WO2015199167A1 - METHOD FOR PRODUCING SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE, AND INTERMEDIATE - Google Patents

METHOD FOR PRODUCING SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE, AND INTERMEDIATE Download PDF

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WO2015199167A1
WO2015199167A1 PCT/JP2015/068295 JP2015068295W WO2015199167A1 WO 2015199167 A1 WO2015199167 A1 WO 2015199167A1 JP 2015068295 W JP2015068295 W JP 2015068295W WO 2015199167 A1 WO2015199167 A1 WO 2015199167A1
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formula
compound
salt
alkyl
reacting
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PCT/JP2015/068295
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French (fr)
Japanese (ja)
Inventor
隆司 嶌田
馨 足達
宮崎　将
誠司 川下
裕隆 磯島
伸 長橋
賢吾 大下
昭伸 東
尊久 嶋崎
文人 下間
峻 山口
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日本たばこ産業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/30—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for producing a substituted spiropyrido [1,2-a] pyrazine derivative or a salt thereof useful as an anti-HIV agent, and a production intermediate.
  • the present invention relates to a compound useful as a synthetic intermediate of an anti-HIV agent having integrase inhibitory activity and a method for producing the same.
  • the present invention also relates to a method for producing an anti-HIV agent using the synthetic intermediate.
  • HIV Human Immunodeficiency Virus
  • retrovirus is a causative virus of AIDS (Acquired Immunodeficiency Syndrome). HIV targets a group of CD4 positive cells such as helper T cells, macrophages, and dendritic cells, destroys these immunocompetent cells, and causes immunodeficiency. Therefore, for the treatment or prevention of AIDS, a drug that eradicates HIV in the living body or suppresses its growth is effective.
  • CD4 positive cells such as helper T cells, macrophages, and dendritic cells
  • HIV has two RNA genes in the shell, and the shell is covered with a coat protein.
  • RNA encodes a plurality of viruses-specific enzymes (protease, reverse transcriptase, integrase), etc., translated reverse transcriptase and integrase are present in the shell, and protease is present inside and outside the shell. HIV contacts and invades the host cell, then undergoes shelling and releases a complex such as RNA and integrase into the cytoplasm. From this RNA, DNA is transcribed by reverse transcriptase to produce full-length double-stranded DNA. The DNA moves into the host cell nucleus and is incorporated into the host cell DNA by integrase. The incorporated DNA is converted into mRNA by the host cell polymerase, and various proteins necessary for virus formation are synthesized from the mRNA by HIV protease and the like, and finally virus particles are formed, budding and releasing.
  • viruses-specific enzymes protease, reverse transcriptase, integr
  • virus-specific enzymes are essential for the growth of HIV, attracting attention as a target for the development of antiviral agents, and several anti-HIV agents have already been developed.
  • tenofovir, abacavir, emtricitabine, lamivudine, etc. as nucleic acid reverse transcriptase inhibitors, efavirenz, nevirapine, etc. as non-nucleic acid reverse transcriptase inhibitors, atazanavir, darunavir, etc. are already commercially available as protease inhibitors .
  • a multi-drug combination therapy (referred to as cART (combination antiretroviral therapy)) that uses these drugs in combination is also used, for example, two nucleic acid reverse transcriptase inhibitors (tenofovir and emtricitabine, or abacavir and lamivudine). And a non-nucleic acid reverse transcriptase inhibitor (efavirenz) or a combination of ritonavir and a protease inhibitor (atazanavir or darunavir) are used in clinical settings. It has become mainstream. However, some of these drugs have known side effects such as liver dysfunction and central nervous system disorders such as dizziness, and acquisition of resistance to the drug is also a problem. In addition, the emergence of HIV showing multidrug resistance to multidrug combination therapy is also known.
  • cART combination antiretroviral therapy
  • anti-HIV agents are effective for the prevention and treatment of AIDS, and particularly compounds having integrase inhibitory activity can be effective anti-HIV agents.
  • compounds having integrase inhibitory activity a compound represented by formula (18)
  • the present invention relates to a compound useful as a production intermediate of a compound of formula (18) or a pharmaceutically acceptable salt thereof, a production method thereof, and a production method of a compound of formula (18) or a salt thereof using the production intermediate.
  • a compound useful as a production intermediate of a compound of formula (18) or a pharmaceutically acceptable salt thereof a production method thereof, and a production method of a compound of formula (18) or a salt thereof using the production intermediate.
  • R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
  • a method comprising a step of subjecting a compound of the formula or a salt thereof to a catalytic hydrogen reduction reaction to obtain a compound of the formula (9) or a salt thereof. [1-1] The method according to [1], wherein R 1 is 4-methoxybenzyl. [1-2] The method according to [1], wherein R 1 is benzyl. [2] Formula [VII]
  • R 5 is C 1-6 alkyl.
  • a compound of the formula R 1 —NH 2 (wherein R 1 is as described in [1]) or a salt thereof, followed by a reaction with a cyanating agent to produce a compound of the formula [XXVI
  • R 5 is isopropyl.
  • R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy. Or a salt thereof.
  • R 1 is 4-methoxybenzyl.
  • R 1 is benzyl.
  • R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy. Or a salt thereof.
  • [16-1] The compound according to [16] or a salt thereof, wherein R 1 is 4-methoxybenzyl.
  • [16-2] The compound or salt thereof according to [16], wherein R 1 is benzyl.
  • [17] Formula [VI]
  • R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
  • Compound. [17-1] The compound according to [17], wherein R 1 is 4-methoxybenzyl.
  • [17-2] The compound according to [17], wherein R 1 is benzyl.
  • [18] Formula [V]
  • R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
  • Compound. [18-1] The compound described in [18], wherein R 1 is 4-methoxybenzyl.
  • [18-2] The compound according to [18], wherein R 1 is benzyl.
  • [19] Formula [IV]
  • R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy. Or a salt thereof.
  • R 1 is 4-methoxybenzyl.
  • R 1 is benzyl.
  • Formula [IV] is converted to Formula [IV-a]
  • a method for producing a compound or a salt thereof comprising: Formula [XX]
  • a method for producing a compound or a salt thereof comprising: Formula (9)
  • R 2 is unsubstituted or halogen, C 1-4 alkyl or benzyl substituted with C 1-4 alkoxy, or C 1-4 alkyl, and R 3 is C 1-4 alkyl.
  • R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy. Benzyl, or C 1-4 alkyl). Or a salt thereof. [32-1] The compound or a salt thereof according to [32], wherein R 2 is benzyl. [33] Equation (18)
  • a method comprising a step of reacting a compound of the formula (I) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula (18) or a salt thereof.
  • R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
  • R 4 is benzyl.
  • R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl). Or a salt thereof. [39-1] The compound or a salt thereof according to [39], wherein R 4 is benzyl. [40] Equation (19)
  • R 2 is unsubstituted or halogen, C 1-4 alkyl or benzyl substituted with C 1-4 alkoxy, or C 1-4 alkyl, and R 3 is C 1-4 alkyl.
  • R 3 is C 1-4 alkyl.
  • R 2 is benzyl.
  • R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
  • R 4 is benzyl.
  • R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy.
  • Benzyl, or C 1-4 alkyl A method comprising a step of reacting a compound of the formula (I) or a salt thereof with sodium hydroxide to obtain a compound of the formula (19). [53-1] The method according to [53], wherein R 2 is benzyl. [54] Formula [XX]
  • R 3 is C 1-4 alkyl.
  • [59-1] The method according to [59], wherein R 2 is benzyl.
  • R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
  • Compound. [62-1] The compound or a salt thereof according to [62], wherein R 4 is benzyl.
  • R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl). Or a salt thereof.
  • R 4 is benzyl.
  • Another embodiment of the present invention is as follows. The structure of each formula is shown below. [64] A method for producing a compound of formula (19), comprising a step of reacting a compound of formula (18) with sodium hydroxide to obtain a compound of formula (19).
  • a method for producing a compound of formula (18) or a salt thereof comprising a step of reacting a compound of formula (17) or a salt thereof with an acid to obtain a compound of formula (18) or a salt thereof.
  • a compound of formula (17) comprising a step of reacting a compound of formula (20) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of formula (17) or a salt thereof A method for producing the salt.
  • a method for producing a compound of the formula (20) or a salt thereof comprising a step of subjecting the compound of the formula (8) or a salt thereof to a catalytic hydrogen reduction reaction to obtain a compound of the formula (9) or a salt thereof.
  • Production of a compound of formula (8) or a salt thereof comprising a step of reacting a compound of formula (7) or a salt thereof with hydroxyamine or a salt thereof to obtain a compound of formula (8) or a salt thereof how to.
  • a method for producing a compound of formula (7) or a salt thereof comprising a step of reacting a compound of formula (6) with an aluminum reducing agent to obtain a compound of formula (7) or a salt thereof.
  • a method for producing a compound of formula (6) comprising a step of reacting a compound of formula (5) with a methylating agent to obtain a compound of formula (6).
  • a method for producing a compound of formula (5) comprising a step of reacting a compound of formula (4) or a salt thereof with a borane reducing agent to obtain a compound of formula (5).
  • a method for producing a compound of formula (4) or a salt thereof comprising a step of subjecting the compound of formula (3) to alkaline hydrolysis to obtain a compound of formula (4) or a salt thereof.
  • a method for producing a compound of formula (3) comprising a step of reacting a compound of formula (2) with a 4-methoxybenzylating agent to obtain a compound of formula (3).
  • a method for producing a compound of formula (2) comprising a step of reacting a compound of formula (1) or a salt thereof with a methylating agent to obtain a compound of formula (2) by recrystallization.
  • a compound of formula (15) or a salt thereof comprising a step of reacting a compound of formula (14) with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of formula (15) or a salt thereof. How to manufacture. [77] A compound of the formula (12) or a salt thereof and diethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide, The method of manufacturing the compound of Formula (14) including the process of obtaining the compound of).
  • a compound of formula (12) or a salt thereof comprising a step of reacting a compound of formula (10) or a salt thereof with benzyloxyacetyl chloride in the presence of an organic base to obtain a compound of formula (12) or a salt thereof.
