WO2023003014A1 - アリールアミド誘導体の製造方法 - Google Patents

アリールアミド誘導体の製造方法 Download PDF

Info

Publication number
WO2023003014A1
WO2023003014A1 PCT/JP2022/028187 JP2022028187W WO2023003014A1 WO 2023003014 A1 WO2023003014 A1 WO 2023003014A1 JP 2022028187 W JP2022028187 W JP 2022028187W WO 2023003014 A1 WO2023003014 A1 WO 2023003014A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
methyl
mmol
fluoro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2022/028187
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
和明 桑田
英寿 染谷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chugai Pharmaceutical Co Ltd
Original Assignee
Chugai Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Priority to US18/579,949 priority Critical patent/US20240327355A1/en
Priority to JP2022563493A priority patent/JP7268255B1/ja
Priority to EP22845947.5A priority patent/EP4375273A4/en
Priority to KR1020237036428A priority patent/KR102671612B1/ko
Priority to MX2024000908A priority patent/MX2024000908A/es
Priority to CN202280050524.4A priority patent/CN117677607A/zh
Priority to IL310123A priority patent/IL310123A/en
Priority to CA3226827A priority patent/CA3226827A1/en
Priority to AU2022312992A priority patent/AU2022312992A1/en
Publication of WO2023003014A1 publication Critical patent/WO2023003014A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds

