] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 9 It is a C1-C6 alkyl group.

[0106] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 9 It is a methyl group.

[0107] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 10 It is hydrogen.

[0108] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 11 It is iodine.

[0109] In some embodiments of the method for preparing compound (II) as described in other parts of this document, step (a) further includes treating compound (I) with an activating agent, followed by reaction with an amine to obtain compound (IIA).

[0110] In some embodiments of the method for preparing compounds of formula (IIA) as described in other parts of this document, the activating agent is carbonyl diimidazole (CDI), 1,1'-thiocarbonyl diimidazole (TCDI), carbonyl dichloride, or thionyl chloride (SOCl2).

[0111] In some embodiments, the treatment of compound (I) with an activating agent is carried out using a molar ratio of compound (I) to activating agent of about 1:1.5, about 1:2, or about 1:2.5.

[0112] In some embodiments of the method for preparing compound (II) as described in another part of this document, in step (a), compound (I) is treated with an activating agent using a molar ratio of compound (I) to activating agent of about 1:2.

[0113] In some embodiments of the method for preparing compound (II) as described in other parts of this document, in step (a), compound (I) is prepared by treating compound (IA) with an electrophile. (IA) The electrophile is I2, Br2, Cl2, an aryl compound, or a heteroaryl compound. in: M represents a divalent metal in a divalent alkali; and X 1 It represents the counter ion of a divalent metal alkali.

[0114] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, in step (a), by using a divalent metal base MX 1 Processed (IB) compounds and prepared (IA) compounds, (IB).

[0115] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, R 1 It is iodine.

[0116] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, the compound of formula (II) is 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzylnitrile, which is prepared by: (a) Reacting 4-chloro-3,6-difluoro-2-iodobenzoic acid with an amine to give 4-chloro-3,6-difluoro-2-iodobenzoamide; (b) Dehydrate 4-chloro-3,6-difluoro-2-iodobenzamide to give 4-chloro-3,6-difluoro-2-iodobenzylnitrile; (c) Coupling 4-chloro-3,6-difluoro-2-iodobenzyl nitrile with an organoboron compound to give 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile; and (b) Iodide 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile to give 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile.

[0117] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, step (a) further includes treating 4-chloro-3,6-difluoro-2-iodobenzoic acid with an activating agent, followed by reaction with an amine to give 4-chloro-3,6-difluoro-2-iodobenzoamide.

[0118] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, the activating agent is CDI, TCDI, carbonyl dichloride, or SOCl2.

[0119] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, in step (a), 4-chloro-3,6-difluoro-2-iodobenzoic acid is prepared by: (1) Treating 4-chloro-2,5-difluorobenzoic acid with a divalent metal alkali yields a mixture; and (b) The mixture was treated with iodine to give 4-chloro-3,6-difluoro-2-iodobenzoic acid.

[0120] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, in step (a), the amine is ammonia or ammonium hydroxide.

[0121] In some embodiments, the method for preparing the (IIA) compound is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0122] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, step (a) is carried out in a solution of THF or 2-MeTHF.

[0123] In some embodiments, the method for preparing the (IIA) compound is carried out in an inert atmosphere at a temperature range of about 20 to about 60°C. Suitable gases for generating the inert atmosphere include nitrogen and argon. Representative temperatures for this reaction are about 50°C and about 55°C.

[0124] In some embodiments of the method for preparing compound (II) as described in another part of this document, step (a) is carried out at a temperature of about 50°C in a nitrogen atmosphere.

[0125] In some embodiments, the method for preparing the (IIA) compound is carried out for at least 0.5 hours. A representative time for completing the reaction is at least 1 hour, or at least 1.5 hours and at least 2 hours.

[0126] In some embodiments of the method for preparing compound (II) as described in another part of this document, step (a) is performed for at least 1 hour.

[0127] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, step (b) is carried out in the presence of trifluoroacetic anhydride (TFAA), phosphoryl chloride (POCl3), SOCl2 or oxalyl chloride (COCl)2.

[0128] In some embodiments, the method for preparing the (IIB) compound is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0129] In some embodiments of the method for preparing compound (II) as described in other parts of this document, step (b) is carried out in a solution of THF or 2-MeTHF.

[0130] In some embodiments, the method for preparing the formula (IIB) compound is carried out in an inert atmosphere at a temperature range of about 0 to about 25°C. Suitable gases for generating the inert atmosphere include nitrogen and argon. Representative temperatures for this reaction are about 0°C, about 10°C, and about 20°C.

[0131] In some embodiments of the method for preparing compound (II) as described in other parts of this document, step (b) is carried out at a temperature of about 10°C in a nitrogen atmosphere.

[0132] In some embodiments, the method for preparing the formula (IIB) compound is carried out for at least 20 minutes. Representative times for completing the reaction are about 0.5 hours and about 1 hour.

[0133] In some embodiments of the method for preparing compound (II) as described in another part of this document, step (b) is performed for about 0.5 hours.

[0134] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, in step (c), the organoboron compound is a boric acid or ester having the structure of formula (IID). (IID) Where R is hydrogen or C1-C6 alkyl.

[0135] In some embodiments of the methods for preparing formula (IIC) compounds as described in other parts of this document, the organoboron compound is... .

[0136] In some embodiments of the methods for preparing compounds of formula (IIC) as described in other parts of this document, the organozinc compound has the structure of formula (IIE). (IIE) Where X is I, Br, or Cl.

[0137] In some embodiments of the method for preparing formula (IIC) compounds as described in other parts of this document, step (c) is carried out in the presence of a catalyst.

[0138] In some embodiments of the methods for preparing formula (IIC) compounds as described in other parts of this document, the catalyst is a palladium catalyst.

[0139] In some embodiments of the method for preparing the (IIC) compound as described in other parts of this document, the palladium catalyst is [P(t-Bu)2(n-Bu)]-Pd-G3, Pd(amphos)Cl, or (amphos)2PdCl2.

[0140] In some embodiments of the method for preparing formula (IIC) compounds as described in other parts of this document, the palladium catalyst is a precatalyst prepared from a palladium source and a ligand.

[0141] In some embodiments of the method for preparing the IIC compound as described in other parts of this document, the palladium source is Pd(OAc)2 or Pd2(dba)3.

[0142] In some embodiments of the methods for preparing formula (IIC) compounds as described in other parts of this document, the ligand is amphos or P(tBu)2(nBu).

[0143] In some embodiments of the methods for preparing formula (IIC) compounds as described in other parts of this document, the catalyst is a nickel catalyst.

[0144] In some embodiments, the method for preparing the formula (IIC) compound is carried out with the formula (IIB) compound and the organoboron compound in a molar ratio of about 1:1.10, about 1:1.12, about 1:1.15, about 1:1.18, or about 1:2.

[0145] In some embodiments of the method for preparing compound (II) as described in another part of this document, in step (c), the molar ratio of compound (IIB) to organoboron compound is about 1:1.15.