  • a method for producing a salt comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of the formula (10) or a salt thereof.
  • a compound of formula (18) comprising a step of reacting a compound of formula (24) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of formula (18) or a salt thereof
  • a method for producing the salt [81] A compound of formula (24) or a salt thereof is produced, which comprises a step of reacting a compound of formula (23) or a salt thereof with an aqueous sodium hydroxide solution to obtain a compound of formula (24) or a salt thereof. Method. [82] The method comprising reacting the compound of the formula (9) or a salt thereof with the compound of the formula (22) in the presence of an organic base to obtain a compound of the formula (23) or a salt thereof. Or a salt thereof.
  • a compound of the formula (21) or a salt thereof and dimethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide to obtain a compound of the formula (22
  • the method of manufacturing the compound of Formula (22) including the process of obtaining the compound of).
  • [84] reacting 3- (dimethylamino) acrylonitrile and benzyloxyacetyl chloride in the presence of an organic base to obtain a compound of the formula (21) or a salt thereof; How to manufacture.
  • a method for producing a compound of formula (19), comprising a step of reacting a compound of formula (17) or a salt thereof with sodium hydroxide to obtain a compound of formula (19).
  • the method comprising the step of reacting the compound of the formula (9) or a salt thereof with the compound of the formula (16) in the presence of an organic base to obtain a compound of the formula (17) or a salt thereof.
  • a method for producing a compound or a salt thereof A process for producing a compound of formula (16), comprising a step of reacting a compound of formula (15) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of formula (16) .
  • Halogen is fluorine, chlorine, bromine or iodine. Preferred “halogen” embodiments are fluorine or chlorine.
  • C 1-6 alkyl represents linear or branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyl Propyl, hexyl, 1,1-dimethylbutyl, 1-ethyl-1-methylpropyl and the like.
  • C 1-4 alkyl represents linear or branched alkyl having 1 to 4 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like are included.
  • a preferred “C 1-4 alkyl” embodiment for R 2 is methyl.
  • a preferred “C 1-4 alkyl” embodiment of R 3 is methyl or ethyl.
  • C 1-4 alkoxy is straight-chain or branched alkoxy having 1 to 4 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butyloxy and the like are included. A preferred “C 1-4 alkoxy” embodiment is methoxy.
  • the salt of the compound of the present invention may be any salt as long as it forms a non-toxic salt with the compound of the present invention. For example, a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, and an organic base And salts with amino acids.
  • Examples of the salt with an inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
  • Examples of salts with organic acids include oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, Examples thereof include salts with benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Examples of the salt with an inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
  • salts with organic bases include methylamine, diethylamine, trimethylamine, n-propylamine, n-butylamine, t-butylamine, cyclohexylamine, dicyclohexylamine, phenethylamine, (S) -phenethylamine, (R) -phenethylamine, Examples include salts with triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine, etc. It is done.
  • the salt with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
  • such a salt can be obtained by reacting the compound of the present invention with an inorganic base, organic base, inorganic acid, organic acid or amino acid.
  • a salt of the compound of the present invention a salt with hydrochloric acid (eg, monohydrochloride, dihydrochloride), a salt with hydrobromic acid (eg, monohydrobromide, dihydrobromide) ),
  • a salt with sulfuric acid, a salt with p-toluenesulfonic acid, a sodium salt, a potassium salt, and a calcium salt are preferred embodiments.
  • the compound of the present invention or a salt thereof may exist as a solvate.
  • the “solvate” is a compound in which a solvent molecule is coordinated to the compound of the present invention or a salt thereof, and also includes a hydrate (also referred to as a hydrate).
  • the solvate is preferably a pharmaceutically acceptable solvate, for example, 0.4 to 0.8 hydrate, 1 hydrate, 1/2 hydrate, 2 hydrate of the compound of the present invention, Sodium salt 0.4 to 0.8 hydrate, sodium salt monohydrate, 1 methanol hydrate, 1 ethanol hydrate, 1 acetonitrile hydrate, 2 hydrochloride 1 ⁇ 2 ethanol hydrate, etc.
  • a preferred embodiment of the solvate of the compound of the present invention is 0.5 to 0.7 hydrate, monohydrate, 1/2 hydrate, 0.6 hydrate, dihydrate, sodium salt 0.5 to 0.7 hydrate, sodium salt monohydrate, sodium salt 0.6 hydrate, sodium salt 0.5 hydrate, sodium salt dihydrate.
  • a solvate of the compound of the present invention or a salt thereof can be obtained.
  • the compounds of the present invention may exist as tautomers. In that case, the compounds of the invention may exist as individual tautomers or mixtures of tautomers.
  • the compound of the present invention may have a carbon double bond. In that case, the compound of the present invention may exist as E-form, Z-form, or a mixture of E-form and Z-form.
  • the compound of the present invention may have a stereoisomer to be recognized as a cis / trans isomer. In that case, the compound of the present invention may exist as a cis form, a trans form, or a mixture of a cis form and a trans form.
  • the compound of the present invention may contain a plurality of structural features that give rise to the above isomers simultaneously. In addition, the compound of the present invention can contain the above isomers in any ratio.
  • the diastereomer mixture can be separated into each diastereomer by a conventional method such as chromatography or crystallization.
  • Each diastereomer can also be made by using a stereochemically single starting material or by a synthetic method using a stereoselective reaction.
  • the steric configuration described in the present application can be specified based on the X-ray structural analysis of the single crystal of the compound (18).
  • the compound of the present invention may be crystalline or amorphous.
  • the compound of the present invention may be labeled with an isotope (eg, 3 H, 14 C, 35 S etc.).
  • an isotope eg, 3 H, 14 C, 35 S etc.
  • a preferred embodiment of the compound of the present invention or a salt thereof is a substantially purified compound of the present invention or a salt thereof.
  • a further preferred embodiment is the compound of the present invention or a salt thereof purified to a purity of 80% or more.
  • each step the reaction is performed in a solvent.
  • the treatment after the reaction can be carried out by a method usually performed by those skilled in the art unless otherwise specified. For example, a method such as distillation, crystallization, recrystallization, column chromatography, preparative HPLC or the like may be appropriately selected, or these methods may be combined to carry out the treatment after the reaction.
  • the next step can be carried out without isolation and purification.
  • room temperature means 15 ° C. to 30 ° C.
  • the specific reaction temperature is allowed to be ⁇ 5 ° C., preferably ⁇ 2 ° C.
  • Production method 1 Production method of compound of formula (9) or salt thereof
  • Compounds of formula (1) can be prepared from 3-oxocyclobutanecarboxylic acid by the Bucherer-Bergs reaction (Journal of Medicinal Chemistry 33 (1990) 2905-2915, or Synlett 11 (2009) 1827-1829).
  • the solvent include methanol, ethanol, 1-propanol, 2-propanol, DMF (N, N-dimethylformamide), DMA (N, N-dimethylacetamide), water alone or a mixed solvent.
  • a preferred solvent is water.
  • the amount of potassium cyanide is 0.9 to 1.0 equivalent, preferably 0.95 equivalent, relative to 3-oxocyclobutanecarboxylic acid.
  • the amount of ammonium carbonate is 1.5 to 2.5 equivalents, preferably 2.0 equivalents, relative to 3-oxocyclobutanecarboxylic acid.
  • the amount of ammonium chloride is 0.2 to 1.0 equivalent, preferably 1.0 equivalent, based on 3-oxocyclobutanecarboxylic acid.
  • the solution before the start of the reaction needs to have a pH close to neutral with 28% aqueous ammonia.
  • the pH of the preferred solution is 6.5 to 9.0.
  • the reaction temperature is 50 ° C to 60 ° C, preferably 55 ° C to 60 ° C.
  • the reaction time is 1 to 20 hours, preferably 4 to 20 hours.
  • the order of reagent addition is preferably to add potassium cyanide last.
  • the compound of formula (2) or a salt thereof is reacted with a compound of formula (1) or a salt thereof and a methylating agent to obtain a mixture of the compound of formula (2) or a salt thereof and a trans isomer thereof, It can be produced by recrystallizing the mixture.
  • the reaction of the compound of formula (1) or a salt thereof and the methylating agent is carried out in the presence of a base.
  • the solvent include DMF, DMSO (dimethyl sulfoxide), DMA, DMI (1,3-dimethyl-2-imidazolidinone) and the like alone or as a mixed solvent.
  • a preferred solvent is DMF.
  • methylating agent examples include methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, and the like.
  • a preferred methylating agent is methyl iodide.
  • the base examples include sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • a preferred base is potassium carbonate.
  • the compound of formula (1) is preferably used after being crushed with a cutter mill or the like.
  • the reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
  • the solvent used for recrystallization include alcohols (methanol, ethanol, 1-propanol, 2-propanol, etc.). A preferred solvent is methanol.
  • R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, preferably unsubstituted benzyl or 4-methoxybenzyl, more preferably Substituted benzyl (also referred to simply as benzyl).)
  • the compound of the formula [III] can be produced by reacting the compound of the formula (2) or a salt thereof with a benzylating agent.
  • the reaction between the compound of formula (2) and the benzylating agent is carried out in the presence of a base.
  • the solvent include MeCN (acetonitrile), DMF, DMSO, DMA, DMI and the like alone or in combination.
  • a preferred solvent is DMF.
  • benzylating agent a compound of formula R 1 -X (wherein R 1 is benzyl which is unsubstituted or substituted by halogen, C 1-4 alkyl or C 1-4 alkoxy, and X is a chlorine atom, bromine A benzyl chloride, benzyl bromide, 3-chlorobenzyl chloride, 3-chlorobenzyl bromide, 4-chlorobenzyl chloride, 4-chlorobenzyl bromide, 3-methylbenzyl chloride.
  • benzylating agents are 4-methoxybenzylating agents such as 4-methoxybenzyl chloride or benzylating agents such as benzyl chloride and benzyl bromide.
  • the base include cesium carbonate, sodium hydride, potassium tert-butoxide and the like.
  • a preferred base is cesium carbonate.
  • the compound of formula [IV-a] or a salt thereof can be produced by hydrolysis reaction of the compound of formula [III].
  • the hydrolysis reaction of the compound of formula [III] is preferably alkaline hydrolysis.