Definitions

  • the present disclosure relates to a method for producing an arylamide derivative.
  • the present disclosure also relates to compounds that can be used to prepare arylamide derivatives and methods for preparing the same.
  • MEK mitogen-activated protein kinase kinase
  • MAPK MAPK signaling pathway
  • PD0325901, CH4987655, trametinib, cobimetinib, selumetinib, etc. have been reported (see Patent Document 1 and Non-Patent Document 2).
  • Patent Document 1 and Non-Patent Document 2 for example, has been reported to show clinical efficacy against malignant melanoma with BRAF mutation (see Non-Patent Documents 3 and 4).
  • CH5126766 (see Patent Document 2 and Non-Patent Documents 7 and 8), which is known not only as a MEK inhibitor but also as a stabilizer of the RAF/MEK complex, has been clinically demonstrated in non-small cell lung cancer with RAS mutations. It has been reported that the above effects are exhibited (see Non-Patent Document 9). It has also been reported that CH5126766 stabilizes the RAF/MEK complex and suppresses the enhancement of MEK phosphorylation (feedback activation of the MAPK signaling pathway) (see Non-Patent Document 10) (Non-Patent Document 7). and 8). This feedback activation is considered to be one of the reasons why the clinical effects of MEK inhibitors against cancers with RAS mutations are not necessarily sufficient (see Non-Patent Document 10).
  • RAF/MEK complex stabilizers or MEK inhibitors are known to be useful in the treatment or prevention of cell proliferative disorders, particularly cancer, there are still insufficient to meet diverse consumer needs. The reality is that we cannot say that there are alternatives.
  • arylamide derivatives compounds represented by the general formula (1) described later
  • RAF/MEK complex stabilizing activity and/or MEK inhibitory activity have RAF/MEK complex stabilizing activity and/or MEK inhibitory activity, and cell proliferative diseases , particularly useful for the treatment or prevention of cancer.
  • An object of the present disclosure is to provide a method for producing such an arylamide derivative, which is capable of obtaining the arylamide derivative in a small number of steps.
  • A1 A method for producing a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt,
  • (I) A step of reacting a compound represented by the following general formula (2) with a compound represented by X 1 -R 9 and a base in a solvent to obtain a compound represented by the following general formula (4). method including.
  • R 11 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a C3-6 cycloalkyl group (the C3 ⁇ 6 cycloalkyl group may be substituted with a C1-6 alkyl group.)
  • R 2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ⁇ 6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alky
  • step (A2) The method according to (A1), wherein the base used in step (I) is at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole.
  • step (A3) The method according to (A2), wherein the base used in step (I) is N,N-dimethylaminopyridine.
  • the solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, and tert-butyl methyl ether.
  • step (A7) The method according to (A6), wherein the catalyst used in step (II) is a palladium catalyst or a nickel catalyst.
  • the palladium catalyst includes at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium (II) acetate, and the following general formula:
  • R 20 and R 21 are cyclohexyl groups, R 22 is a methoxy group, an isopropoxy group or an N,N-dimethylamino group; R 23 is a hydrogen atom, a methoxy group or an isopropoxy group, R24 is a hydrogen atom, The method according to (A9).
  • the palladium catalyst includes at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium (II) acetate; 6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
  • the method according to (A10) which is a combination of at least one selected from the group consisting of (A12)
  • the palladium catalysts include bis(allylchloropalladium), 2′,6′-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohex
  • R 20 and R 21 are cyclohexyl groups, R 22 is a methoxy group, an isopropoxy group or an N,N-dimethylamino group; R 23 is a hydrogen atom, a methoxy group or an isopropoxy group, R 25 is a hydrogen atom or a methyl group, R 26 is a methyl group, The method according to (A13).
  • the palladium catalyst is (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2′-amino-1,1′-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-dicyclohexylphosphino -2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.
  • the palladium catalyst is (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methane
  • the nickel catalyst includes at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride, tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene , and at least one selected from the group consisting of 1,3-bis(diphenylphosphino)propane, the method according to (A17).
  • the nickel catalyst is dichlorobis(tricyclohexylphosphine)nickel(II), Dichloro[1,1′-bis(diphenylphosphino)ferrocene]nickel(II) and dichloro[1,3-bis(diphenylphosphino)propane]nickel(II)
  • the method according to (A17) which is at least one selected from the group consisting of
  • Said catalyst used in step (II) is a combination of bis(allylchloropalladium) and 2′,6′-dimethoxy-2-(dicyclohexylphosphino)biphenyl; a combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; a combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(
  • Said catalyst used in step (II) is (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl )] palladium(II) methanesulfonate.
  • step (A22) The method of any of (A6)-(A21), wherein the solvent used in step (II) comprises a C1-6 alcohol.
  • step (II) comprises a C2-3 alcohol.
  • step (II) comprises ethanol.
  • R 12 is a C1-6 alkyl group or an aryl group;
  • (A27) The method according to (A26), wherein R 2 is a halogen atom.
  • R2 is a fluorine atom
  • R 11 is a C1-4 alkyl group
  • R 3 is a hydrogen atom or a cyclopropyl group
  • R5 is a fluorine atom
  • R6 is a hydrogen atom
  • R4 is an iodine atom or a cyclopropyl group
  • R7 is a fluorine atom
  • R8 is a fluorine atom
  • X 1 is a chlorine atom
  • the compound represented by the general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine -4-yl]methyl]benzamide, the method according to any one of (A1) to (A29).
  • (B1) A method for producing a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt
  • (II) A compound represented by the following general formula (4) is reacted with a compound represented by the following general formula (10) in the presence of a catalyst in a solvent to obtain a compound represented by the following general formula (5)
  • R 11 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a C3-6 cycloalkyl group (the C3 ⁇ 6 cycloalkyl group may be substituted with a C1-6 alkyl group.)
  • R 2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ⁇ 6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alky
  • step (B2) The method according to (B1), wherein the catalyst used in step (II) is a palladium catalyst or a nickel catalyst.
  • the palladium catalyst includes at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium (II) acetate, and the following general formula:
  • the method according to (B3) which is a combination of (L1) and a compound represented by (L1).
  • R 20 and R 21 are each independently a C3-6 cycloalkyl group;
  • R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group);
  • R 23 is a hydrogen atom or a C1-6 alkoxy group,
  • R 20 and R 21 are cyclohexyl groups, R 22 is a methoxy group, an isopropoxy group or an N,N-dimethylamino group; R 23 is a hydrogen atom, a methoxy group or an isopropoxy group, R24 is a hydrogen atom, The method as described in (B4).
  • the palladium catalyst includes at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium (II) acetate; 6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
  • the method according to (B5) which is a combination of at least one selected from the group consisting of (B7)
  • the palladium catalysts include bis(allylchloropalladium), 2′,6′-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexy
  • R 20 and R 21 are each independently a C3-6 cycloalkyl group;
  • R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group);
  • R 23 is a hydrogen atom or a C1-6 alkoxy group,
  • R24 is a hydrogen atom,
  • R 25 is a hydrogen atom or a C1-6 alkyl group,
  • R 26 is a C1-6 alkyl group, Arrows represent coordinate bonds.