[0146] In some embodiments, the method for preparing the formula (IIC) compound is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0147] In some embodiments of the method for preparing formula (IIC) compounds as described in other parts of this document, step (c) is carried out in a solution of THF or toluene.

[0148] In some embodiments, the method for preparing the formula (IIC) compound is carried out in an inert atmosphere at a temperature range of about 60 to about 80°C. Suitable gases for generating the inert atmosphere include nitrogen and argon. Representative temperatures for this reaction are about 65°C, about 70°C, and about 75°C.

[0149] In some embodiments of the method for preparing formula (IIC) compounds as described in other parts of this document, step (c) is carried out at a temperature of about 75°C in a nitrogen atmosphere.

[0150] In some embodiments, the method for preparing the (IIC) compound is carried out for at least 15 hours. Representative times for completing the reaction are about 18 hours, about 20 hours, and about 22 hours.

[0151] In some embodiments of the method for preparing formula (IIC) compounds as described in other parts of this document, step (c) is performed for approximately 20 hours.

[0152] In some embodiments of the method for preparing compound (II) as described in other parts of this document, step (d) comprises an iodination step (c) to obtain compound (II).

[0153] In some embodiments of the method for preparing compounds of formula (II) as described in other parts of this document, step (d) is carried out in the presence of an iodine reagent.

[0154] In some embodiments of the methods for preparing compounds of formula (II) as described in other parts of this document, the iodizing agent is molecular iodine or N-iodosuccinimide (NIS).

[0155] In some embodiments, the halogenation of the formula (IIC) compound is carried out using a molar ratio of the formula (IIC) compound to an iodide compound of about 1:1, about 1:1.1, or about 1:1.2.

[0156] In some embodiments of the method for preparing compound (II) as described in another part of this document, in step (d), the molar ratio of compound (IIC) to iodide compound is about 1:1.1.

[0157] In some embodiments, the halogenation of the compound of formula (IIC) is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0158] In some embodiments of the method for preparing compound (II) as described in another part of this document, step (d) is carried out in a solution of acetonitrile.

[0159] In some embodiments, the halogenation of the (IIC) compound is carried out in an inert atmosphere at a temperature range of about 40–60 °C. Suitable gases for generating an inert atmosphere include nitrogen and argon. Representative temperatures for this reaction are about 45 °C, about 50 °C, and about 55 °C.

[0160] In some embodiments of the method for preparing compound (II) as described in another part of this document, step (d) is carried out at a temperature of about 55°C in a nitrogen atmosphere.

[0161] In some embodiments, the halogenation of the (IIC) compound is carried out for at least 3 hours. Representative times for completing the reaction are at least 3.5 hours, at least 4 hours, and at least 4.5 hours.

[0162] In some embodiments of the method for preparing compound (II) as described in another part of this document, step (d) is performed for at least 4 hours.

[0163] In one aspect, this disclosure provides a method for preparing compound (MRTX-1719) of formula (III). (III) The method includes: (a) Treatment of 4-chloro-2,5-difluorobenzoic acid with a divalent metal base yields a mixture; (b) Treating the mixture with iodine yields 4-chloro-3,6-difluoro-2-iodobenzoic acid; (c) React 4-chloro-3,6-difluoro-2-iodobenzoic acid with an amine to give 4-chloro-3,6-difluoro-2-iodobenzoamide; (d) Dehydrate 4-chloro-3,6-difluoro-2-iodobenzamide to give 4-chloro-3,6-difluoro-2-iodobenzylnitrile; (e) Couple 4-chloro-3,6-difluoro-2-iodobenzyl nitrile with an organoboron compound to give 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile; (f) Iodide-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile to give 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile; and (g) 4-Chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile is reacted with cyclopropanol to give 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile.

[0164] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, the divalent metal base is TMPMgCl·LiCl, (TMP)2Mg·2LiCl or i-PrMgCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

[0165] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, the divalent metal base is (TMP)2Zn·2LiCl or TMPZnCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

[0166] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, the divalent metal base is a dialkylzinc or a dialkylzinc halide.

[0167] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, the divalent metal base is Et₂Zn or EtZnCl.

[0168] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, step (a) is carried out in a solution of 2-MeTHF at about -20°C in an inert atmosphere.

[0169] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, step (b) is carried out in a solution of 2-MeTHF at about -15°C in an inert atmosphere.

[0170] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (b), iodine is used as a solution of I2 in 2-MeTHF.

[0171] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, step (b) further includes treating 4-chloro-3,6-difluoro-2-iodobenzoic acid with CDI, followed by treatment with an amine in step (c).

[0172] In some embodiments of the methods for preparing compounds of formula (III) as described in other parts of this document, the amine is ammonia or ammonium hydroxide.

[0173] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (e), the organoboron compound is 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole.

[0174] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, iodination is performed using NIS in step (f).

[0175] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, the method further includes: (h) Coupling 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile with the protected organoborophytazine compound; and (i) Deprotect the product of step (h).

[0176] In some embodiments, the coupling of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile with the protected organoborophytazine compound is carried out using a molar ratio of about 1.2:1 or about 1.5:1.

[0177] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (h), the molar ratio of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile to the protected organoborophytazine compound is about 1.2:1.

[0178] In some embodiments, the coupling of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile with the protected organoborophytazine compound is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0179] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, step (h) is carried out in a solution of toluene.

[0180] In some embodiments, the coupling of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzylnitrile with the protected organoborophytazine compound is carried out in an inert atmosphere at a temperature range of about 50 to about 70°C. Suitable gases for generating an inert atmosphere include nitrogen and argon. Representative temperatures for this reaction are about 55°C, about 60°C, and about 65°C.

[0181] In some embodiments of the method for preparing compound (III) as described in another part of this document, step (h) is carried out at a temperature of about 60°C.

[0182] In some embodiments of the methods described in other parts of this document, the protected organoborophthalazine compound is tert-butyl carbamate ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,4-dihydrophthalazine-1-yl)methyl)carbamate.

[0183] In certain embodiments of the methods described elsewhere herein, the protected organoborophytazine compound is prepared by treating ((7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate tert-butyl with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboronylcyclopentane) in the presence of tris(dibenzylideneacetone)dipalladium(O).

[0184] In some embodiments, the preparation of the protected organoborophthalazine compound is carried out using a molar ratio of about 1:1.2 or about 1:1.5 or about 1:1.8 or about 1:2 of tert-butyl ((7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboranecyclopentane).

[0185] In certain embodiments for preparing the protected organoborophthalazine compound, as described in other parts of this document, the molar ratio of ((7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate tert-butyl to 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) is about 1:1.5.

[0186] In some embodiments, the preparation of the protected organoborophthalazine compound is carried out using ((7-chloro-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl ester with tris(dibenzylideneacetone)dipalladium(0) in a molar ratio of about 1:0.10, about 1:0.15, or about 1:0.2.

[0187] In some embodiments of the method for preparing the protected organoborophthalazine compound as described in another part of this document, the molar ratio of ((7-chloro-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate tert-butyl ester to tris(dibenzylideneacetone)dipalladium(0) is about 1:0.10.