  • the solvent include methanol, water, toluene, THF (tetrahydrofuran) and the like alone or as a mixed solvent.
  • a preferred solvent is THF.
  • the base include sodium hydroxide and potassium hydroxide.
  • a preferred base is sodium hydroxide.
  • the reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
  • the compound of the formula [V] or a salt thereof can be produced by reacting the compound of the formula [IV-a] or a salt thereof with a borane reducing agent.
  • the reaction of the compound of the formula [IV-a] or a salt thereof and the borane reducing agent may be performed in the presence of an additive.
  • the solvent include THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane and the like alone or in a mixed solvent.
  • a preferred solvent is THF.
  • the borane-based reducing agent include sodium borohydride and additives, borane-tetrahydrofuran complex, and the like.
  • Preferred borane reducing agents are sodium borohydride and additives.
  • the amount of sodium borohydride is, for example, 1.00 to 2.00 equivalents, preferably 1.10 equivalents, relative to the compound of formula [IV-a].
  • the additive include boron trifluoride diethyl etherate (boron trifluoride-diethyl ether complex), iodine, sulfuric acid and the like.
  • a preferred additive is boron trifluoride diethyl etherate.
  • the amount of boron trifluoride diethyl etherate is 0.95 equivalents to 1.50 equivalents, preferably 0.995 equivalents, relative to the compound of formula [IV-a].
  • the reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
  • the compound of the formula [V] or a salt thereof is converted into an active ester by reacting the compound of the formula [IV-a] or a salt thereof with a C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base. And then reacting with sodium borohydride.
  • the solvent include THF, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, water and the like alone or as a mixed solvent.
  • a preferred solvent is a mixed solvent of THF and water.
  • the reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
  • the compound of the formula [VI] can be produced by reacting the compound of the formula [V] or a salt thereof with a methylating agent.
  • the reaction of the compound of formula [V] or a salt thereof and the methylating agent is carried out in the presence of a base.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, DMF, DMA, DMI and the like alone or in combination.
  • a preferred solvent is THF.
  • the methylating agent include methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, and the like.
  • a preferred methylating agent is methyl iodide.
  • the base include sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide and the like.
  • a preferred base is potassium tert-butoxide.
  • the reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
  • the compound of formula [VII] or a salt thereof can be produced by reacting the compound of formula [VI] with an aluminum-based reducing agent.
  • the solvent include toluene, xylene, ethylbenzene, chlorobenzene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane and the like alone or in a mixed solvent.
  • a preferred solvent is toluene.
  • the aluminum reducing agent include bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride and the like.
  • a preferred reducing agent is sodium bis (2-methoxyethoxy) aluminum hydride.
  • the reaction temperature is from room temperature to 75 ° C, preferably from 65 ° C to 75 ° C.
  • the compound of formula [VIII] or a salt thereof can be produced from the compound of formula [VII] or a salt thereof by the method described in J. AM. CHEM. SOC. 2003, 125, 11836-11837. Specifically, it can be produced by reacting a compound of the formula [VII] or a salt thereof with hydroxyamine or a salt thereof.
  • the reaction of the compound of formula [VII] or a salt thereof and hydroxyamine or a salt thereof is carried out in an acidic solution.
  • an aqueous hydrochloric acid solution having a concentration of 2 mol / L or less is preferable.
  • the reaction temperature is 0 ° C.
  • the compound of formula [VIII] can be obtained as a hydrochloride as a solid.
  • the method for preparing the hydrochloride of the formula [VIII] may be a method for preparing the hydrochloride in a non-aqueous or non-alcoholic solvent.
  • the hydrochloride include monohydrochloride and dihydrochloride.
  • a preferred hydrochloride salt is the dihydrochloride salt.
  • the compound of formula (9) or a salt thereof can be produced by subjecting the compound of formula [VIII] or a salt thereof to a catalytic hydrogen reduction reaction.
  • an additive such as sodium acetate may be added.
  • Solvents are alcohol (methanol, ethanol, 1-propanol, 2-propanol, etc.) alone, or alcohol and aromatic hydrocarbon solvents (toluene, benzene, etc.), ether solvents (tetrahydrofuran, diethyl ether, etc.), ester solvents (acetic acid, etc.) And a mixed solvent with ethyl and the like.
  • a preferred solvent is methanol.
  • the palladium catalyst examples include palladium carbon, palladium black, palladium hydroxide carbon, and the like.
  • a preferred palladium catalyst is 10% palladium on carbon.
  • the hydrogen pressure is 0.1 to 1.0 MPa, and the preferred hydrogen pressure is 0.3 to 0.4 MPa.
  • the reaction temperature is 0 ° C to 50 ° C, preferably 15 ° C to 30 ° C.
  • R 5 is C 1-6 alkyl, preferably C 1-4 alkyl, and more preferably isopropyl.
  • a compound of formula [XXV] can be prepared by reacting 3-oxocyclobutanecarboxylic acid with an alcohol of formula R 5 —OH in the presence of a catalytic amount of acid.
  • Alcohols of the formula R 5 —OH can be used as solvents. Examples of the solvent include methanol, ethanol, 1-propanol, and 2-propanol. A preferred solvent is 2-propanol.
  • the catalytic amount of acid include concentrated hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • the amount of the catalyst is exemplified by 0.500% to 10.0% based on the weight of 3-oxocyclobutanecarboxylic acid.
  • a preferred amount of catalyst is 1.00%.
  • Examples of the reaction temperature include room temperature to reflux temperature.
  • a preferred reaction temperature is the reflux temperature.
  • a compound of formula [XXVI] can be prepared by condensing a compound of formula [XXV] and a compound of formula R 1 —NH 2 followed by reaction with a cyanating agent (TETRAHEDRON ASYMMETRY 14 (2003)). 497-502).
  • a cyanating agent TETRAHEDRON ASYMMETRY 14 (2003). 497-502.
  • the compound of formula R 1 —NH 2 is benzylamine, 3-chlorobenzylamine, 4-chlorobenzylamine, 3-methylbenzylamine , 4-methylbenzylamine, 3-methoxybenzylamine, 4-methoxybenzylamine.
  • a preferred compound of formula R 1 —NH 2 is 4-methoxybenzylamine or benzylamine, more preferably benzylamine.
  • the amount of the compound of formula R 1 —NH 2 is from 1.00 equivalents to 2.00 equivalents, preferably 1.05 equivalents, relative to the compound of formula [XXV].
  • the solvent include alcohols (methanol, ethanol, 2-propanol, etc.), ethers (diethyl ether, tetrahydrofuran, cyclopentylmethyl ether, etc.), toluene, water and the like alone or a mixed solvent.
  • a preferred solvent is toluene.
  • Examples of the cyanating agent include acetone cyanohydrin, trimethylsilyl cyanide, ethyl cyanoformate, sodium cyanide, and potassium cyanide.
  • a preferred cyanating agent is acetone cyanohydrin.
  • Examples of the reaction temperature include room temperature to reflux temperature. The preferred reaction temperature is the reflux temperature. In the subsequent reaction with the cyanating agent, the amount of the cyanating agent is 1.00 to 3.00 equivalents, preferably 1.50 equivalents, relative to the compound of formula [XXV].
  • Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. A preferred base is triethylamine.
  • the amount of the base is 0.500 equivalents to 3.00 equivalents, preferably 1.50 equivalents, relative to the compound of formula [XXV].
  • the reaction temperature is exemplified by 0 ° C. to room temperature.
  • the preferred reaction temperature is 0 ° C.
  • the compound of the formula [XXVII] can be produced by reacting the compound of the formula [XXVI] or a salt thereof with potassium cyanate or sodium cyanate.
  • the amount of potassium cyanate or sodium cyanate is, for example, 1.00 equivalent to 3.00 equivalent, preferably 1.10 equivalent, relative to the compound of formula [XXVI].
  • the solvent include alcohols (methanol, ethanol, 2-propanol, etc.), DMF, DMSO (dimethyl sulfoxide), acetic acid, water and the like alone or as a mixed solvent.
  • a preferred solvent is a mixed solvent of acetic acid and water.
  • the reaction temperature is exemplified by 0 ° C. to room temperature.
  • the preferred reaction temperature is room temperature.
  • Examples of the acid used in the acid hydrolysis of amidine after cyclization include hydrochloric acid, phosphoric acid aqueous solution, and sulfuric acid aqueous solution.
  • a preferred acid is hydrochloric acid.
  • the reaction temperature is exemplified by 10 ° C to 40 ° C.
  • the preferred reaction temperature is room temperature.
  • a compound of formula [XXVIII] can be produced by reacting a compound of formula [XXVII] or a salt thereof with a methylating agent.
  • a methylating agent examples include DMF, DMSO (dimethyl sulfoxide), DMA, DMI (1,3-dimethyl-2-imidazolidinone) and the like alone or as a mixed solvent.
  • a preferred solvent is DMF.
  • the methylating agent include methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, and the like.
  • a preferred methylating agent is methyl iodide.
  • the amount of the methylating agent is, for example, 1.00 equivalent to 2.00 equivalent, preferably 1.00 equivalent, relative to the compound of the formula [XXVII].
  • the base include sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • a preferred base is potassium carbonate.
  • the amount of the base is, for example, 1.00 equivalent to 2.00 equivalent, preferably 1.00 equivalent, relative to the compound of the formula [XXVII].
  • the reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
  • the compound of formula [IV] or a salt thereof can be produced by hydrolysis reaction of the compound of formula [XXVIII].
  • the hydrolysis reaction of the compound of the formula [XXVIII] is preferably alkaline hydrolysis.
  • the solvent include alcohols (methanol, ethanol, 2-propanol and the like), water, toluene, THF (tetrahydrofuran) and the like alone or as a mixed solvent.
  • a preferred solvent is 2-propanol.
  • the base include sodium hydroxide and potassium hydroxide.
  • a preferred base is sodium hydroxide.
  • the amount of the base is, for example, 1.00 equivalent to 2.00 equivalent, preferably 1.00 equivalent, relative to the compound of the formula [XXVIII].