  • R 20 and R 21 are cyclohexyl groups, R 22 is a methoxy group, an isopropoxy group or an N,N-dimethylamino group; R 23 is a hydrogen atom, a methoxy group or an isopropoxy group, R 25 is a hydrogen atom or a methyl group, R 26 is a methyl group, The method according to (B8).
  • the palladium catalyst is (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2′-amino-1,1′-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-dicyclohexylphosphino -2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.
  • the method according to (B9) which is at least one.
  • the palladium catalyst is (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methane
  • the method according to (B10) which is a sulfonate.
  • the nickel catalyst includes at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride, tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene , and at least one selected from the group consisting of 1,3-bis(diphenylphosphino)propane, the method according to (B12).
  • the nickel catalyst is dichlorobis(tricyclohexylphosphine)nickel(II), Dichloro[1,1′-bis(diphenylphosphino)ferrocene]nickel(II) and dichloro[1,3-bis(diphenylphosphino)propane]nickel(II)
  • the method according to (B12) which is at least one selected from the group consisting of
  • Said catalyst used in step (II) is a combination of bis(allylchloropalladium) and 2′,6′-dimethoxy-2-(dicyclohexylphosphino)biphenyl; a combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; a combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(
  • Said catalyst used in step (II) is (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl )] palladium(II) methanesulfonate.
  • step (B17) The method of any of (B1)-(B16), wherein the solvent used in step (II) comprises a C1-6 alcohol.
  • step (B18) The method of (B17), wherein the solvent used in step (II) comprises a C2-3 alcohol.
  • step (B19) The method according to (B18), wherein the solvent used in step (II) comprises ethanol.
  • R 12 is a C1-6 alkyl group or an aryl group;
  • B22 The method according to (B21), wherein R 2 is a halogen atom.
  • R2 is a fluorine atom
  • R 11 is a C1-4 alkyl group
  • R 3 is a hydrogen atom or a cyclopropyl group
  • R5 is a fluorine atom
  • R6 is a hydrogen atom
  • R4 is an iodine atom or a cyclopropyl group
  • R7 is a fluorine atom
  • R8 is a fluorine atom
  • the compound represented by the general formula (1) is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine -4-yl]methyl]benzamide, the method according to any one of (B1) to (B24).
  • the compound of general formula (5) can be obtained using a compound with a protected amino group, for example, as described in Synthesis Example 4 (4-2) below. Deprotection of the group is required.
  • the compound of general formula (5) is obtained by using a compound in which the amino group is unprotected. Accordingly, it becomes possible to obtain the arylamide derivative of general formula (1) with a correspondingly smaller number of steps.
  • the invention provided by the present disclosure includes, for example, the method described in (C1) below.
  • (C1) 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide sodium salt
  • the invention provided by the present disclosure also includes, for example, the composition described in (D1) below.
  • (D1) 2-(4-Cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide sodium salt and a compound represented by the following formula (X) or a sodium salt thereof, wherein the amount of the compound of formula (X) or a sodium salt thereof contained in the composition is 2- Weight of sodium salt of (4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide 3.0 w/w% or less, 2.0 w/w% or less, 1.0 w/w% or less, 0.8 w/w% or less, 0.5 w/w% or less, or 0.3
  • the inventions provided by the present disclosure also include, for example, the methods described in (E1) to (E7) below.
  • (E1) A method for producing a compound represented by the following general formula (4), (I) a step of reacting a compound represented by the following general formula (2) with a compound represented by X 1 -R 9 and a base in a solvent to obtain a compound represented by the general formula (4); How to include.
  • R 2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • X 1 is a halogen atom or —O—R 9
  • R 12 is a C1-6 alkyl group or an aryl group.
  • the solvent used in step (I) is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, and tert-butyl methyl ether.
  • R 12 is a C1-6 alkyl group or an aryl group;
  • E7 The method according to (E6), wherein R 2 is a halogen atom.
  • inventions provided by the present disclosure also include, for example, compounds described in (F1) below.
  • (F1) (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate.
  • a method for producing a specific arylamide derivative having RAF/MEK complex stabilizing activity and/or MEK inhibitory activity and useful for the treatment or prevention of cell proliferative diseases, particularly cancer comprising: Provided is a method capable of obtaining an amide derivative in a small number of steps.
  • FIG. 1 shows the powder X-ray diffraction pattern of sample 1a (Form I).
  • FIG. 2 shows the powder X-ray diffraction pattern of sample 1b (Form I).
  • FIG. 3 shows the powder X-ray diffraction pattern of sample 1c.
  • FIG. 4 shows MEK1 added together with a test compound (ref-2, ref-3, ref-4, A-1, ref-1, ref-5 or B-1) on the RAF1-immobilized sensor chip surface. is a sensorgram showing the time course of the binding amount of .
  • FIG. 5 shows MEK1 added together with a test compound (A-2, A-25, J-1, E-1, M-1, N-1 or H-3) on the RAF1-immobilized sensor chip surface.
  • FIG. 6 shows the binding amount of MEK1 added together with a test compound (I-1, H-4, L-1, P-1, E-7 or A-27) to the RAF1-immobilized sensor chip surface. It is a sensorgram which shows a time-dependent transition.
  • FIG. 7 shows MEK1 added together with a test compound (A-33, A-18, N-2, A-20, A-8, E-13 or H-1) on the RAF1-immobilized sensor chip surface. is a sensorgram showing the time course of the binding amount of .
  • FIG. 8 shows the results of Western blotting of proteins (p-MEK, MEK, p-ERK, and ERK) extracted from A549 cells cultured in the presence of test compounds (ref-5 or compound A-1). It is an electrophoretic image.
  • FIG. 9 is a graph showing changes over time in tumor volume (mean ⁇ standard deviation) in nude mice subcutaneously implanted with human lung cancer cell line Calu-6.
  • a halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a C1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • a C2-7 alkenyl group means a linear or branched alkenyl group having 2 to 7 carbon atoms.
  • Examples include vinyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl, and heptatrienyl groups.
  • a C2-7 alkynyl group means a linear or branched alkynyl group having 2 to 7 carbon atoms.
  • a C1-6 alkoxy group means an alkyloxy group having a linear or branched alkyl group with 1-6 carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy groups.
  • a C1-6 alkylthio group means an alkylthio group having a linear or branched alkyl group with 1-6 carbon atoms. Examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, and n-hexylthio.
  • a C3-6 cycloalkyl group means a monocyclic cyclic alkyl group having 3 to 6 atoms constituting the ring. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • an aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples include phenyl, 1-naphthyl, and 2-naphthyl groups.
  • pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; , toluenesulfonate; formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandel carboxylates such as acid salts, benzoates, salicylates, fluoroacetates, trifluoroacetates, tartrates, propionates, glutarate; lithium salts, sodium salts, potassium salts, cesium salts, rubidium salts, etc.
  • inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; , toluenesulfonate; formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, glucon
  • alkaline earth metal salts such as magnesium salts and calcium salts
  • ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts.
  • alkali metal salts such as lithium salts, sodium salts, potassium salts, cesium salts and rubidium salts are preferred, and sodium salts and potassium salts are more preferred.
  • solvates are solvates with, for example, water, alcohols (such as methanol, ethanol, 1-propanol, or 2-propanol), acetone, dimethylformamide, or dimethylacetamide. is. It may be a solvate with a single solvent or a solvate with multiple solvents. Preferred solvates include, for example, hydrates.