[0188] In some embodiments, the preparation of the protected organoborophytazine compound is carried out in the presence of a base. Suitable bases include sodium acetate, potassium acetate, and magnesium acetate.

[0189] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (h), the preparation of the protected organoborophytazine compound is carried out in the presence of potassium acetate.

[0190] In some embodiments, the preparation of the protected organoborophytazine compound is carried out in a solvent. Suitable solvents include ether solvents and aprotic solvents. In some embodiments as described in other parts of this document, the solvent is dimethyl ether, diethyl ether, THF, 2-MeTHF, 1,4-dioxane, 1,2-dimethoxyethane, MTBE, CPME, toluene, or acetonitrile.

[0191] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (h), the preparation of the protected organoborophytazine compound is carried out in a solution of 1,4-dioxane.

[0192] In some embodiments, the preparation of the protected organoborophytazine compound is carried out in an inert atmosphere at a temperature range of about 80 to about 120°C. Suitable gases for generating the inert atmosphere include nitrogen and argon. Representative temperatures for this reaction are about 90°C, about 100°C, and about 110°C.

[0193] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (h), the preparation of the protected organoborophytazine compound is carried out at about 100°C in a nitrogen atmosphere.

[0194] In some embodiments, the deprotection of the product of step (h) is carried out under acidic conditions. Suitable acids for generating acidic conditions include HCl and trifluoroacetic acid (TFA).

[0195] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (h), the product of step (h) is deprotected using HCl or TFA.

[0196] In some embodiments, the deprotection of the product in step (h) is carried out in a temperature range of about 10 to about 40°C. Representative temperatures used for this reaction are about 15°C, about 20°C, about 25°C, about 30°C, and about 35°C.

[0197] In some embodiments of the method for preparing compounds of formula (III) as described in other parts of this document, in step (h), the product of step (h) is deprotected at a temperature of about 30°C.

[0198] Compounds and Compositions

[0199] In one aspect, this disclosure provides compounds of formula (IV), (IV) in: R 1 It is iodine, aryl, or heteroaryl; R 3 It is bromine or chlorine; and R 12 For -OR 13 or -NR 14 R 15 , where R 13 R 14 and R 15 Each is independently hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl.

[0200] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 1 It is iodine.

[0201] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 1 It is an aryl group.

[0202] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 1 For C6-C 10 The aryl group is optionally substituted with one or more of a C1-C6 alkyl, a halo-C1-C6 alkyl, a C3-C6 cycloalkyl, or a C1-C6 alkoxy group.

[0203] In some embodiments of the compounds of formula (IV) as described in other parts of this document, the aryl group is phenyl, naphthyl, anthraceneyl, fluorenyl, benzyl, phenethyl, or naphthylmethyl.

[0204] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 1 It is a heteroaryl group.

[0205] In some embodiments of the compound of formula (IV) as described in other parts of this document, R1 It is a 5- or 6-membered heteroaryl group, which may be optionally substituted by one or more C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy groups.

[0206] In certain embodiments of compounds of formula (IV) as described in other parts of this document, the heteroaryl group is furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrroleyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, or triazinyl.

[0207] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 3 It is chlorine.

[0208] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 3 It is bromine.

[0209] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 12 It is -OH.

[0210] In some embodiments of the compound of formula (IV) as described in other parts of this document, R 12 It is -NH2.

[0211] In another aspect, this disclosure provides compositions comprising a mixture of 4-chloro-2,5-difluorobenzoic acid and 4-chloro-3,6-difluoro-2-iodobenzoic acid.

[0212] In some embodiments of the compositions as described in other parts of this document, the mixture is substantially free of 4-chloro-2,5-difluoro-3-iodobenzoic acid.

[0213] In certain embodiments of the compositions as described in other parts of this document, the mixture comprises more than about 90% (w / w) of 4-chloro-3,6-difluoro-2-iodobenzoic acid and less than about 10% of 4-chloro-2,5-difluoro-3-iodobenzoic acid, based on the combined weight of 4-chloro-3,6-difluoro-2-iodobenzoic acid and 4-chloro-2,5-difluoro-3-iodobenzoic acid.

[0214] In some embodiments of the compositions as described in other parts of this document, the mixture comprises 4-chloro-3,6-difluoro-2-iodobenzoic acid and 4-chloro-2,5-difluoro-3-iodobenzoic acid in a ratio of 99:1.

[0215] In some embodiments of the compositions as described in other parts of this document, the compositions further comprise a divalent base.

[0216] In certain embodiments of the compositions as described in other parts of this document, the divalent base is TMPMgCl·LiCl, (TMP)2Mg·2LiCl, or i-PrMgCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

[0217] In certain embodiments of the compositions as described in other parts of this document, the divalent metal base is (TMP)2Zn·2LiCl or TMPZnCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

[0218] In some embodiments of the compositions as described in other parts of this document, the divalent metal base is a dialkylzinc or a dialkylzinc halide.

[0219] In some embodiments of the composition as described in other parts of this document, the divalent metal base is Et₂Zn or EtZnCl.

[0220] In some embodiments of the composition as described in other parts of this document, the composition further comprises iodine.

[0221] Methods for separating enantiomers

[0222] The compound of formula (III) (MRTX-1719) prepared by the methods described herein is axially chiral and contains a mixture of its M- and P-enantiomers.

[0223]

[0224] However, only the M-enantiomer possesses pharmacological activity. A method for separating mixtures of M- and P-enantiomers is described in International Application Publication No. 2023 / 059798, published on April 13, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0225] In short, in one respect, separation methods include: (a) Treating the mixture with N-Boc-D-phenylalanine to form a mixture of M- and P-enantiomers of N-Boc-D-phenylalanine salts; (b) Filter the mixture of M- and P-enantiomers of N-Boc-D-phenylalanine salt to obtain a solid phase rich in M-enantiomers of N-Boc-D-phenylalanine salt; and (c) React the solid phase with a base to obtain a solid rich in the M-enantiomer of compound (IV) as a free base.

[0226] In one aspect, separation methods include: (a) Treating the mixture with N-Boc-L-phenylalanine to form a mixture of M- and P-enantiomers of N-Boc-L-phenylalanine salts; (b) Filtering a mixture of M- and P-enantiomers of N-Boc-L-phenylalanine salts to obtain a liquid phase rich in M-enantiomers of N-Boc-L-phenylalanine salts; and (c) The liquid phase is reacted with a base to obtain a solid rich in the M-enantiomer of the compound of formula (III) as a free base.

[0227] In one aspect, the method includes: (a) Protecting the M- and P-enantiomers of compound (III) with a protecting group; (b) Chromatographic separation of the M-enantiomer and the P-enantiomer of the protected compound (III); and (c) Deprotect the M-enantiomer of the protected compound (III) to obtain the M-enantiomer of the compound (III) as a free base.