  • the reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
  • the compound of formula [IV] is a compound of formula [IV-a]
  • a compound of formula [IV-a] can be prepared by forming a salt from a compound of formula [IV]. Furthermore, the purity can be improved by purification such as recrystallization.
  • the salt examples include a salt with an inorganic base or a salt with an organic base.
  • Preferred salts are salts with organic bases such as n-propylamine, n-butylamine, t-butylamine, cyclohexylamine, dicyclohexylamine, phenethylamine, (S) -phenethylamine, (R) -phenethylamine.
  • a more preferred salt is n-propylamine salt.
  • the amount of the inorganic base or the organic base is, for example, 0.950 equivalent to 1.50 equivalent, preferably 0.995 equivalent, relative to the compound of the formula [IV].
  • Examples of the solvent used for salt formation and recrystallization include methanol, acetonitrile, ethyl acetate, isopropyl acetate, toluene and the like alone or as a mixed solvent.
  • a preferred solvent is a mixed solvent of ethyl acetate-isopropyl acetate.
  • the reaction temperature is exemplified by 0 ° C to 70 ° C.
  • the preferred reaction temperature is room temperature.
  • the compound of the formula [IV-a] can be produced by neutralizing or acidifying the salt of the compound of the formula [IV-a] by a general method. As an example, it can manufacture by neutralizing or acidifying using acids, such as concentrated hydrochloric acid or concentrated sulfuric acid.
  • Production of the compound of formula [IV-a] or a salt thereof to the compound of formula (9) or a salt thereof can be carried out according to Production Method 1-1, Step 5 to Step 9.
  • the stereoselectivity of the compound of the formula [XXVI] can be improved by using the compound of the formula [XXV] which is an ester compared to 3-oxocyclobutanecarboxylic acid in the step 2.
  • the compound of the formula [XXIX] produced from the compound of the formula [XXVI] having improved stereoselectivity through the step 3-5 is obtained by selecting a salt with an organic base as a salt thereof, thereby achieving the purpose of crystallization.
  • a highly pure compound of the formula [IV-a] or a salt thereof can be obtained efficiently with a minimum of product loss.
  • Production method 2 Method for producing compound of formula [XV]
  • R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy.
  • Benzyl, or C 1-4 alkyl preferably unsubstituted benzyl or 4-methoxybenzyl, more preferably unsubstituted benzyl (also simply referred to as benzyl)
  • R 3 is C 1- 4 alkyl, preferably methyl or ethyl.
  • the compound of the formula (10) or a salt thereof can be produced by reacting tert-butyl propiolate with diethylamine.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, MeCN and the like alone or in combination. .
  • a preferred solvent is MeCN.
  • the reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
  • a compound of formula [XII] or a salt thereof can be produced by reacting a compound of formula (10) or a salt thereof with a compound of formula [XI] in the presence of a base.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMI, MeCN and the like alone or in combination.
  • a preferred solvent is MeCN.
  • the base examples include organic bases such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium hydrogen carbonate.
  • organic bases such as pyridine, triethylamine and diisopropylethylamine
  • inorganic bases such as potassium hydrogen carbonate.
  • a preferred base is pyridine.
  • the reaction temperature is from 0 ° C. to room temperature, preferably 0 ° C.
  • the compound of the formula [XIV] is a compound of the formula [XII] or a salt thereof and di (C 1-4 alkyl) oxalate of the formula [XIII] (eg, diethyl oxalate, dimethyl oxalate) -It can be produced by reacting diazabicyclo [5.4.0] -7-undecene with anhydrous lithium bromide.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, DMF, DMA, DMSO, DMI, MeCN and the like alone or in combination.
  • a preferred solvent is MeCN.
  • the reaction temperature is from room temperature to 85 ° C, preferably 70 ° C.
  • the compound of the formula [XV] or a salt thereof can be produced by reacting the compound of the formula [XIV] with an acid.
  • the solvent include hexane, toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, water and the like alone or in a mixed solvent. Is done.
  • a preferred solvent is ethyl acetate.
  • the acid include an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid.
  • a preferred acid is 4 mol / L hydrogen chloride in ethyl acetate.
  • the reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
  • the compound of the formula [XVII] can be produced by the production method 3-1 or the production method 3-2.
  • a compound of formula [XX] or a salt thereof can be produced by reacting a compound of formula (9) or a salt thereof with a compound of formula [XV] or a salt thereof.
  • the reaction between the compound of formula (9) or a salt thereof and the compound of formula [XV] or a salt thereof may be performed in the presence of an organic base.
  • Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol , MeCN, water alone or a mixed solvent.
  • a preferred solvent is methanol.
  • Examples of the organic base include pyridine, triethylamine, diisopropylethylamine and the like.
  • a preferred base is triethylamine.
  • the reaction temperature is from 0 ° C. to room temperature, preferably room temperature. In order to reduce reaction impurities, it is preferable to add the compound of the formula [XV] continuously or dividedly according to the progress of the reaction.
  • a compound of formula [XVII] or a salt thereof can be produced by reacting a compound of formula [XX] or a salt thereof with 3-chloro-2-fluorobenzylamine.
  • a compound of formula [XVII] or a salt thereof is obtained by reacting a compound of formula [XX] or a salt thereof with a C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base.
  • a C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base.
  • Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP (1-methyl-2-pyrrolidone), Examples thereof include single or mixed solvents such as MeCN. A preferred solvent is NMP. Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is diisopropylethylamine.
  • the reaction temperature is from ⁇ 50 ° C. to room temperature, preferably 0 ° C.
  • the compound of formula [XVII] or a salt thereof is activated by reacting the compound of formula [XX] or a salt thereof with 1,1′-carbonyldiimidazole, and then activating 3-chloro-2-fluoro It can be produced by reacting with benzylamine.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP, MeCN, etc., alone or in combination. Is done.
  • a preferred solvent is NMP.
  • the reaction temperature is from 0 ° C.
  • the compound of formula [XVII] or a salt thereof is obtained by reacting a compound of formula [XX] or a salt thereof with a chlorinating agent to convert it to an acid chloride, and then in the presence of a base with 3-chloro It can also be produced by reacting with -2-fluorobenzylamine.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent.
  • a preferred solvent is NMP.
  • Examples of the chlorinating agent include thionyl chloride and oxalyl dichloride.
  • a preferred chlorinating agent is thionyl chloride.
  • the reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
  • the reaction between the acid chloride and 3-chloro-2-fluorobenzylamine is carried out in the presence of a base.
  • Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent.
  • a preferred solvent is NMP.
  • Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like.
  • a preferred base is triethylamine.
  • the reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
  • a preferred reaction is to react a compound of formula [XX] or a salt thereof with a C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base, convert it to an active ester, and then 3-chloro-2-fluorobenzyl. It is a method of producing by reacting with an amine.
  • the compound of formula [XVI] or a salt thereof can be produced by reacting the compound of formula [XV] or a salt thereof with 3-chloro-2-fluorobenzylamine.
  • the compound of the formula [XVI] or a salt thereof is converted into an acid chloride by reacting the compound of the formula [XV] or a salt thereof with a chlorinating agent, and then the acid chloride is converted into 3-chloro-2- It can also be produced by reacting with fluorobenzylamine.
  • the reaction of the compound of the formula [XV] or a salt thereof and the chlorinating agent may be performed in the presence of a base.
  • Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF and the like alone or in a mixed solvent.
  • a preferred solvent is a mixed solvent of toluene and DMF.
  • Examples of the chlorinating agent include thionyl chloride and oxalyl dichloride.
  • a preferred chlorinating agent is thionyl chloride.
  • the reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
  • the reaction between the acid chloride and 3-chloro-2-fluorobenzylamine is carried out in the presence of a base.
  • Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF and the like alone or in a mixed solvent.
  • a preferred solvent is a mixed solvent of toluene and DMF.
  • Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like.
  • a preferred base is triethylamine.
  • the reaction temperature is -78 ° C to 0 ° C, preferably -50 ° C.
  • a compound of formula [XVII] or a salt thereof can be produced by reacting a compound of formula (9) or a salt thereof with a compound of formula [XVI] or a salt thereof in the presence of a base.
  • Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol, MeCN And a single or mixed solvent such as water.
  • a preferred solvent is methanol.
  • the base examples include organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene.
  • a preferred organic base is triethylamine.
  • the reaction temperature is from room temperature to 80 ° C, preferably from 55 ° C to 60 ° C. In order to reduce reaction impurities, it is preferable to add the compound of the formula [XVI] continuously or divided according to the progress of the reaction.
  • Production method 4 Production method of compound of formula (18)
  • the compound of formula (18) can be produced by production method 4-1, or production method 4-2. Manufacturing method 4-1 Process 1
  • the compound of the formula (18) or a salt thereof can be produced by reacting the compound of the formula [XVII] or a salt thereof with an acid.
  • an acid When reducing the residual Pd, it is preferable to treat the solution of the compound of the formula [XVII] or a salt thereof with activated carbon such as Carborafine (registered trademark).
  • Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol, water Examples thereof include single or mixed solvents.
  • a preferred solvent is toluene.
  • the acid include trifluoroacetic acid, hydrochloric acid, magnesium chloride and the like.
  • a preferred acid is trifluoroacetic acid.
  • the reaction temperature is 0 ° C. to 50 ° C., preferably 5 ° C. to room temperature.
  • R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl, preferably unsubstituted benzyl or 4-methoxybenzyl, more preferably unsubstituted benzyl (also simply referred to as benzyl).
  • a compound of the formula [XXI] or a salt thereof can be produced by reacting 3- (dimethylamino) acrylonitrile with a compound of the formula [XI ′] in the presence of a base.
  • Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMI, MeCN and the like alone or in combination.
  • a preferred solvent is MeCN.
  • Examples of the base include organic bases such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium hydrogen carbonate.
  • a preferred base is pyridine.
  • the reaction temperature is from ⁇ 20 ° C. to room temperature, preferably 0 ° C.
  • the compound of the formula [XXI] or a salt thereof is advantageous in removing impurities because of its good crystallinity compared to the compound of the formula [XII] obtained in Step 2 of the production method 2 or a salt thereof, and is easily isolated. .
  • the compound of formula [XXII] or a salt thereof can be produced by reacting the compound of [XXI] or a salt thereof with dimethyl oxalate in the presence of a base.