  • a first aspect of the present disclosure is a method for producing a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, Provided is a method comprising the following step (I).
  • a second aspect of the present disclosure is a method for producing a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, Provided is a method comprising the following step (II).
  • R 11 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group) or a C3-6 cycloalkyl group (the C3 ⁇ 6 cycloalkyl group may be substituted with a C1-6 alkyl group.)
  • R 2 is a hydrogen atom, a halogen atom or a C1-6 alkyl group
  • R 3 is a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3 ⁇ 6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alky
  • the method of the first aspect of the present disclosure further includes the following step (II) in a preferred embodiment.
  • the method of the first aspect of the present disclosure further comprises the following steps (II) and (III) in a preferred embodiment.
  • the method of the second aspect of the present disclosure further comprises the following step (III) in a preferred embodiment.
  • a third aspect of the present disclosure provides a method for producing a compound represented by the following general formula (4), which method includes the following step (I).
  • R2 is as defined above;
  • X 1 is a halogen atom or —O—R 9
  • R 12 is a C1-6 alkyl group or an aryl group.
  • R 13 is -B(-OR 14 )(-OR 15 ) or -BF 3 K
  • R 14 and R 15 are each independently a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a C1-6 alkoxy group or an aryl group), or R 14 and R 15 together with intervening oxygen and boron atoms is a 5- to 8-membered saturated or unsaturated ring (the ring is substituted with a C1-6 alkyl group, a C1-6 alkoxy group or an aryl group; or may be condensed with a benzene ring.) is formed, R 2 to R 9 have the same definitions as above. ]
  • R 11 is preferably a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), more preferably a C1-4 alkyl group (the C1-4 alkyl group may be substituted with a fluorine atom or a C1-4 alkoxy group ) or a cyclopropyl group (the cyclopropyl group may be substituted with a C1-4 alkyl group), more preferably a C1-4 alkyl group.
  • R 2 is preferably a hydrogen atom or a halogen atom, more preferably a halogen atom, still more preferably a fluorine atom.
  • R 3 is preferably a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxy group), and more It is preferably a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group or a C1-4 alkoxy group (the C1-4 alkoxy group may be substituted with a hydroxy group), more preferably a hydrogen atom or cyclopropyl is the base.
  • R 4 is preferably a halogen atom or a cyclopropyl group, more preferably an iodine atom or a cyclopropyl group.
  • R5 is preferably a halogen atom, more preferably a fluorine atom.
  • R6 is preferably a hydrogen atom.
  • R7 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, still more preferably a fluorine atom.
  • R8 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, still more preferably a fluorine atom.
  • X 1 is preferably a halogen atom, more preferably a chlorine atom.
  • Examples of compounds of general formula (1) include 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine -4-yl]methyl]benzamide.
  • Examples of compounds of general formula (4) include (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate.
  • Examples of compounds of general formula (2) include (2-amino-3-fluoropyridin-4-yl)methanol.
  • (2-amino-3-fluoropyridin-4-yl)methanol is available as a commercial reagent.
  • Compounds of X 1 -R 9 include, for example, methyl chloroformate, ethyl chloroformate, acetic anhydride, acetyl chloride, dimethyl chlorophosphate, diethyl chlorophosphate, and diphenyl chlorophosphate.
  • methyl chloroformate is available as a commercial reagent.
  • Bases used in step (I) include, for example, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, N,N-dimethylaminopyridine, 2,6-dimethylpyridine, 1-methyl imidazole, and 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • at least one selected from the group consisting of N,N-dimethylaminopyridine and 1-methylimidazole and more preferably, for example, N,N-dimethylaminopyridine.
  • Solvents used in step (I) include, for example, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolidinone, dimethyl Sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, tert-butyl methyl ether, toluene, xylene, heptane, and cyclohexane.
  • acetonitrile for example, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, cyclopentyl methyl ether, and at least one selected from the group consisting of tert-butyl methyl ether, more preferably, for example, acetonitrile.
  • the reaction of step (I) can be carried out by stirring the reaction mixture at an appropriate temperature (eg, 0°C to 40°C) for a certain period of time (eg, 0.5 hours to 24 hours).
  • an appropriate temperature eg, 0°C to 40°C
  • a certain period of time eg, 0.5 hours to 24 hours.
  • the mixture after completion of the reaction in step (I) may be directly subjected to the next step, or may be subjected to the next step after isolation or purification, for example.
  • R 13 is preferably a group of the following formula (a), a group of the following formula (b), -B(-OH) 2 or -BF 3 K, more preferably a group of the following formula (a) be.
  • Examples of compounds of general formula (10) include 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaboran-2-yl)benzamides.
  • Examples of compounds of general formula (5) include 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4- Difluorobenzamides may be mentioned.
  • catalysts used in step (II) include palladium catalysts and nickel catalysts.
  • the palladium catalyst for example, at least one selected from the group consisting of bis(allylchloropalladium), tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, and palladium (II) acetate, and the following and a compound represented by general formula (L1).
  • R 20 and R 21 are each independently a C3-6 cycloalkyl group;
  • R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group);
  • R 23 is a hydrogen atom or a C1-6 alkoxy group,
  • Palladium catalysts also include, for example, compounds represented by the following general formula (L2).
  • R 20 and R 21 are each independently a C3-6 cycloalkyl group
  • R 22 is a C1-6 alkoxy group or an amino group (the amino group may be substituted with a C1-6 alkyl group or an aryl group)
  • R 23 is a hydrogen atom or a C1-6 alkoxy group
  • R24 is a hydrogen atom
  • R 25 is a hydrogen atom or a C1-6 alkyl group
  • R 26 is a C1-6 alkyl group
  • Arrows represent coordinate bonds.
  • R 20 and R 21 are preferably cyclohexyl groups.
  • R 22 is preferably a methoxy group, an isopropoxy group or an N,N-dimethylamino group.
  • R 23 is preferably a hydrogen atom, a methoxy group or an isopropoxy group.
  • R24 is preferably a hydrogen atom.
  • R25 is preferably a hydrogen atom or a methyl group.
  • R 26 is preferably a methyl group.
  • Compounds represented by general formula (L1) are preferably, for example, 2',6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl , and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl.
  • the compound represented by the general formula (L2) is preferably, for example, (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2′-amino-1,1′-biphenyl-2-yl)palladium(II) methanesulfonate, and (2-dicyclohexylphosphino -2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.
  • nickel catalyst examples include at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride, tricyclohexylphosphine, 1,1′-bis(diphenylphosphino ) with at least one selected from the group consisting of ferrocene and 1,3-bis(diphenylphosphino)propane.
  • Nickel catalysts also include, for example, dichlorobis(tricyclohexylphosphine)nickel(II), Dichloro[1,1′-bis(diphenylphosphino)ferrocene]nickel(II) and dichloro[1,3-bis(diphenylphosphino)propane]nickel(II) At least one selected from the group consisting of
  • the catalyst used in step (II) is preferably, for example a combination of bis(allylchloropalladium) and 2′,6′-dimethoxy-2-(dicyclohexylphosphino)biphenyl; a combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; a combination of bis(allylchloropalladium) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl; (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate, 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl
  • a combination of two or more compounds When a combination of two or more compounds is used as catalyst, they may, for example, form a complex in a solvent.
  • solvents used in step (II) include C1-6 alcohols. Preferred are, for example, C2-3 alcohols, more preferred are, for example, ethanol.
  • step (II) can be carried out by stirring the reaction mixture at an appropriate temperature (eg, 40°C to 90°C) for a certain period of time (eg, 0.5 hours to 24 hours).
  • an appropriate temperature eg, 40°C to 90°C
  • a certain period of time eg, 0.5 hours to 24 hours.
  • the mixture after completion of the reaction in step (II) may be directly subjected to the next step, or may be subjected to the next step after isolation or purification, for example.
  • Solvents used in step (III) include, for example, acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylimidazolidinone, N,N-dimethylpropyleneurea, tetramethylurea , dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, pyridine, dichloromethane, and mixed solvents thereof.
  • solvents used for producing sodium salt include acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and and a mixed solvent of Preferred are, for example, acetone, tetrahydrofuran, or a mixed solvent thereof.
  • the solvent used for precipitating the sodium salt as crystals includes, for example, acetone, acetonitrile, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydrofuran, Examples include pyran, cyclopentyl methyl ether, tert-butyl methyl ether, toluene, xylene, heptane, and mixed solvents thereof.
  • the reaction of step (III) can be carried out by stirring the reaction mixture at an appropriate temperature (eg, -10°C to 30°C) for a certain period of time (eg, 0.5 hours to 24 hours).
  • an appropriate temperature eg, -10°C to 30°C
  • a certain period of time eg, 0.5 hours to 24 hours.
  • the present disclosure provides a compound represented by formula (X) or a sodium salt thereof.
  • the present disclosure provides 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-
  • a composition comprising the sodium salt of 4-yl]methyl]benzamide and a compound represented by formula (X) or a sodium salt thereof is provided.
  • the composition is a pharmaceutical composition, preferably 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfuric acid).
  • the pharmaceutical composition is a pharmaceutical composition for treating or preventing cell proliferative diseases, especially cancer.
  • the amount of the compound of formula (X) or its sodium salt produced is small and the produced 2-(4-cyclopropyl-2-fluoroanilino )-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide relative to the weight of the sodium salt, for example 3.0 w/w % or less, 2.0 w/w % or less, 1.0 w/w % or less, 0.8 w/w % or less, 0.5 w/w % or less, or 0.3 w/w % or less.
  • the amount of the compound of formula (X) or its sodium salt contained in the composition is 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-
  • the weight of [[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide sodium salt for example, 3.0 w/w% or less, 2.0 w/w% or less , 1.0 w/w% or less, 0.8 w/w% or less, 0.5 w/w% or less, or 0.3 w/w% or less.
  • HPLC analysis conditions include, for example, analysis conditions C described in Table 1 below.
  • the peak area of the compound of formula (X) is 2-(4-cyclopropyl-2-fluoroanilino )-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, the compound of formula (X), and 2-(4-cyclopropyl -2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide total peak area of other degradation products , for example, 3.0% or less, 2.0% or less, 1.0% or less, 0.8% or less, 0.5% or less, or 0.3% or less.
  • Seed crystals of a compound or a salt thereof may be used in connection with the practice of the invention of the present disclosure.
  • seed crystals are formed by, for example, cooling the solution of the compound or salt, adding a solvent (anti-solvent) that has low solubility for the compound or salt, or removing the walls of a container containing the solution of the compound or salt. It can be obtained by a method well known to those skilled in the art, such as rubbing with a spatula, purification by silica gel column chromatography, and then concentrating a solution of the compound or salt under reduced pressure.
  • Root temperature as used herein means a temperature of about 20°C to about 25°C.
  • NMR nuclear magnetic resonance apparatus JNM-ECZ500R (manufactured by JEOL). NMR data are given in ppm (parts per million) ( ⁇ ) and are referenced to the deuterium lock signal from the sample solvent.
  • MeCN is superior in terms of reaction selectivity and reaction rate.
  • XPhos-Pd-G3 (440 mg, 0.519 mmol) was added to the resulting mixture, and the inside of the reaction vessel was replaced with nitrogen again. The mixture was heated to an external temperature of 80° C. and stirred for 6 hours. After the mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure. Cyclopentyl methyl ether (50 mL) was added to the residue and concentrated again under reduced pressure. Cyclopentyl methyl ether (50 mL) was added to the obtained concentrated residue, and after concentration under reduced pressure again, cyclopentyl methyl ether (50 mL) was added to the residue, and the precipitated solid was collected by filtration.
  • the filtrate was concentrated under reduced pressure to a total volume of 75 mL, and toluene (225 mL) was added to the concentrated residue. After distilling off the solvent under reduced pressure until the solution volume reached 75 mL, toluene (225 mL) was added again. After distilling off the solvent under reduced pressure to a solution volume of 75 mL, 1-butanol (12 mL) was added as an internal standard, 1 H-NMR was measured to calculate the toluene content, toluene was added, and the toluene volume was 240 mL. A solution of The internal temperature of the reaction solution was raised to 110°C, and after confirming complete dissolution of the solid, the temperature was lowered to 90°C.
  • EtOH is superior in terms of reaction selectivity and reaction rate.
  • Table 4 shows the results. Table 4 shows the peak area ratio of compound 5A and impurity D described in (3-2) above, and the reaction rate calculated according to the formula described in (3-2) above.
  • pyridine (1.69 mL, 20.91 mmol) was added and cooled to 0°C. After adding N-methylsulfamoyl chloride (0.67 mL, 7.67 mmol) and stirring for 45 minutes, pyridine (0.10 mL, 1.26 mmol) and N-methylsulfamoyl chloride (0.30 mL, 3.42 mmol) were added. ) was added and stirred for 35 minutes.
  • the reaction liquid was liquid-separated and the upper layer (organic layer) was washed with 10% sodium chloride aqueous solution (24 g).
  • the resulting organic layer was concentrated under reduced pressure to 15 mL and diluted with THF (45 mL). After repeating this operation two more times, the precipitated inorganic salts were filtered off.
  • the filtered inorganic salts were washed with THF (15 mL), combined with the filtrate, and concentrated under reduced pressure to 15 mL. After diluting the residue with acetone (11 mL), THF (9.3 mL) was added.
  • a compound represented by the following formula (X) was detected in the HPLC analysis of the obtained sample 1a (Form I).
  • the peak area ratio of the compound of formula (X) was 0.27 when the sum of the peak areas of the compound 1A, the compound of formula (X), and other degradation products of compound 1A was taken as 100. It can be said that the content of the compound of formula (X) or its sodium salt in sample 1a (Form I) is sufficiently low.
  • Tris(dibenzylideneacetone)dipalladium(0) (14.9 g, 16.3 mmol) and toluene (540 mL) were added, and the mixture was further degassed under reduced pressure and replaced with nitrogen. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 120° C. and stirred for 7 hours. After cooling the external temperature to room temperature, the reaction mixture was filtered and washed with toluene (450 mL). Activated carbon (9.00 g, 749 mmol) was added to the filtrate and stirred at room temperature for 1 hour.
  • Sample 1b (Form I) and sample 1c were subjected to powder X-ray diffraction measurement under the following conditions.
  • Measuring device SmartLab, D/Tex Ultra detector (manufactured by Rigaku)
  • Anticathode Cu Tube voltage: 45kV Tube current: 200mA Sampling width: 0.02°
  • FIG. 1 shows the powder X-ray diffraction pattern of sample 1a (Form I).
  • FIG. 2 shows the powder X-ray diffraction pattern of sample 1b (Form I).