[0228] Other aspects and implementation schemes of the separation method are readily apparent from the detailed description provided herein.

[0229] General reaction schemes and examples

[0230] The compounds of this invention can be prepared using commercially available reagents and conventional methods well known to those skilled in the art, such as those described in the general reaction schemes and examples herein. Those skilled in the art can adjust the reaction sequence of the schemes provided herein to suit a desired target molecule. Of course, in some cases, those skilled in the art may use different reagents to influence one or more individual steps, or to use certain protected forms with substituents. Furthermore, those skilled in the art will recognize that the compounds of this disclosure can be synthesized using entirely different routes. For example, those skilled in the art can prepare the compounds described herein using the methods described herein and / or other methods well known to those skilled in the art.

[0231] Numerous general references can be used to provide known chemical synthesis schemes and conditions for synthesizing the disclosed compounds. For example, the compounds of the present invention can be prepared using the reagents and methods described in International Application Publication No. 2021 / 050915, published March 18, 2021, and International Application Publication No. 2023 / 059798, published April 13, 2023, the disclosures of which are incorporated herein by reference in their entirety.

[0232] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as HPLC, preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal-phase and reversed-phase, as well as ion exchange resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, edited by LR Snyder and JJ Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edited by E. Stahl, Springer-Verlag, New York, 1969.

[0233] In any of the methods for preparing the subject compound, protecting sensitive or reactive groups on any relevant molecule involved is essential and / or desirable. This can be achieved using conventional protecting groups as described in standard publications, such as JFW McOmie, “Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973; TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis,” 3rd ed., Wiley, New York 1999; “The Peptides”; Vol. 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981; “Methodender organic Chemistry,” Houben-Weyl, 4th Supplement, Vol. 15 / 1; Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine,” Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982; and / or Jochen Lehmann, “Chemie… “The Kohlenhydrate: Monosaccharide and Derivate,” Georg Thieme Verlag, Stuttgart 1974. The protecting group can be removed at a convenient subsequent stage using methods known in the art.

[0234] General Reaction Scheme 1

[0235] Where M represents Mg or Zn, a divalent metal alkali, and X 1 It represents the counter ion of a divalent metal alkali.

[0236] General Reaction Scheme 2

[0237] General Reaction Scheme 3

[0238] General Reaction Scheme 4

[0239] General Reaction Scheme 5

[0240] Where PG represents a protecting group, and R is hydrogen or a C1-C6 alkyl group.

[0241] General Reaction Scheme 6

[0242] Example 1

[0243] Synthesis of 4-chloro-3,6-difluoro-2-iodobenzoic acid

[0244] 1.5 kg (7.8 mol) of 4-chloro-2,5-difluorobenzoic acid was dissolved in 6.0 L of 2-MeTHF, and the solution was degassed with nitrogen and stirred at room temperature. The solution was then cooled to approximately -25 °C under nitrogen, and 17.2 L (2.2 equivalents; TMP = 2,2,6,6-tetramethylpiperidinyl) of 1.0 MtMPMgCl·LiCl solution was added to the solution while maintaining the reaction temperature at approximately -20 °C. The resulting reaction mixture was stirred at approximately -20 °C for approximately 3 h to obtain the first reaction mixture. In another container, a solution of iodine (2.5 kg, 9.8 mol) in 6.0 L of 2-MeTHF was prepared, and the solution was degassed with nitrogen and stirred at room temperature to obtain the second reaction mixture. The second reaction mixture was then cooled to approximately -35 °C. The first reaction mixture was added to the second reaction mixture at a temperature not exceeding -25 °C, and the resulting mixture was stirred at approximately -25 °C for approximately 1 h. Slowly add 4.5 L of saturated NH4Cl aqueous solution to the resulting mixture at a temperature not exceeding 10 °C, followed by 9.8 L of saturated NaHSO3 aqueous solution at a temperature not exceeding 10 °C. Concentrate the resulting mixture by vacuum distillation at a temperature not exceeding 45 °C, and add 15 L of methyl tert-butyl ether (MTBE) to the residue. Stir the resulting mixture at about 20 °C for about 0.5 h. Slowly add 6 N HCl solution to the resulting mixture until the pH of the aqueous layer is 1–2, and then filter. Wash the waste filter cake with MTBE (2 × 3 L), and combine all MTBE filtrates. Wash the resulting organic layer with water (7.5 L), and then exchange the solvent with THF by vacuum distillation at a temperature not exceeding 45 °C (target: <5 L) to give a colorless or brown solution of 4-chloro-3,6-difluoro-2-iodobenzoic acid in THF (5.35 kg, 7.0 mol, 90% determination yield), which can be used for subsequent synthesis without further purification.

[0245] Example 2

[0246] Synthesis of 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzylnitrile

[0247] Step 1: Synthesis of 4-chloro-3,6-difluoro-2-iodobenzamide

[0248] Carbonyl diimidazole (2.3 kg, 14 mol, 2.0 equivalent; CDI) was added in portions to a solution of 4-chloro-3,6-difluoro-2-iodobenzoic acid in THF (5.35 kg, 7.0 mol) at a temperature not exceeding 25 °C, and the reaction mixture was degassed with nitrogen and stirred at about 20 °C for about 0.5 h. The reaction mixture was then stirred at about 55 °C for at least 2 h. A ~28 wt% aqueous solution of ammonium hydroxide (6.7 L) was added to the reaction mixture at a temperature not exceeding 55 °C, and the resulting reaction mixture was stirred at about 50 °C for at least 1 h. The resulting mixture was concentrated by vacuum distillation at a temperature not exceeding 45 °C, and water (11 L) was added to the residue. The residue was stirred at about 20 °C for at least 1 h, followed by filtration. The filtered residue was slurried again in water (6.7 L) and then in heptane (6.7 L), and the residue was dried under vacuum at a temperature not exceeding 55 °C to give 4-chloro-3,6-difluoro-2-iodobenzamide as a solid (2.1 kg, 6.6 mol, 95% yield).

[0249] Step 2: Synthesis of 4-chloro-3,6-difluoro-2-iodobenzylnitrile

[0250] 4-Chloro-3,6-difluoro-2-iodobenzamide (2.1 kg, 6.6 mol) was dissolved in THF (10.5 L) at room temperature and then degassed with nitrogen. The solution was then cooled to approximately 0 °C. Triethylamine (2.4 L, 17 mol, 2.6 equivalents; Et3N) was added dropwise to the solution at a temperature not exceeding 10 °C, followed by trifluoroacetic anhydride (1.2 L, 8.6 mol, 1.3 equivalents; TFAA) at a temperature not exceeding 10 °C. The resulting mixture was stirred at a temperature not exceeding 10 °C for approximately 0.5 h, and then stirred at a temperature not exceeding 25 °C for at least 2 h. The resulting mixture was then cooled to approximately 0 °C. Water (2.1 L) was added dropwise to the resulting mixture at a temperature not exceeding 10 °C, and the resulting mixture was stirred at a temperature not exceeding 10 °C for approximately 0.5 h. The resulting mixture was then concentrated by vacuum distillation at a temperature not exceeding 45 °C, and a 5% w / w aqueous solution of K2CO3 (8.4 L) was added to the residue. The resulting residue was stirred at a temperature not exceeding 25°C for about 0.5 h, and then filtered. The filtered residue was washed with water (4.2 L) and dried under vacuum at a temperature not exceeding 60°C to give 4-chloro-3,6-difluoro-2-iodobenzyl nitrile as a solid (1.88 kg, 6.27 mol, 95% yield).