  • a base is 1,8-diazabicyclo [5.4.0] -7-undecene
  • anhydrous lithium bromide is added.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, DMF, DMA, DMSO, DMI, MeCN and the like alone or in combination.
  • a preferred solvent is MeCN.
  • Examples of the base include 1,8-diazabicyclo [5.4.0] -7-undecene, sodium tert-butoxide, potassium tert-butoxide and the like.
  • a preferred base is 1,8-diazabicyclo [5.4.0] -7-undecene.
  • the reaction temperature is 0 ° C. to 70 ° C., preferably room temperature.
  • the compound of the formula [XXII] is advantageous in removing impurities and easy to isolate because it has better crystallinity than the compound of the formula [XIV] obtained in the production method 2 step 3. Moreover, this reaction can be performed at low temperature compared with the manufacturing method 2 process 3.
  • FIG. 1 A schematic diagram of the compound of the formula [XXII] is advantageous in removing impurities and easy to isolate because it has better crystallinity than the compound of the formula [XIV] obtained in the production method 2 step 3. Moreover, this reaction can be performed at low temperature compared with the manufacturing method 2 process 3.
  • the compound of formula [XXIII] or a salt thereof can be produced by reacting the compound of formula (9) or a salt thereof with the compound of formula [XXII] or a salt thereof.
  • the reaction between the compound of formula (9) or a salt thereof and the compound of formula [XXII] or a salt thereof may be performed in the presence of an organic base.
  • Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol , MeCN, water alone or a mixed solvent.
  • a preferred solvent is methanol.
  • Examples of the organic base include pyridine, triethylamine, diisopropylethylamine and the like.
  • a preferred organic base is triethylamine.
  • the reaction temperature is 0 ° C. to 60 ° C., preferably room temperature. In order to reduce reaction impurities, it is preferable to add the compound of the formula [XXII] continuously or dividedly according to the progress of the reaction.
  • the compound of the formula (24) or a salt thereof can be produced by reacting the compound of the formula [XXIII] or a salt thereof with an alkaline aqueous solution.
  • alkaline aqueous solution examples include a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution.
  • a preferred aqueous alkaline solution is a 25% aqueous sodium hydroxide solution.
  • Solvents are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, 2-methylpropyl alcohol, 2-methyl-2-butanol, ethylene glycol, propylene glycol, DMI, NMP And a single or mixed solvent such as DMSO.
  • a preferred solvent is DMSO.
  • the reaction temperature is 70 ° C to 140 ° C, preferably 95 ° C.
  • the compound of formula (18) or a salt thereof can be produced by reacting the compound of formula (24) or a salt thereof with 3-chloro-2-fluorobenzylamine.
  • the compound of formula (18) or a salt thereof is obtained by reacting a compound of formula (24) or a salt thereof with C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base.
  • C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base.
  • Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP, MeCN, etc., alone or in combination. Is done.
  • a preferred solvent is NMP.
  • Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is diisopropylethylamine.
  • the reaction temperature is from ⁇ 50 ° C. to room temperature, preferably 0 ° C.
  • the compound of formula (18) or a salt thereof is activated by reacting the compound of formula (24) or a salt thereof with carbodiimidazole and then reacting with 3-chloro-2-fluorobenzylamine.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP, MeCN, etc., alone or in combination. Is done.
  • a preferred solvent is NMP.
  • the reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
  • the compound of formula (18) or a salt thereof is obtained by reacting a compound of formula (24) or a salt thereof with a chlorinating agent to convert to an acid chloride, and then in the presence of a base with 3-chloro It can also be produced by reacting with -2-fluorobenzylamine.
  • a chlorinating agent examples include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent.
  • a preferred solvent is NMP.
  • the chlorinating agent include thionyl chloride and oxalyl dichloride.
  • a preferred chlorinating agent is thionyl chloride.
  • the reaction temperature is ⁇ 5 ° C. to room temperature, preferably 0 ° C. to 10 ° C.
  • the reaction between the acid chloride and 3-chloro-2-fluorobenzylamine is carried out in the presence of a base.
  • the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent.
  • a preferred solvent is NMP.
  • the base include pyridine, triethylamine, diisopropylethylamine and the like.
  • a preferred base is triethylamine.
  • the reaction temperature is from ⁇ 5 ° C. to room temperature, preferably room temperature.
  • a preferred reaction is that the compound of formula (24) or a salt thereof is reacted with C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base, converted to an active ester, and then 3-chloro-2-fluorobenzyl It is a method of producing by reacting with an amine.
  • Production Method 5 Production Method of Compound of Formula (19)
  • the compound of formula (19) can be produced by production method 5-1 or production method 5-2. Manufacturing method 5-1 Process 1
  • the compound of formula (19) can be produced by adding a base to the compound of formula (18) to form a salt, and then recrystallizing.
  • Solvents are THF, 1,2-dimethoxyethane, 1,4-dioxane, acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), DMF, DMA, DMSO, methanol, ethanol, 1-propanol, 2-propanol, Examples thereof include 1-butanol, 2-butanol, tert-butanol, 1-pentanol, MeCN, propionitrile, water and the like alone or in a mixed solvent.
  • a preferred solvent is a mixed solvent of water and ethanol.
  • the base include sodium hydroxide, sodium tert-butoxide and the like.
  • a preferred base is sodium hydroxide.
  • the reaction temperature is 0 ° C. to 70 ° C., preferably room temperature.
  • the compound of the formula (19) can be produced by reacting the compound of the formula [XVII] or a salt thereof with a base.
  • the solvent is a mixed solvent of DMF, DMA, DMSO, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, 1-pentanol, MeCN, propionitrile, etc. and water. Illustrated.
  • a preferred solvent is a mixed solvent of DMSO and water.
  • Examples of the base include sodium hydroxide, sodium tert-butoxide and the like.
  • a preferred base is a 4 mol / L aqueous sodium hydroxide solution.
  • the reaction temperature is from room temperature to 90 ° C, preferably 80 ° C.
  • the resulting suspension was stirred for 2 hours and 30 minutes, and concentrated hydrochloric acid was added dropwise to adjust the pH of the solution to 0.2. This was stirred at room temperature for 1 hour and then stirred at 75 ° C. for 2 hours. The suspension was returned to room temperature, further cooled under ice cooling, and stirred for 2 hours. The precipitated crystals were collected by filtration, and the crystals were washed with cooled water (120 mL) until the pH of the washing solution reached 2.5 or higher.
  • ammonium chloride (33.4 kg, 624 mol), ammonium carbonate (119.9 kg, 1248 mol) and potassium cyanide (38.6 kg, 593 mol) were added.
  • the mixture was stirred at 55 ° C. for 22.5 hours.
  • the solution was cooled to room temperature.
  • Concentrated hydrochloric acid was added dropwise at room temperature to adjust the pH of the solution to 4.0.
  • concentrated hydrochloric acid was added dropwise to adjust the pH of the solution to 0.4. This was stirred at room temperature for 15 hours and then stirred at 70 ° C. for 2 hours.
  • the suspension was returned to room temperature, further cooled under ice cooling, and stirred for 17 hours.
  • N-Heptane (214 L) was added dropwise to the obtained suspension at 35 ° C., and the mixture was stirred at the same temperature for 1 hour.
  • the suspension was cooled to room temperature and stirred for 16 hours.
  • the precipitated crystals were collected by filtration, and the crystals were washed with a mixed solvent of ethyl acetate (43 L) and n-heptane (128 L).
  • this solution was added dropwise to a mixed solution of 5% aqueous sodium bicarbonate (84 L) and 10% brine (84 L) at 5 ° C., and the reaction vessel was washed with THF (42 L). The mixed solution was stirred at room temperature for 30 minutes, and then extracted with a mixed solution of ethyl acetate (168 L) and toluene (168 L). The organic layer was washed twice with 5% aqueous sodium bicarbonate (126 L) and once with 10% brine (126 L). The solvent of the organic layer was distilled off at 50 ° C. or lower under reduced pressure. Toluene (84 L) was added to the residue, and the solvent was distilled off at 50 ° C.
  • N- (4-methoxybenzyl) -cis-2- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine dihydrochloride (8 ′) (36.2 kg, 103 mol) in methanol ( 253 L) sodium acetate (16.9 kg, 206 mol), acetic acid (12.4 kg, 206 mol) and 10% palladium carbon (PE type manufactured by NE CHEMCAT, 56.76% water content, 4.18 kg) were added at room temperature.
  • the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature at a hydrogen gas pressure of 0.4 MPa for 45 hours.
  • a solution of tert-butyl propiolate (24.9 kg, 197 mol) in acetonitrile (112.5 L) was cooled to 0 ° C., and diethylamine (15.2 kg, 207 mol) was added dropwise. The solution was stirred at 0 ° C. for 2 hours. After completion of the reaction, an acetonitrile solution (128.4 kg, corresponding to 197 mol) of tert-butyl (10) (E) -3- (diethylamino) acrylate was obtained. The acetonitrile solution of the obtained compound (10) was used in the next step with a yield of 100%.
  • Example 3 7 7 '- ⁇ [(3-Chloro-2-fluorophenyl) methyl] carbamoyl ⁇ -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ' Of 8,8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -9'-oleate monosodium (19)
  • the activated carbon in the suspension was removed by filtration at 80 ° C., and the reaction vessel and the activated carbon were washed with toluene (104 L). The solvent of the filtrate was distilled off at 50 ° C. or lower under reduced pressure. Trifluoroacetic acid (53.7 kg, 471 mol) was added dropwise to the residue at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethanol (522 L) and N-[(3-chloro-2-fluorophenyl) methyl] -9'-hydroxy-cis-3- (methoxymethyl) -2'-methyl-1 'were added to this solution.
  • compound (18) (5 mg) was dissolved in acetonitrile (0.6 mL) and allowed to stand at room temperature to obtain a single crystal.
  • the configuration of compound (18) was determined by X-ray structural analysis of the obtained single crystal. NMR and MS were measured for the compound (18) synthesized according to the above method.