  • FIG. 3 shows the powder X-ray diffraction pattern of sample 1c. 1 to 3, the horizontal axis (X-axis) represents the diffraction angle 2 ⁇ (°), and the vertical axis (Y-axis) represents the diffraction intensity.
  • Mass spectral data was obtained with a single quadrupole mass spectrometer (LCMS-2020) with ultra-performance liquid chromatography (Nexera UC) manufactured by Shimadzu Corporation or Acquity ultra-performance liquid chromatography (UPLC or UPLC I-Class) manufactured by Waters. Data were obtained using a single quadrupole mass spectrometer (SQD or SQD2).
  • HPLC High performance liquid chromatography
  • the microwave reaction was performed using a Biotage Initiator. Snap-cap reaction vials were used for microwave reactions.
  • HOOBt 8.8 mg, 0.054 mmol
  • EDC.HCl (10.4 mg, 0.054 mmol) were added and stirred at room temperature for 1 hour.
  • DIPEA 0.189 mL, 1.08 mmol
  • Water and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture at a ratio of 1:1, and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1 mL) and hexane (10 mL) was added.
  • reaction mixture was added to a solution of 2,3,4-trifluorobenzoic acid (1.50 g, 8.52 mmol) in THF (9.0 mL) at ⁇ 78° C., stirred for 10 min, then anhydrous DMF (0.759 mL, 9.80 mmol) was added and stirred at 0° C. for 2 hours.
  • anhydrous DMF 0.59 mL, 9.80 mmol
  • a THF solution (30 mL) of benzo[b]thiophenon-5-amine (1.65 g, 11.1 mmol) was cooled to ⁇ 78° C.
  • reaction mixture was added to anhydrous THF solution (15 mL) of 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene (Compound h9, 3.00 g, 11.2 mmol) at -78°C, The mixture was stirred for 3 hours and then stirred for 30 minutes while carbon dioxide gas was introduced. 1M Hydrochloric acid (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure.
  • THF solution 15 mL
  • 1,2,3-trifluoro-4-[(4-methoxyphenyl)methoxy]benzene Compound h9, 3.00 g, 11.2 mmol
  • RAF1 (Carna Biosciences) fused with a GST tag was immobilized on the surface of Sensor Chip CM5 (GE Healthcare) using Anti-GST Antibody (GE Healthcare). Thereafter, a running buffer (blank), a 40 nM MEK1 solution, or a mixed solution of 40 nM MEK1 and 3 ⁇ M test compound was flowed over the surface of the sensor chip for 120 seconds, and then the running buffer was flowed.
  • MEK1 Recombinant Human protein, Inactive (Thermo Fisher Scientific) was used.
  • As a running buffer PBS ( Sigma -Aldrich), and a running buffer was also used for the preparation of the sample solution. Measurements were made at 15°C. Both RAF1 and MEK1 were dephosphorylated with Lambda Protein Phosphatase (New England Biolabs) before use, and MEK1 was purified by size exclusion chromatography.
  • the resulting sensorgram (a graph showing changes over time in the amount of MEK1 bound to immobilized RAF1) was subjected to double-referencing using Biacore Insight Evaluation Software, and further, RAF1 was analyzed using TIBCO Spotfire. Sensorgrams were normalized by immobilized amount. Normalized sensorgrams are shown in Figures 4-7. Above each sensorgram, an experiment ID, a Biacore channel number, and a compound number are written in order (where "no compound” indicates that there is no test compound). In each sensorgram, the horizontal axis (X-axis) represents the time (seconds) after the start of addition of the sample solution, and the vertical axis (Y-axis) represents the normalized MEK1 binding amount.
  • A549 cells were seeded in a 12-well plate at 400,000 cells per well, and placed in a 5% carbon dioxide gas incubator at 37°C using Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (manufactured by Sigma). cultured. On the next day, the test compound (0.3 ⁇ M ref-5 or 0.05 ⁇ M compound A-1) or DMSO was added to the medium, cultured for 30 minutes or 2 hours, and then the cells were collected with a cell scraper and solubilized. Extracted proteins were separated by SDS-PAGE and transferred to PVDF membranes.
  • FIG. 8 is an electropherogram showing the results of Western blotting.
  • Phospho-MEK1/2 and p-ERK represent phosphorylated MEK and phosphorylated ERK, respectively.
  • CRAF manufactured by Thermo Fisher
  • MEK1 manufactured by Thermo Fisher
  • ERK2 manufactured by Carna Biosciences
  • CRAF manufactured by Thermo Fisher
  • FAM-labeled Erktide manufactured by Molecular Devices
  • IMAP registered trademark
  • Progressive Binding Reagent manufactured by Molecular Devices
  • Test example 4 BRAF Inhibitory Activity
  • Table 6 The BRAF inhibitory activity of the compounds shown in Table 6 below was evaluated by the time-resolved fluorescence-fluorescence resonance energy transfer method as follows.
  • a test compound, BRAF (manufactured by Eurofins) and MEK1 (manufactured by Thermo Fisher) were mixed in a buffer containing ATP and allowed to react at 30° C. for 90 minutes. Then, LANCE (registered trademark) Eu-Phospho-MEK1/2 (Ser217/221) antibody (manufactured by PerkinElmer) was added and allowed to react at room temperature for 60 minutes. After the reaction, fluorescence resonance energy transfer was measured with a fluorescence plate reader, and the 50% inhibitory concentration ( IC50 ) was calculated based on the inhibition rate against the control group containing no test compound. Table 6 shows the results.
  • test compound After serially diluting the test compound with DMSO, it was diluted 25-fold with Ca 2+ and Mg 2+ -free phosphate-buffered saline, and this was dispensed into a 96-well plate at 5 ⁇ L per well.
  • a 1 ⁇ M warfarin aqueous solution (50 ⁇ L) was added as an internal standard to each reaction solution in which the metabolic reaction had been stopped.
  • the reaction solution was filtered, followed by LC/MS/MS (LC: NEXERA manufactured by SHIMADZU; MS: 4000Qtrap manufactured by ABSciex; Column: Ascentis Express C18 HPLC column (5 cm ⁇ 2.1 mm, 2.7 ⁇ m); ionization method: electrospray ionization method. ) was analyzed. From the resulting test compound/internal standard peak area ratio, the residual rate relative to the amount of the test compound at 0 minutes was calculated.
  • mice Human lung cancer cell line Calu-6 with KRAS mutation was injected subcutaneously into the ventral region of nude mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, 5 weeks old, Charles River Laboratories) with a 26G injection needle. Implanted into mice by injection. 17 days after transplantation when the tumor volume reached approximately 200 mm 3 , the mice were divided into 5 groups (8 mice per group) according to the dosage of the test compound, and administration of the test compound was started. Mice in group 4 (A-1 administration group) were given 0.0625 mg/kg and 0.25 mg each time using 10% DMSO/10% Cremophor EL/15% PEG400/15% HPCD as a vehicle. /kg, 1 mg/kg or 4 mg/kg of Compound A-1 was administered orally. The remaining one group (vehicle control group) of mice was orally administered with the solvent alone. The test compound or vehicle was administered once a day for 10 days.
  • Tumor volumes were measured at 20, 24 and 27 days post-implantation.
  • the tumor volume was calculated according to the following formula after measuring the major axis and minor axis of the tumor using vernier calipers. The results are shown in FIG.
  • FIG. 9 is a graph showing changes in tumor volume (mean ⁇ standard deviation) over time.
  • the horizontal axis (X-axis) represents days post-implantation and the vertical axis (Y-axis) represents tumor volume.
  • Tumor volume (mm 3 ) 1/2 x major axis (mm) x minor axis (mm) x minor axis (mm)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
PCT/JP2022/028187 2021-07-21 2022-07-20 アリールアミド誘導体の製造方法 Ceased WO2023003014A1 (ja)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US18/579,949 US20240327355A1 (en) 2021-07-21 2022-07-20 Method for producing arylamide derivative
JP2022563493A JP7268255B1 (ja) 2021-07-21 2022-07-20 アリールアミド誘導体の製造方法
EP22845947.5A EP4375273A4 (en) 2021-07-21 2022-07-20 Method for producing arylamide derivative
KR1020237036428A KR102671612B1 (ko) 2021-07-21 2022-07-20 아릴아마이드 유도체의 제조 방법
MX2024000908A MX2024000908A (es) 2021-07-21 2022-07-20 Metodo para producir derivado de arilamida.
CN202280050524.4A CN117677607A (zh) 2021-07-21 2022-07-20 芳基酰胺衍生物的制造方法
IL310123A IL310123A (en) 2021-07-21 2022-07-20 Method for producing arylamide derivative
CA3226827A CA3226827A1 (en) 2021-07-21 2022-07-20 Method for producing arylamide derivative
AU2022312992A AU2022312992A1 (en) 2021-07-21 2022-07-20 Method for producing arylamide derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021120977 2021-07-21
JP2021-120977 2021-07-21