[0251] Step 3: Synthesis of 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzylnitrile

[0252] A mixture of toluene (19 L), 4-chloro-3,6-difluoro-2-iodobenzyl nitrile (1.88 kg, 6.27 mol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (1.50 kg, 7.2 mol, 1.15 equivalents), and K3PO4 (2.8 kg, 13 mol, 2.0 equivalents) was degassed with nitrogen and stirred at room temperature under surface nitrogen injection for about 0.5 h. [P(t-Bu)2(n-Bu)]-Pd-G3 (3.0 mol%, 0.19 mol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature under surface nitrogen injection for about 0.5 h. The reaction mixture was then heated to about 70 °C, and degassed water (0.94 L) was added to the reaction mixture. The reaction mixture was then stirred at about 75 °C for about 20 h. The reaction mixture was then cooled to 20°C, and water (19 L) was added, followed by filtration. The resulting organic layer was concentrated by vacuum distillation at a temperature not exceeding 55°C, and heptane (9.4 L) was added to the residue at about 55°C. The resulting residue was cooled to about 20°C and stirred for at least 5 h, followed by filtration. The filtered residue was washed with heptane (2 × 2 L) and dried under vacuum at a temperature not exceeding 45°C to give 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile as a solid (1.11 kg, 4.39 mol, 70% yield).

[0253] Step 4: Synthesis of 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzylnitrile

[0254] 4-Chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile (1.11 kg, 4.39 mol) was dissolved in acetonitrile (6.6 L) at room temperature, and the solution was degassed with nitrogen. N-iodosuccinimide (1.09 kg, 4.8 mol, 1.1 equivalent; NIS) was added to the solution at about 20 °C, followed by dropwise addition of trifluoroacetic acid (0.17 L, 2.2 mol) at a temperature not exceeding 25 °C. The reaction mixture was then heated to about 55 °C and stirred for at least 4 h. The reaction mixture was concentrated by vacuum distillation at a temperature not exceeding 45 °C, and MTBE (11 L) was added to the residue at about 20 °C. A 15% w / w aqueous solution of Na₂SO₃ (3.3 L) was added to the resulting residue, and the residue was stirred at about 20 °C for at least 0.5 h. The organic layer was washed with 6.1 L of 5% w / w NaHCO3 aqueous solution and 6.6 L of brine, and concentrated by vacuum distillation at a temperature not exceeding 45 °C. Heptane (11 L) was added to the residue. The residue was cooled to 20 °C and stirred for at least 5 h, followed by filtration. The filtered residue was washed with heptane (3.3 L) and dried under vacuum at a temperature not exceeding 45 °C to give 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile as a solid (1.45 kg, 3.82 mol, 87% yield).

[0255] Example 3

[0256] Synthesis of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile

[0257] A mixture of dimethylformamide (8.7 L; DMF), 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzylnitrile (1.45 kg, 3.82 mol), cyclopropanol (233 g, 4.01 mol, 1.05 equivalent; cPrOH), and K3PO4 (2.43 kg, 11.5 mol, 3.0 equivalent) was degassed with nitrogen at room temperature. Water (0.22 L) was added to the reaction mixture at about 20 °C. The reaction mixture was then heated to about 35 °C and stirred for at least 15 h. Subsequently, the reaction mixture was heated to about 45 °C and stirred for at least 2 h. The reaction mixture was then cooled to about 0 °C. Water (17 L) was slowly added to the reaction mixture at about 0 °C, and the resulting mixture was stirred for at least 3 h, followed by filtration. The residue obtained was a crude product of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile. The crude product was then dissolved in acetone (8.7 L). Water (8.7 L) was added to the resulting mixture at approximately 20 °C, and the mixture was stirred for at least 3 h, followed by filtration. The filtered residue was vacuum dried at a temperature not exceeding 60 °C to give a purified product of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile as a solid (1.28 kg, 3.06 mol, 80% yield).

[0258] Example 4

[0259] Synthesis of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile

[0260] Step 1: Synthesis of tert-butyl carbamate ((7-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate

[0261] Add 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile (18.1 kg, 43.3 mol, 1.00 equivalent), ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate tert-butyl ester (19.5 kg, 48.5 mol, 1.12 equivalent), toluene (12 vol; vol = L / kg), water (4 vol), and Cs₂CO₃ (42.4 kg, 130 mol, 3.00 equivalent) to a 1000 L reactor. Stir the mixture at 15–25 °C for approximately 15 minutes, then degas under vacuum and back-purge with nitrogen (repeated three times). Add Ad2nBuP-Pd-G3 (946 g, 1.30 mol, 0.03 equivalents), and degas the mixture under vacuum, then back-purge with nitrogen (repeated three times). Heat the reactor contents to 55–60 °C and continue stirring within this temperature range until Suzuki coupling is complete (by LC, <5.0% of 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile residue). Cool the batch to 45–50 °C. Add an aqueous solution of cysteine ​​(20 w / w%) and 2-MeTHF (12 vol) to the reactor, and stir the two-phase mixture at 45–50 °C for approximately 6–8 hours. Discard the aqueous phase and wash the organic phase with a 17% NaCl aqueous solution (2 × 5 vol). Anhydrous MgSO4 (18 kg, 100 w / w%) and activated carbon (3.6 kg, 20 w / w%) were added to the crude organic layer, and the mixture was stirred at 45–50 °C for approximately 4–6 hours. The inorganic solids were filtered off, and the waste cake was washed with 2-MeTHF (vol mL). The combined organic filtrate was concentrated under reduced pressure to 2–4 mL at 30–60 °C. The mixture was then subjected to repeated vacuum feed-discharge distillation with MeOH (3 vol) at 30–60 °C to reduce the toluene content (<5.0%). This batch was diluted with MeOH (7 vol) (approximately 3 vol), and stirred at 45–50 °C for approximately 6 hours. The batch was cooled to 20-25°C and stirred for approximately 12 hours to reduce the supernatant concentration of ((7-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazine-1-yl)methyl)carbamate to <5.0%). The solid was collected by filtration and washed with MeOH (2 vol). If the purity of the wet cake was insufficient (any single impurity >1.5% by LC), a slurry was formed in MeOH (8 vol).The wet cake was dried at 60-65°C for about 24 hours (LOD < 10.0%) to obtain ((7-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl) tert-butyl carbamate, as an off-white solid (18.3 kg, 99.0% LC purity, content determined by QNMR 91.5 wt%, 74.7% separation yield, Pd determined by ICP-MS 22 ppm).