  • This solution was subjected to dust filtration at 80 ° C., and the reaction vessel and piping were washed with a mixed solution of ethanol (38.2 L) and water (38.2 L) heated to 75 ° C.
  • the filtrate was stirred at 75 ° C. for 1 hour and stirred at 45 ° C. for 1 hour.
  • the resulting suspension was stirred at room temperature for 1 hour and stirred at 5 ° C. for 5 hours.
  • the precipitated crystals were collected by filtration, and the collected crystals were washed with a mixed solution of ethanol (45.9 L) and water (30.6 L) cooled to 5 ° C.
  • the wet crystals were dried under reduced pressure at 50 ° C. or lower for 22 hours.
  • Example 6 7 '- ⁇ [(3-Chloro-2-fluorophenyl) methyl] carbamoyl ⁇ -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ' Of 8,8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -9'-oleate monosodium (19)
  • N-Propylamine (1.36 mL, 19.1 mmol) was added to the solution at the same temperature (the solution was suspended). The suspension was cooled to room temperature and then stirred for 1 hour. After stirring, isopropyl acetate (24 mL) was added to the suspension, and the mixture was stirred at room temperature for 6 hours. The precipitated crystals were collected by filtration and washed with isopropyl acetate (9.0 mL).
  • HPLC analysis condition column Atlantis (registered trademark) T3: 3 ⁇ m, 4.6 mm ⁇ 150 mm (Waters) Column temperature: Constant temperature around 40 ° C.
  • Mobile phase B MeCN Gradient condition: Time (minutes) 0 25 35 36 40 A (%) 80 20 20 80 80 B (%) 20 80 80 20 20 20 Flow rate: 1.0 mL / min
  • Detection method UV 220 nm Reference; Retention time: cis form (approximately 8.3 minutes), trans form (approximately 8.5 minutes)
  • the mixed solution was extracted with ethyl acetate (5.0 mL). The obtained organic layer was washed with 10% brine (3.0 mL). The solvent of the organic layer was distilled off under reduced pressure to obtain a crude product of N-benzyl-cis-2- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine (33a). Ethyl acetate was added to the crude product of the compound (33a) to adjust the liquid volume to 8.0 mL. Ethanol (3.0 mL) was added to this solution. To this solution was added 4 mol / L HCl / ethyl acetate solution (0.79 mL, 3.16 mmol) at room temperature.
  • the resulting suspension was stirred for 30 minutes at room temperature, and 4 mol / L HCl / ethyl acetate solution (0.65 mL, 2.60 mmol) was added thereto.
  • the suspension was stirred at room temperature for 2 hours.
  • the precipitated crystals were collected by filtration, and the collected solid was washed with a mixed solution of ethyl acetate (4.5 mL) and ethanol (1.5 mL).
  • N-benzyl-cis-2- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine dihydrochloride (33a-2HCl) 200 mg, 0.622 mmol
  • sodium acetate 102 mg, 1.24 mmol
  • acetic acid 74 mg, 1.23 mmol
  • 10% palladium carbon PE type manufactured by NE CHEMCAT, 50% water content, 20 mg
  • reaction vessel was replaced with nitrogen, and insoluble matters were removed by filtration.
  • the reaction vessel and insoluble material were washed with methanol (1.0 mL) to obtain a methanol solution (corresponding to 0.622 mmol) of cis-3- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine (9).
  • the methanol solution of the obtained compound (9) was used in the next step with a yield of 100%.
  • An appropriate amount of sodium methoxide (methanol solution) was added to a methanol solution of the compound (9) synthesized according to the above method, and NMR and MS of the concentrated dry solid were measured.
  • Triethylamine (283 mg, 2.80 mmol) was added to a methanol solution of cis-3- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine (9) (equivalent to 1.30 g, 0.622 mmol), and then at room temperature.
  • 3- (Benzyloxy) -2- (ethoxycarbonyl) -4-oxo-4H-pyran-5-carboxylic acid (15) (218 mg, 0.685 mmol) was added in portions over 1 hour. The mixture was stirred at room temperature for 1.5 hours.
  • an intermediate for producing a compound of formula (18) or a salt thereof having HIV integrase inhibitory activity and useful as an anti-HIV agent and a method for producing the intermediate.
  • the manufacturing method of the compound or its salt of Formula (18) is provided.

Abstract

Provided is a method for producing a substituted spiropyrido[1,2-a]pyrazine derivative, or a salt thereof, that are useful as anti-HIV agents. Also provided is a production intermediate. Compound [VIII] is obtained by reacting compound [VII] (in the formula, R1 represents a benzyl that is either unsubstituted or substituted with a halogen, a C1-4 alkyl, or a C1-4 alkoxy) and hydroxyamine, or a salt thereof. Compound (9) is obtained by subjecting compound [VIII] to a catalytic reduction reaction. Compound (18) is produced from compound (9).

Description

置換されたスピロピリド［１，２－ａ］ピラジン誘導体の製造方法および中間体Process for preparing substituted spiropyrido [1,2-a] pyrazine derivatives and intermediates
　本発明は、抗ＨＩＶ剤として有用な、置換されたスピロピリド［１，２－ａ］ピラジン誘導体又はその塩の製造方法、ならびに製造中間体に関する。
　本発明は、インテグラーゼ阻害活性を有する抗ＨＩＶ剤の合成中間体として有用な化合物及びその製造方法に関する。また、本発明は、当該合成中間体を用いた抗ＨＩＶ剤の製造方法などに関する。 The present invention relates to a method for producing a substituted spiropyrido [1,2-a] pyrazine derivative or a salt thereof useful as an anti-HIV agent, and a production intermediate.
The present invention relates to a compound useful as a synthetic intermediate of an anti-HIV agent having integrase inhibitory activity and a method for producing the same. The present invention also relates to a method for producing an anti-HIV agent using the synthetic intermediate.
　レトロウイルスに属するＨＩＶ（Ｈｕｍａｎ　Ｉｍｍｕｎｏｄｅｆｉｃｉｅｎｃｙ　Ｖｉｒｕｓ：ヒト免疫不全症ウイルス）は、エイズ（ＡＩＤＳ：Ａｃｑｕｉｒｅｄ　Ｉｍｍｕｎｏｄｅｆｉｃｉｅｎｃｙ　Ｓｙｎｄｒｏｍｅ：後天性免疫不全症候群）の原因ウイルスである。
　ＨＩＶは、ヘルパーＴ細胞、マクロファージ、樹状細胞といったＣＤ４陽性細胞群を標的とし、これら免疫担当細胞を破壊し、免疫不全症を引き起こす。
　従って、エイズの治療若しくは予防のためには、生体内のＨＩＶを根絶する或いはその増殖を抑制する薬剤が有効である。 HIV (Human Immunodeficiency Virus) belonging to retrovirus is a causative virus of AIDS (Acquired Immunodeficiency Syndrome).
HIV targets a group of CD4 positive cells such as helper T cells, macrophages, and dendritic cells, destroys these immunocompetent cells, and causes immunodeficiency.
Therefore, for the treatment or prevention of AIDS, a drug that eradicates HIV in the living body or suppresses its growth is effective.
　ＨＩＶは、２分子のＲＮＡ遺伝子を殻内に有し、更にその殻を外皮蛋白質で覆っている。ＲＮＡにはウイルス特有の複数の酵素（プロテアーゼ、逆転写酵素、インテグラーゼ）等がコードされ、殻内には翻訳された逆転写酵素及びインテグラーゼが、殻内外にはプロテアーゼが存在する。
　ＨＩＶは宿主細胞内に接触・侵入後、脱殻を起こし、細胞質内にＲＮＡとインテグラーゼ等の複合体を放出する。該ＲＮＡからは逆転写酵素によりＤＮＡが転写され、完全長の二本鎖ＤＮＡが生成される。該ＤＮＡは宿主細胞核内に移行し、インテグラーゼにより宿主細胞ＤＮＡに組み込まれる。組み込まれたＤＮＡは宿主細胞のポリメラーゼによってｍＲＮＡに変換され、該ｍＲＮＡからはＨＩＶプロテアーゼ等により、ウイルス形成に必要な種々の蛋白質が合成され、最終的にウイルス粒子が形成され、出芽・遊離する。 HIV has two RNA genes in the shell, and the shell is covered with a coat protein. RNA encodes a plurality of viruses-specific enzymes (protease, reverse transcriptase, integrase), etc., translated reverse transcriptase and integrase are present in the shell, and protease is present inside and outside the shell.
HIV contacts and invades the host cell, then undergoes shelling and releases a complex such as RNA and integrase into the cytoplasm. From this RNA, DNA is transcribed by reverse transcriptase to produce full-length double-stranded DNA. The DNA moves into the host cell nucleus and is incorporated into the host cell DNA by integrase. The incorporated DNA is converted into mRNA by the host cell polymerase, and various proteins necessary for virus formation are synthesized from the mRNA by HIV protease and the like, and finally virus particles are formed, budding and releasing.
　ＨＩＶの増殖にはこれらウイルス特異的酵素が必須とされており、抗ウイルス剤開発のターゲットとして注目され、既に、いくつかの抗ＨＩＶ剤が開発されている。
　例えば、核酸系逆転写酵素阻害剤として、テノホビル、アバカビル、エムトリシタビン、ラミブジン等、非核酸系逆転写酵素阻害剤として、エファビレンツ、ネビラピン等、プロテアーゼ阻害剤として、アタザナビル、ダルナビル等が既に市販されている。
　また、これらの薬剤を併用する多剤併用療法（ｃＡＲＴ（ｃｏｍｂｉｎａｔｉｏｎ　ａｎｔｉｒｅｔｒｏｖｉｒａｌ　ｔｈｅｒａｐｙ）と呼ばれる。）も用いられ、例えば、核酸系逆転写酵素阻害剤（テノホビルとエムトリシタビン、若しくは、アバカビルとラミブジン）の２剤と、非核酸系逆転写酵素阻害剤（エファビレンツ）、或いは、リトナビル併用のプロテアーゼ阻害剤（アタザナビル、又は、ダルナビル）との３剤併用等が臨床で用いられ、これら多剤併用療法がエイズ治療の主流となってきている。
　しかし、これら薬剤には肝機能障害、めまい等の中枢神経障害等の副作用が知られているものもあり、薬剤に対する耐性の獲得も問題となっている。そればかりか、多剤併用療法に対する多剤耐性を示すＨＩＶの出現も知られている。 These virus-specific enzymes are essential for the growth of HIV, attracting attention as a target for the development of antiviral agents, and several anti-HIV agents have already been developed.