Publications (1)

Publication Number Publication Date
WO2023003014A1 true WO2023003014A1 (ja) 2023-01-26

Family

ID=84980009

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/028187 Ceased WO2023003014A1 (ja) 2021-07-21 2022-07-20 アリールアミド誘導体の製造方法

Country Status (12)

Country Link
US (1) US20240327355A1 (enExample)
EP (1) EP4375273A4 (enExample)
JP (2) JP7268255B1 (enExample)
KR (1) KR102671612B1 (enExample)
CN (1) CN117677607A (enExample)
AR (1) AR126517A1 (enExample)
AU (1) AU2022312992A1 (enExample)
CA (1) CA3226827A1 (enExample)
IL (1) IL310123A (enExample)
MX (1) MX2024000908A (enExample)
TW (1) TW202321198A (enExample)
WO (1) WO2023003014A1 (enExample)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025007811A1 (zh) * 2023-07-06 2025-01-09 成都华健未来科技有限公司 一类芳香酰胺类衍生物及其用途
WO2025146040A1 (zh) * 2024-01-01 2025-07-10 华健未来（成都）科技股份有限公司 芳香酰肼类衍生物及其医药用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118604164B (zh) * 2024-05-15 2025-06-06 石家庄四药有限公司 一种非奈利酮中间体中杂质的检测方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028426A1 (ja) * 2003-09-19 2005-03-31 Chugai Seiyaku Kabushiki Kaisha 新規４−フェニルアミノ−ベンズアルドオキシム誘導体並びにそのmek阻害剤としての使用
WO2006011466A1 (ja) 2004-07-26 2006-02-02 Chugai Seiyaku Kabushiki Kaisha Mek阻害物質としての５－置換－２－フェニルアミノ－ベンズアミド類
WO2007091736A1 (ja) 2006-02-09 2007-08-16 Chugai Seiyaku Kabushiki Kaisha 抗腫瘍活性を有する新規クマリン誘導体
JP2016034900A (ja) * 2012-11-26 2016-03-17 中外製薬株式会社 ５−置換−２−フェニルアミノ−ベンズアミド類の製造方法
WO2021149776A1 (ja) * 2020-01-22 2021-07-29 中外製薬株式会社 抗腫瘍活性を有するアリールアミド誘導体