[0262] Step 2: Synthesis of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile (MRTX-1719)

[0263] Add tert-butyl carbamate (18.2 kg, 32.2 mol, 1.00 equivalent) and EtOAc (15 vol; vol = L / kg) to a 1000 L reactor at 10–20 °C. Slowly add a 4 M HCl solution of EtOAc (5 vol) to the mixture while maintaining the internal temperature at 10–20 °C. The mixture was stirred at 15–25 °C for approximately 18 hours to complete the deprotection of tert-butyl carbamate ((7-(5-(3-chloro-6-cyano-5-cyclopropoxy-2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (by LC, <0.3% residue). The resulting slurry was filtered, and the filter cake was washed with EtOAc (10 vol) at 20–25 °C. The wet cake was vacuum dried at 40–45 °C for approximately 6–8 hours (LOD <10.0%) to give 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile·HCl). 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazole-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile·HCl and MeOH (10 vol) were added to a 500 L reactor at 10-15 °C. A 7 M NH3 solution of MeOH (1 vol) was slowly added while maintaining the internal temperature at 10-15 °C. The resulting slurry was stirred at 10-15 °C for approximately 12 hours to reduce the supernatant contents of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazole-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile (<1.0% by LC). The slurry was centrifuged at 10–15 °C, and the wet cake was allowed to form a slurry in water (2 × 10 vol). Residual NH4Cl was removed (by IC, <0.05 wt%) to give 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile as a white solid (24.1 kg, 99.3% LC purity, determined by QNMR at 56.1 wt%, 89.0% separation yield, by ICP-MS 6 ppm Pd).

[0264] Example 5

[0265] Synthesis of tert-butyl carbamate ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,4-dihydrophthalazine-1-yl)methyl)carbamate

[0266] Add tert-butyl ((7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate (1.0 g, 3.2 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (1.2 g, 4.8 mmol, 1.5 equivalent), potassium acetate (951 mg, 9.7 mmol, 3.0 equivalent), XPhos (3.8 mg, 8.1 µmol, 0.0025 equivalent), and 1,4-dioxane (10 mL) to a 40 mL vial containing a magnetic stir bar. Degas the mixture by bubbling nitrogen through the solution for approximately 2 minutes. Tris(dibenzylacetone)dipalladium(0) (3.7 mg, 4.0 µmol, 0.00125 equivalents) was added against a nitrogen stream, and the reaction mixture was sealed with insulating tape. The reaction mixture was stirred at 100 °C for about 2 hours. The reaction was then cooled to 50 °C, and water (15 mL) was slowly added. The mixture was then cooled to 20 °C, and stirring was continued for about 1 hour. The resulting crystalline solid was separated by filtration and washed with a 1,4-dioxane / water solution (40 / 60 v / v, 3.0 mL) to give tert-butyl ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,4-dihydrophthalazin-1-yl)methyl)carbamate, as a white crystalline solid (1.18 g, 2.9 mmol, 91% yield).

[0267] It should be understood that the embodiments and implementations described herein are for illustrative purposes only and may inspire those skilled in the art to make various modifications or changes based thereon, which will be incorporated into the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference for all purposes.

Claims

1. A method for preparing compounds of formula (I), (I) in: R 1 It is halogen, aryl, or heteroaryl; R 2 and R 3 Each is an independent halogen; and R 4 Halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or OR 5 , where R 5 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl. This method involves treating compounds of formula (IA) with an electrophile. (IA) The electrophile is I2, Br2, Cl2, an aryl compound, or a heteroaryl compound. in: M represents a divalent metal in a divalent alkali; and X 1 It represents the counter ion of a divalent metal alkali.

2. The method according to claim 1, wherein R 1 It is a halogen.

3. The method according to claim 2, wherein R 1 It is iodine.

4. The method according to claim 1, wherein R 1 It is an aryl group.

5. The method according to claim 4, wherein R 1 For C6-C 10 Aryl group, optionally substituted by one or more C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy groups.

6. The method according to claim 4 or claim 5, wherein the aryl group is phenyl, naphthyl, anthracene, fluorenyl, benzyl, phenethyl, or naphthylmethyl.

7. The method of claim 1, wherein R 1 It is a heteroaryl group.

8. The method of claim 7, wherein R 1 It is a 5- or 6-membered heteroaryl group, which may be optionally substituted by one or more C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy groups.

9. The method according to claim 7 or claim 8, wherein the heteroaryl group is furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrroleyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl or triazinyl.

10. The method according to claim 1, wherein the electrophile is a heteroaryl compound of formula (IB). (ONE) in: X 2 It can be I, Br, or Cl; R 6 It is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; and R 7 and R 8 Each is independently hydrogen or a protecting group, or R 7 and R 8 Together with the N it combines, it forms a ring structure.

11. The method of claim 10, wherein R 6 It is a methyl group.

12. The method according to claim 10 or claim 11, wherein R 7 and R 8 Each is hydrogen independently.

13. The method according to claim 10 or claim 11, wherein R 7 and R 8 One is hydrogen, and the other is a protecting group.

14. The method according to claim 10 or claim 13, wherein the protecting group is tert-butoxycarbonyl (Boc).

15. The method of claim 10, wherein the ring structure is an phthalimide group.

16. The method according to any one of claims 1-15, wherein R 2 It is fluorine.

17. The method according to any one of claims 1-16, wherein R 3 It is chlorine.

18. The method according to any one of claims 1-16, wherein R 3 It is bromine.

19. The method according to any one of claims 1-18, wherein R 4 It is fluorine.

20. The method according to any one of claims 1-18, wherein R 4 OR 5 And R 5 It is cyclopropyl.

21. The method according to any one of claims 1-20, wherein the compound of formula (IA) is in an ether solvent.

22. The method according to any one of claims 1-21, wherein the method is carried out in an ether solvent.

23. The method according to claim 21 or claim 22, wherein the ether solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), 1,4-dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether (MTBE), or cyclopentylmethyl ether (CPME).

24. The method according to any one of claims 1-23, wherein the method is carried out in an inert atmosphere in a temperature range of -10 to -30°C.

25. The method according to any one of claims 1-24, wherein the method is carried out by using a divalent metal base MX 1 Processed (IC) compounds and preparative (IA) compounds: (IC)。 26. The method of claim 25, wherein the treatment of the compound of formula (IC) is carried out in a proton-free solvent.

27. The method according to claim 25 or claim 26, wherein the treatment of the compound of formula (IC) is carried out at a temperature of -30°C or above in an inert atmosphere.