For example, tenofovir, abacavir, emtricitabine, lamivudine, etc. as nucleic acid reverse transcriptase inhibitors, efavirenz, nevirapine, etc. as non-nucleic acid reverse transcriptase inhibitors, atazanavir, darunavir, etc. are already commercially available as protease inhibitors .
In addition, a multi-drug combination therapy (referred to as cART (combination antiretroviral therapy)) that uses these drugs in combination is also used, for example, two nucleic acid reverse transcriptase inhibitors (tenofovir and emtricitabine, or abacavir and lamivudine). And a non-nucleic acid reverse transcriptase inhibitor (efavirenz) or a combination of ritonavir and a protease inhibitor (atazanavir or darunavir) are used in clinical settings. It has become mainstream.
However, some of these drugs have known side effects such as liver dysfunction and central nervous system disorders such as dizziness, and acquisition of resistance to the drug is also a problem. In addition, the emergence of HIV showing multidrug resistance to multidrug combination therapy is also known.
　この様な状況下、更なる新規の薬剤の開発、特に新しいメカニズムによる抗ＨＩＶ剤の開発が望まれており、レトロウイルスに特徴的なインテグラーゼがＨＩＶの増殖に必須の酵素であることから、インテグラーゼ阻害活性を有する抗ＨＩＶ剤の開発が期待されている。 Under such circumstances, the development of further new drugs, particularly the development of anti-HIV drugs by a new mechanism, is desired, and the integrase characteristic of retroviruses is an enzyme essential for the growth of HIV. Development of anti-HIV agents having integrase inhibitory activity is expected.
　これまでの薬理研究及び臨床結果から得られた知見より、抗ＨＩＶ剤はエイズの予防及び治療に有効であり、特にインテグラーゼ阻害活性を有する化合物は有効な抗ＨＩＶ剤に成り得る。このようなインテグラーゼ阻害活性を有する化合物の１つとして、式（１８） Based on the knowledge obtained from past pharmacological studies and clinical results, anti-HIV agents are effective for the prevention and treatment of AIDS, and particularly compounds having integrase inhibitory activity can be effective anti-HIV agents. As one of such compounds having integrase inhibitory activity, a compound represented by formula (18)
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
の化合物又はその塩がＷＯ２０１４／１０４２７９に記載されており、その効率的な製造方法が求められている。
　本発明は、式（１８）の化合物又はその製薬上許容される塩の製造中間体として有用な化合物およびその製造方法、当該製造中間体を用いた式（１８）の化合物又はその塩の製造方法に関する。 These compounds or salts thereof are described in WO2014 / 104279, and an efficient production method thereof is demanded.
The present invention relates to a compound useful as a production intermediate of a compound of formula (18) or a pharmaceutically acceptable salt thereof, a production method thereof, and a production method of a compound of formula (18) or a salt thereof using the production intermediate. About.
　本発明者らは上記課題を鑑み、式（１８）の化合物又はその塩の製造方法を見出すべく鋭意研究を重ねた結果、式（９）で表される化合物（以下、化合物（９）と略記する場合もある）又はその塩をはじめ、多くの有用な製造中間体があることを見出し、本発明を完成するに至った。
　より詳しくは、本発明の一態様は下記に示す通りである。
[1]　式（９） In view of the above problems, the present inventors conducted extensive research to find a method for producing a compound of formula (18) or a salt thereof, and as a result, a compound represented by formula (9) (hereinafter abbreviated as compound (9)). The present invention has been completed by discovering that there are many useful production intermediates including a salt thereof or a salt thereof.
More specifically, one embodiment of the present invention is as follows.
[1] Equation (9)
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
の化合物又はその塩を製造する方法であって、式[VIII] Or a salt thereof, comprising the formula [VIII]
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
の化合物又はその塩を接触水素還元反応に付し、式（９）の化合物又はその塩を得る工程を含む方法。
[1-1]　Ｒ１が４－メトキシベンジルである［1］記載の方法。
[1-2]　Ｒ１がベンジルである［1］記載の方法。
[2]　式[VII] Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
A method comprising a step of subjecting a compound of the formula or a salt thereof to a catalytic hydrogen reduction reaction to obtain a compound of the formula (9) or a salt thereof.
[1-1] The method according to [1], wherein R 1 is 4-methoxybenzyl.
[1-2] The method according to [1], wherein R 1 is benzyl.
[2] Formula [VII]
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
（式中、Ｒ１は［1］に記載の通りである。）
の化合物又はその塩と、ヒドロキシアミン又はその塩とを反応させ、式[VIII]の化合物又はその塩を得る工程をさらに含む［1］記載の方法。
[2-1]　Ｒ１が４－メトキシベンジルである［2］記載の方法。
[2-2]　Ｒ１がベンジルである［2］記載の方法。
[3]　式[VI] (Wherein R 1 is as described in [1].)
The method according to [1], further comprising a step of reacting a compound of the formula (I) or a salt thereof with a hydroxyamine or a salt thereof to obtain a compound of the formula [VIII] or a salt thereof.
[2-1] The method according to [2], wherein R 1 is 4-methoxybenzyl.
[2-2] The method according to [2], wherein R 1 is benzyl.
[3] Formula [VI]
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
（式中、Ｒ１は［1］に記載の通りである。）
の化合物と、アルミニウム系還元剤とを反応させ、式[VII]の化合物又はその塩を得る工程をさらに含む［2］記載の方法。
[3-1]　Ｒ１が４－メトキシベンジルである［3］記載の方法。
[3-2]　Ｒ１がベンジルである［3］記載の方法。
[4]　式[V] (Wherein R 1 is as described in [1].)
The method according to [2], further comprising a step of reacting a compound of the above with an aluminum-based reducing agent to obtain a compound of formula [VII] or a salt thereof.
[3-1] The method according to [3], wherein R 1 is 4-methoxybenzyl.
[3-2] The method according to [3], wherein R 1 is benzyl.
[4] Formula [V]
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
（式中、Ｒ１は［1］に記載の通りである。）
の化合物と、メチル化剤を反応させ、式[VI]の化合物を得る工程をさらに含む［3］記載の方法。
[4-1]　Ｒ１が４－メトキシベンジルである［4］記載の方法。
[4-2]　Ｒ１がベンジルである［4］記載の方法。
[5]　式[IV-a] (Wherein R 1 is as described in [1].)
The method according to [3], further comprising a step of reacting a compound of the above with a methylating agent to obtain a compound of the formula [VI].
[4-1] The method according to [4], wherein R 1 is 4-methoxybenzyl.
[4-2] The method according to [4], wherein R 1 is benzyl.
[5] Formula [IV-a]
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
（式中、Ｒ１は［1］に記載の通りである。）
の化合物又はその塩と、ボラン系還元剤とを反応させ、式[V]の化合物を得る工程をさらに含む［4］記載の方法。
[5-1]　Ｒ１が４－メトキシベンジルである［5］記載の方法。
[5-2]　Ｒ１がベンジルである［5］記載の方法。
[6]　式[III] (Wherein R 1 is as described in [1].)
The method according to [4], further comprising a step of reacting the compound or a salt thereof with a borane-based reducing agent to obtain a compound of the formula [V].
[5-1] The method according to [5], wherein R 1 is 4-methoxybenzyl.
[5-2] The method according to [5], wherein R 1 is benzyl.
[6] Formula [III]
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
（式中、Ｒ１は［1］に記載の通りである。）
の化合物を、アルカリ加水分解に付し、式[IV-a]の化合物又はその塩を得る工程をさらに含む［5］記載の方法。
[6-1]　Ｒ１が４－メトキシベンジルである［6］記載の方法。
[6-2]　Ｒ１がベンジルである［6］記載の方法。
[7]　式（２） (Wherein R 1 is as described in [1].)
The method according to [5], further comprising a step of subjecting the compound of the above to alkali hydrolysis to obtain a compound of the formula [IV-a] or a salt thereof.
[6-1] The method according to [6], wherein R 1 is 4-methoxybenzyl.
[6-2] The method according to [6], wherein R 1 is benzyl.
[7] Equation (2)
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
の化合物と、ベンジル化剤とを反応させ、式[III]の化合物を得る工程をさらに含む［6］記載の方法。
[7-1]　Ｒ１が４－メトキシベンジルである［7］記載の方法。
[7-2]　Ｒ１がベンジルである［7］記載の方法。
[8]　式（１） The method according to [6], further comprising a step of reacting a compound of the above with a benzylating agent to obtain a compound of the formula [III].
[7-1] The method according to [7], wherein R 1 is 4-methoxybenzyl.
[7-2] The method according to [7], wherein R 1 is benzyl.
[8] Equation (1)
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
の化合物又はその塩と、メチル化剤とを反応させ、再結晶により式（２）の化合物を得る工程をさらに含む［7］記載の方法。
[9]　式[IV] [7] The method according to [7], further comprising a step of reacting a compound of the above or a salt thereof with a methylating agent to obtain a compound of formula (2) by recrystallization.
[9] Formula [IV]
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
（式中、Ｒ１は［1］に記載の通りである。）
の化合物又はその塩から式[IV-a]の化合物又はその塩を得る工程をさらに含む［5］記載の方法。
[9-1]　Ｒ１が４－メトキシベンジルである［9］記載の方法。
[9-2]　Ｒ１がベンジルである［9］記載の方法。
[10]　式[XXVIII] (Wherein R 1 is as described in [1].)
The method according to [5], further comprising a step of obtaining a compound of the formula [IV-a] or a salt thereof from the compound of
[9-1] The method according to [9], wherein R 1 is 4-methoxybenzyl.
[9-2] The method according to [9], wherein R 1 is benzyl.