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2022018875A1 (enExample) * 2020-07-22 2022-01-27
WO2022019329A1 (ja) * 2020-07-22 2022-01-27 中外製薬株式会社 アリールアミド誘導体を含む組成物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028426A1 (ja) * 2003-09-19 2005-03-31 Chugai Seiyaku Kabushiki Kaisha 新規４−フェニルアミノ−ベンズアルドオキシム誘導体並びにそのmek阻害剤としての使用
WO2006011466A1 (ja) 2004-07-26 2006-02-02 Chugai Seiyaku Kabushiki Kaisha Mek阻害物質としての５－置換－２－フェニルアミノ－ベンズアミド類
WO2007091736A1 (ja) 2006-02-09 2007-08-16 Chugai Seiyaku Kabushiki Kaisha 抗腫瘍活性を有する新規クマリン誘導体
JP2016034900A (ja) * 2012-11-26 2016-03-17 中外製薬株式会社 ５−置換−２−フェニルアミノ−ベンズアミド類の製造方法
WO2021149776A1 (ja) * 2020-01-22 2021-07-29 中外製薬株式会社 抗腫瘍活性を有するアリールアミド誘導体

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
ACS MEDCHEM. LETT., vol. 5, no. 4, 2014, pages 309 - 314
ANN. ONCOL., vol. 26, no. 5, 2015, pages 894 - 901
BIOORG. MED. CHEM. LETT., vol. 18, no. 24, 2008, pages 6501 - 6504
BIOORG. MED. CHEM. LETT., vol. 23, no. 8, 2013, pages 2384 - 2390
CANCER CELL, vol. 25, no. 5, 2014, pages 697 - 710
CANCER RES., vol. 73, no. 13, 2013, pages 4050 - 4060
CHEM. MED. CHEM., vol. 10, no. 12, 2015, pages 2004 - 2013
J. CLIN. ONCOL., vol. 35, no. 15, 2017
JAMA, vol. 317, no. 18, 2017, pages 1844 - 1853
MOLECULES, vol. 22, 2017, pages e1551
N. ENGL. J. MED., vol. 367, 2012, pages 1694 - 1703
NAT. REV. CLIN. ONCOL, vol. 15, 2018, pages 709 - 720
NAT. REV. CLIN. ONCOL., vol. 11, 2014, pages 385 - 400

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025007811A1 (zh) * 2023-07-06 2025-01-09 成都华健未来科技有限公司 一类芳香酰胺类衍生物及其用途
WO2025146040A1 (zh) * 2024-01-01 2025-07-10 华健未来（成都）科技股份有限公司 芳香酰肼类衍生物及其医药用途

Also Published As

Publication number Publication date
KR20230152797A (ko) 2023-11-03
KR102671612B1 (ko) 2024-05-31
TW202321198A (zh) 2023-06-01
US20240327355A1 (en) 2024-10-03
AR126517A1 (es) 2023-10-18
CA3226827A1 (en) 2023-01-26
EP4375273A4 (en) 2025-05-21
CN117677607A (zh) 2024-03-08
JPWO2023003014A1 (enExample) 2023-01-26
JP7268255B1 (ja) 2023-05-02
AU2022312992A1 (en) 2024-02-29
EP4375273A1 (en) 2024-05-29
IL310123A (en) 2024-03-01
JP2023084138A (ja) 2023-06-16
MX2024000908A (es) 2024-02-07

Similar Documents

Publication Publication Date Title
JP6971432B1 (ja) 抗腫瘍活性を有するアリールアミド誘導体
JP7022873B1 (ja) アリールアミド誘導体を含む組成物
JP7268255B1 (ja) アリールアミド誘導体の製造方法
JP7168734B2 (ja) アリールアミド誘導体を含む細胞増殖性疾患の治療又は予防用医薬組成物
EP3498694A1 (en) New benzamide derivatives as ppar-gamma modulators
EA050002B1 (ru) Способ получения производного ариламида
KR102904379B1 (ko) 항종양 활성을 갖는 아릴 아마이드 유도체
CA3066011A1 (en) Carboxylic acid derivatives as protein kinase inhibitors
HK40084009A (en) Composition containing arylamide derivative
HK40073328A (en) Arylamide derivative having antitumor activity
EA047579B1 (ru) Производное ариламида, обладающее противоопухолевой активностью
HK40073328B (zh) 具有抗肿瘤活性的芳基醯胺衍生物
HK40084009B (zh) 包含芳基酰胺衍生物的组合物
EA041069B1 (ru) Производные бензамида в качестве модуляторов ppar-гамма

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2022563493

Country of ref document: JP

Kind code of ref document: A

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22845947

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 20237036428

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020237036428

Country of ref document: KR

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023027245

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 310123

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 18579949

Country of ref document: US

Ref document number: 202280050524.4

Country of ref document: CN

Ref document number: 3226827

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2024/000908

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 202490187

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: AU2022312992

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2022845947

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022845947

Country of ref document: EP

Effective date: 20240221

ENP Entry into the national phase

Ref document number: 2022312992

Country of ref document: AU

Date of ref document: 20220720

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112023027245

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20231222