28. The method according to any one of claims 1-27, wherein the divalent metal alkali is a magnesium alkali.

29. The method according to claim 28, wherein the magnesium base is an alkyl Grignard reagent.

30. The method according to claim 28, wherein the magnesium base is TMPMgCl·LiCl, (TMP)2Mg·2LiCl or i-PrMgCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

31. The method according to any one of claims 28-30, wherein the magnesium base is in a solution of THF or 2-MeTHF.

32. The method according to any one of claims 1-27, wherein the divalent metal alkali is a zinc alkali.

33. The method according to claim 32, wherein the zinc base is (TMP)2Zn·2LiCl or TMPZnCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

34. The method according to claim 32, wherein the zinc base is a dialkylzinc or a dialkylzinc halide.

35. The method according to claim 34, wherein the zinc alkali is Et2Zn or EtZnCl.

36. The method according to any one of claims 1-35, wherein the compound of formula (I) is 4-chloro-3,6-difluoro-2-iodobenzoic acid, which is prepared by: (a) Treatment of 4-chloro-2,5-difluorobenzoic acid with a divalent metal base yields a mixture; and (b) Treat the mixture with iodine to obtain 4-chloro-3,6-difluoro-2-iodobenzoic acid.

37. A method for preparing compounds of formula (II), (II) in: R 2 R 3 and R 11 Each is an independent halogen; R 4 Halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, or OR 5 , where R 5 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or a halo-C1-C6 alkyl; R 9 It is a C1-C6 alkyl, C3-C6 cycloalkyl, or halo-C1-C6 alkyl; and R 10 It is hydrogen. The method includes: (a) Make compound (I) (I) It reacts with an amine to give a compound of formula (IIA). (IIA) Where R 1 It is halogen, aryl, or heteroaryl; (b) Dehydrating compound (IIA) to obtain compound (IIB), (IIB); (c) Couple the compound of formula (IIB) with an organoboron compound or an organozinc compound to obtain the compound of formula (IIC). (IIC); and (d) Halogenated (IIC) compounds yield compounds of formula (II).

38. The method of claim 37, wherein R 2 It is fluorine.

39. The method according to claim 37 or claim 38, wherein R 3 It is chlorine.

40. The method according to claim 37 or claim 38, wherein R 3 It is bromine.

41. The method according to any one of claims 37-40, wherein R 4 It is fluorine.

42. The method according to any one of claims 37-40, wherein R 4 OR 5 And R 5 It is cyclopropyl.

43. The method according to any one of claims 37-42, wherein R 9 It is a C1-C6 alkyl group.

44. The method of claim 43, wherein R 9 It is a methyl group.

45. The method according to any one of claims 37-44, wherein R 10 It is hydrogen.

46. ​​The method according to any one of claims 37-45, wherein R 11 It is iodine.

47. The method according to any one of claims 37-46, wherein step (a) further comprises treating the compound of formula (I) with an activating agent, followed by reaction with an amine to obtain the compound of formula (IIA).

48. The method according to claim 47, wherein the activating agent is carbonyl diimidazole (CDI) or carbonyl dichloro.

49. The method according to any one of claims 37-48, wherein in step (a), the compound of formula (I) is prepared by treating the compound of formula (IA) with an electrophile: (IA) The electrophile is I2, Br2, Cl2, an aryl compound, or a heteroaryl compound. in: M represents a divalent metal in a divalent alkali; and X 1 It represents the counter ion of a divalent metal alkali.

50. The method according to claim 49, wherein the compound of formula (IA) is obtained by using a divalent metal base MX 1 Preparation of processed (IB) compounds: (IB).

51. The method according to any one of claims 37-50, wherein R 1 It is iodine.

52. The method according to any one of claims 37-51, wherein the compound of formula (II) is 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile, which is prepared by: (a) Reacting 4-chloro-3,6-difluoro-2-iodobenzoic acid with an amine to give 4-chloro-3,6-difluoro-2-iodobenzoamide; (b) Dehydrate 4-chloro-3,6-difluoro-2-iodobenzamide to give 4-chloro-3,6-difluoro-2-iodobenzylnitrile; (c) Couple 4-chloro-3,6-difluoro-2-iodobenzyl nitrile with an organoboron compound or an organozinc compound to give 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile; and (d) Iodide 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile to give 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile.

53. The method according to claim 52, wherein step (a) further comprises treating 4-chloro-3,6-difluoro-2-iodobenzoic acid with an activating agent, followed by reaction with an amine to obtain 4-chloro-3,6-difluoro-2-iodobenzoamide.

54. The method according to claim 53, wherein the activating agent is CDI or carbonyl dichloride.

55. The method according to any one of claims 52-54, wherein in step (a), 4-chloro-3,6-difluoro-2-iodobenzoic acid is prepared by: (1) Treatment of 4-chloro-2,5-difluorobenzoic acid with a divalent metal alkali yields a mixture; and (2) Treat the mixture with iodine to obtain 4-chloro-3,6-difluoro-2-iodobenzoic acid.

56. The method according to any one of claims 37-55, wherein in step (a), the amine is ammonia or ammonium hydroxide.

57. The method according to any one of claims 37-56, wherein step (a) is carried out in a solution of THF or 2-MeTHF.

58. The method according to any one of claims 37-57, wherein step (a) is carried out in an inert atmosphere at a temperature range of 20-60°C.

59. The method according to any one of claims 37-58, wherein step (b) is carried out in the presence of trifluoroacetic anhydride (TFAA), phosphoryl chloride (POCl3), thionyl chloride (SOCl2) or oxalyl chloride (COCl)2.

60. The method according to any one of claims 37-59, wherein step (b) is carried out in a solution of THF or 2-MeTHF.

61. The method according to any one of claims 37-60, wherein step (b) is carried out in an inert atmosphere at a temperature range of 0-25°C.

62. The method according to any one of claims 37-61, wherein in step (c), the organoboron compound is a boric acid or ester having the structure of formula (IID). (IID) Where R is hydrogen or C1-C6 alkyl.

63. The method according to claim 62, wherein the organoboron compound is .

64. The method according to any one of claims 37-61, wherein in step (c), the organozinc compound has the structure of formula (IIE). (IIE) Where X is I, Br, or Cl.

65. The method according to any one of claims 37-64, wherein step (c) is carried out in the presence of a catalyst.

66. The method of claim 65, wherein the catalyst is a palladium catalyst.

67. The method according to claim 66, wherein the palladium catalyst is [P(t-Bu)2(n-Bu)]-Pd-G3, Pd(amphos)Cl, or (amphos)2PdCl2.

68. The method of claim 66, wherein the palladium catalyst is a precatalyst prepared from a palladium source and a ligand.

69. The method according to claim 68, wherein the palladium source is Pd(OAc)2 or Pd2(dba)3.

70. The method according to claim 68 or claim 69, wherein the ligand is amphos or P(tBu)2(nBu).

71. The method of claim 65, wherein the catalyst is a nickel catalyst.

72. The method according to any one of claims 37-71, wherein step (c) is carried out in a solution of THF or toluene.

73. The method according to any one of claims 37-72, wherein step (c) is carried out in an inert atmosphere at a temperature range of 60-80°C.

74. The method according to any one of claims 37-73, wherein step (d) comprises iodizing the compound of step (c) to obtain the compound of formula (II).

75. The method according to any one of claims 37-74, wherein step (d) is carried out in the presence of an iodine reagent.

76. The method according to claim 75, wherein the iodizing agent is molecular iodine or N-iodosuccinimide (NIS).

77. The method according to any one of claims 37-76, wherein step (d) is carried out in a solution of acetonitrile.

78. The method according to any one of claims 37-77, wherein step (d) is carried out in an inert atmosphere at a temperature range of 40-60°C.

79. A method for preparing compounds of formula (III), (III) The method includes: (a) Treatment of 4-chloro-2,5-difluorobenzoic acid with a divalent metal base yields a mixture; (b) Treating the mixture with iodine yields 4-chloro-3,6-difluoro-2-iodobenzoic acid; (c) React 4-chloro-3,6-difluoro-2-iodobenzoic acid with an amine to give 4-chloro-3,6-difluoro-2-iodobenzoamide; (d) Dehydrate 4-chloro-3,6-difluoro-2-iodobenzamide to give 4-chloro-3,6-difluoro-2-iodobenzylnitrile; (e) Couple 4-chloro-3,6-difluoro-2-iodobenzyl nitrile with an organoboron compound or an organozinc compound to obtain 4-chloro-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile; (f) Iodide-3,6-difluoro-2-(1-methyl-1H-pyrazol-5-yl)benzyl nitrile to give 4-chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile; and (g) 4-Chloro-3,6-difluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile is reacted with cyclopropanol to give 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile.

80. The method according to claim 79, wherein the divalent metal base is TMPMgCl·LiCl, (TMP)2Mg·2LiCl or i-PrMgCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

81. The method according to claim 79, wherein the divalent metal base is (TMP)2Zn·2LiCl or TMPZnCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

82. The method according to claim 79, wherein the divalent metal base is a dialkylzinc or a dialkylzinc halide.

83. The method according to claim 82, wherein the divalent metal alkali is Et₂Zn or EtZnCl.

84. The method according to any one of claims 79-83, wherein step (a) is carried out in a solution of 2-MeTHF at about -20°C in an inert atmosphere.

85. The method according to any one of claims 79-84, wherein step (b) is carried out in a solution of 2-MeTHF at about -15°C in an inert atmosphere.

86. The method according to any one of claims 79-85, wherein in step (b), iodine is used as a solution of I2 in 2-MeTHF.

87. The method according to any one of claims 79-86, wherein step (b) further comprises treating 4-chloro-3,6-difluoro-2-iodobenzoic acid with CDI, followed by treatment with the amine in step (c).

88. The method according to any one of claims 79-87, wherein the amine is ammonia or ammonium hydroxide.

89. The method according to any one of claims 79-88, wherein in step (e), the organoboron compound is 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole.

90. The method according to any one of claims 79-89, wherein in step (f), iodination is performed using NIS.

91. The method according to any one of claims 79-90, wherein the method further comprises: (h) Coupling 4-chloro-6-cyclopropoxy-3-fluoro-2-(4-iodo-1-methyl-1H-pyrazol-5-yl)benzyl nitrile with the protected organoborophytazine compound; and (i) Deprotect the product of step (h).

92. The method according to claim 91, wherein the protected organoborophthalazine compound is tert-butyl carbamate ((4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydrophthalazine-1-yl)methyl)carbamate.

93. The method according to claim 92, wherein the protected organoborophyzine compound is prepared by treating ((7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaboranecyclopentane)-(7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)carbamate in the presence of tris(dibenzylacetone)dipalladium(O).

94. The method according to claim 93, wherein the preparation of the protected organoborophytazine compound is carried out in the presence of potassium acetate.

95. The method according to claim 93 or claim 94, wherein the preparation of the protected organoborophytazine compound is carried out in a solution of 1,4-dioxane.

96. The method according to any one of claims 93-95, wherein the preparation of the protected organoborophytazine compound is carried out at about 100°C in an inert atmosphere.

97. Compounds of formula (IV), (IV) in: R 1 It is iodine, aryl, or heteroaryl; R 3 It is bromine or chlorine; and R 12 For -OR 13 or -NR 14 R 15 , where R 13 R 14 and R 15 Each is independently a halogen, a C1-C6 alkyl, or a C3-C6 cycloalkyl.

98. The compound according to claim 97, wherein R 1 It is iodine.

99. The compound according to claim 97, wherein R 1 It is an aryl group.

100. The compound according to claim 99, wherein R 1 For C6-C 10 Aryl group, optionally substituted by one or more C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy groups.

101. The compound according to claim 99 or claim 100, wherein the aryl group is phenyl, naphthyl, anthracene, fluorenyl, benzyl, phenethyl, or naphthylmethyl.

102. The compound according to claim 97, wherein R 1 It is a heteroaryl group.

103. The compound according to claim 102, wherein R 1 It is a 5- or 6-membered heteroaryl group, which may be optionally substituted by one or more C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy groups.

104. The compound according to claim 102 or claim 103, wherein the heteroaryl group is furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrroleyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl or triazinyl.

105. The compound according to any one of claims 97-104, wherein R 3 It is chlorine.

106. The compound according to any one of claims 97-104, wherein R 3 It is bromine.

107. The compound according to any one of claims 97-106, wherein R 12 It is -OH.

108. The compound according to any one of claims 97-106, wherein R 12 It is -NH2.

109. A composition comprising a mixture of 4-chloro-2,5-difluorobenzoic acid and 4-chloro-3,6-difluoro-2-iodobenzoic acid.

110. The composition of claim 109, wherein the mixture is substantially free of 4-chloro-2,5-difluoro-3-iodobenzoic acid.

111. The composition of claim 109, wherein the mixture comprises more than about 90% (w / w) of 4-chloro-3,6-difluoro-2-iodobenzoic acid and less than about 10% of 4-chloro-2,5-difluoro-3-iodobenzoic acid, based on the combined weight of 4-chloro-3,6-difluoro-2-iodobenzoic acid and 4-chloro-2,5-difluoro-3-iodobenzoic acid.

112. The composition according to any one of claims 109-111, wherein the mixture comprises 4-chloro-3,6-difluoro-2-iodobenzoic acid and 4-chloro-2,5-difluoro-3-iodobenzoic acid in a ratio of 99:

1.

113. The composition according to any one of claims 109-112, wherein the composition further comprises a divalent base.

114. The composition according to claim 113, wherein the divalent metal base is TMPMgCl·LiCl, (TMP)2Mg·2LiCl or i-PrMgCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

115. The composition according to claim 113, wherein the divalent metal base is (TMP)2Zn·2LiCl or TMPZnCl·LiCl, and wherein TMP is 2,2,6,6-tetramethylpiperidinyl.

116. The composition according to claim 113, wherein the divalent metal base is a dialkylzinc or a dialkylzinc halide.

117. The composition according to claim 116, wherein the divalent metal base is Et₂Zn or EtZnCl.

118. The composition according to any one of claims 109-117, wherein the composition further comprises iodine.

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