[10] Formula [XXVIII]
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
（式中、Ｒ５は、Ｃ１－６アルキルであり、Ｒ１は［1］に記載の通りである。）
の化合物を、アルカリ加水分解に付し、式[IV]の化合物又はその塩を得る工程をさらに含む［9］記載の方法。
[10-1]　Ｒ１が４－メトキシベンジル又はベンジルである［10］記載の方法。
[10-2]　Ｒ１が４－メトキシベンジルであり、かつＲ５がメチルである［10］記載の方法。
[10-3]　Ｒ１がベンジルであり、かつＲ５がイソプロピルである［10］記載の方法。
[11]　式[XXVII] (Wherein R 5 is C 1-6 alkyl, and R 1 is as described in [1].)
The method according to [9], further comprising a step of subjecting the compound of the above to alkali hydrolysis to obtain a compound of the formula [IV] or a salt thereof.
[10-1] The method according to [10], wherein R 1 is 4-methoxybenzyl or benzyl.
[10-2] The method according to [10], wherein R 1 is 4-methoxybenzyl and R 5 is methyl.
[10-3] The method according to [10], wherein R 1 is benzyl and R 5 is isopropyl.
[11] Formula [XXVII]
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
（式中、Ｒ５は、Ｃ１－６アルキルであり、Ｒ１は［1］に記載の通りである。）
の化合物又はその塩と、メチル化剤を反応させ、式[XXVIII]の化合物を得る工程をさらに含む［10］記載の方法。
[11-1]　Ｒ１が４－メトキシベンジル又はベンジルである［10］記載の方法。
[11-2]　Ｒ１が４－メトキシベンジルであり、かつＲ５がメチルである［11］記載の方法。
[11-3]　Ｒ１がベンジルであり、かつＲ５がイソプロピルである［11］記載の方法。
[12]　式[XXVI] (Wherein R 5 is C 1-6 alkyl, and R 1 is as described in [1].)
The method according to [10], further comprising a step of reacting a compound of the formula (I) or a salt thereof with a methylating agent to obtain a compound of the formula [XXVIII].
[11-1] The method according to [10], wherein R 1 is 4-methoxybenzyl or benzyl.
[11-2] The method according to [11], wherein R 1 is 4-methoxybenzyl and R 5 is methyl.
[11-3] The method according to [11], wherein R 1 is benzyl and R 5 is isopropyl.
[12] Formula [XXVI]
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
（式中、Ｒ５は、Ｃ１－６アルキルであり、Ｒ１は請求項１に記載の通りである。）
の化合物又はその塩とシアン酸カリウム又はシアン酸ナトリウムを反応させ、式[XXVII]の化合物又はその塩を得る工程をさらに含む［11］記載の方法。
[12-1]　Ｒ１が４－メトキシベンジル又はベンジルである［12］記載の方法。
[12-2]　Ｒ１が４－メトキシベンジルであり、かつＲ５がメチルである［12］記載の方法。
[12-3]　Ｒ１がベンジルであり、かつＲ５がイソプロピルである［12］記載の方法。
[13]　式[XXV] (Wherein R 5 is C 1-6 alkyl and R 1 is as defined in claim 1)
The method according to [11], further comprising a step of reacting a compound of the above or a salt thereof with potassium cyanate or sodium cyanate to obtain a compound of the formula [XXVII] or a salt thereof.
[12-1] The method according to [12], wherein R 1 is 4-methoxybenzyl or benzyl.
[12-2] The method according to [12], wherein R 1 is 4-methoxybenzyl and R 5 is methyl.
[12-3] The method according to [12], wherein R 1 is benzyl and R 5 is isopropyl.
[13] Formula [XXV]
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
（式中、Ｒ５は、Ｃ１－６アルキルである。）
の化合物と式Ｒ１－ＮＨ２（式中、Ｒ１は［1］に記載の通りである。）の化合物又はその塩を反応させた後、続いてシアノ化剤を反応させ、式[XXVI]の化合物又はその塩を得る工程をさらに含む［12］記載の方法。
[13-1]　Ｒ５がイソプロピルである［1］記載の方法。
[14]　式（９） Wherein R 5 is C 1-6 alkyl.
And a compound of the formula R 1 —NH 2 (wherein R 1 is as described in [1]) or a salt thereof, followed by a reaction with a cyanating agent to produce a compound of the formula [XXVI The method according to [12], further comprising a step of obtaining a compound or a salt thereof.
[13-1] The method according to [1], wherein R 5 is isopropyl.
[14] Equation (9)
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
の化合物又はその塩。
[15]　式[VIII] Or a salt thereof.
[15] Formula [VIII]
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
の化合物又はその塩。
[15-1]　Ｒ１が４－メトキシベンジルである[15]記載の化合物又はその塩。
[15-2]　Ｒ１がベンジルである[15]記載の化合物又はその塩。
[16]　式[VII] Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
Or a salt thereof.
[15-1] The compound according to [15] or a salt thereof, wherein R 1 is 4-methoxybenzyl.
[15-2] The compound according to [15] or a salt thereof, wherein R 1 is benzyl.
[16] Formula [VII]
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
の化合物又はその塩。
[16-1]　Ｒ１が４－メトキシベンジルである[16]記載の化合物又はその塩。
[16-2]　Ｒ１がベンジルである[16]記載の化合物又はその塩。
[17]　式[VI] Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
Or a salt thereof.
[16-1] The compound according to [16] or a salt thereof, wherein R 1 is 4-methoxybenzyl.
[16-2] The compound or salt thereof according to [16], wherein R 1 is benzyl.
[17] Formula [VI]
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
の化合物。
[17-1]　Ｒ１が４－メトキシベンジルである[17]記載の化合物。
[17-2]　Ｒ１がベンジルである[17]記載の化合物。
[18]　式[V] Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
Compound.
[17-1] The compound according to [17], wherein R 1 is 4-methoxybenzyl.
[17-2] The compound according to [17], wherein R 1 is benzyl.
[18] Formula [V]
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
の化合物。
[18-1]　Ｒ１が４－メトキシベンジルである[18]記載の化合物。
[18-2]　Ｒ１がベンジルである[18]記載の化合物。
[19]　式[IV] Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
Compound.
[18-1] The compound described in [18], wherein R 1 is 4-methoxybenzyl.
[18-2] The compound according to [18], wherein R 1 is benzyl.
[19] Formula [IV]
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
の化合物又はその塩。
[19-1]　Ｒ１が４－メトキシベンジルである[19]記載の化合物又はその塩。
[19-2]　Ｒ１がベンジルである[19]記載の化合物又はその塩。
[19-3]　式[IV]が、式[IV-a] Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
Or a salt thereof.
[19-1] The compound according to [19] or a salt thereof, wherein R 1 is 4-methoxybenzyl.
[19-2] The compound according to [19] or a salt thereof, wherein R 1 is benzyl.
[19-3] Formula [IV] is converted to Formula [IV-a]
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
（式中、Ｒ１は［19］に記載の通りである。）
である[19]記載の化合物又はその塩。
[19-4]　Ｒ１が４－メトキシベンジルである[19-3]記載の化合物又はその塩。
[19-5]　Ｒ１がベンジルである[19-3]記載の化合物又はその塩。
[19-6]　塩が有機塩基との塩である[19-3]記載の化合物の塩。
[19-7]　有機塩基が、ｎ－プロピルアミン、ｎ－ブチルアミン、ｔ－ブチルアミン、シクロヘキルアミン、ジシクロヘキルアミン、フェネチルアミン、（S）－フェネチルアミン又は（R）－フェネチルアミンである[19-6]記載の化合物の塩。
[19-8]　有機塩基が、ｎ－プロピルアミン、ｔ－ブチルアミン又はジシクロヘキルアミンである[19-7]記載の化合物の塩。
[19-9]　有機塩基が、ｎ－プロピルアミンである[19-8]記載の化合物の塩。
[20]　式[XXVIII] (Wherein R 1 is as described in [19].)
[19] The compound or a salt thereof according to [19].
[19-4] The compound according to [19-3] or a salt thereof, wherein R 1 is 4-methoxybenzyl.
[19-5] The compound according to [19-3] or a salt thereof, wherein R 1 is benzyl.
[19-6] The salt of the compound according to [19-3], wherein the salt is a salt with an organic base.
[19-7] The description [19-6] is that the organic base is n-propylamine, n-butylamine, t-butylamine, cyclohexylamine, dicyclohexylamine, phenethylamine, (S) -phenethylamine or (R) -phenethylamine. Salt of the compound.
[19-8] The salt of the compound according to [19-7], wherein the organic base is n-propylamine, t-butylamine or dicyclohexylamine.
[19-9] The salt of the compound according to [19-8], wherein the organic base is n-propylamine.
[20] Formula [XXVIII]
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、Ｒ５は、Ｃ１－６アルキルである。）
の化合物。
[20-1]　式[XXVIII]が、式[III] (Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, and R 5 is C 1-6 alkyl.)
Compound.
[20-1] Formula [XXVIII] is converted to Formula [III]
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
（式中、Ｒ１は［20］に記載の通りである。）
である[20]記載の化合物。
[20-2]　Ｒ１が４－メトキシベンジルである[20-1]記載の化合物。
[20-3]　Ｒ１がベンジルである[20]記載の化合物。
[20-4]　Ｒ５がイソプロピルである[20]記載の化合物。
[20-5]　Ｒ１がベンジルであり、かつＲ５がイソプロピルである[20]記載の化合物。
[21]　式（２） (Wherein R 1 is as described in [20].)
[20] The compound according to [20].
[20-2] The compound described in [20-1], wherein R 1 is 4-methoxybenzyl.
[20-3] The compound according to [20], wherein R 1 is benzyl.
[20-4] The compound described in [20], wherein R 5 is isopropyl.
[20-5] The compound according to [20], wherein R 1 is benzyl and R 5 is isopropyl.
[21] Equation (2)
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
の化合物。
[22]　式[XXVII] Compound.
[22] Formula [XXVII]
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、Ｒ５は、Ｃ１－６アルキルである。）
の化合物又はその塩。
[22-1]　式(27) (Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, and R 5 is C 1-6 alkyl.)
Or a salt thereof.
[22-1] Equation (27)
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
の化合物又はその塩。
[23]　式[XXVI] Or a salt thereof.
[23] Formula [XXVI]
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、Ｒ５は、Ｃ１－６アルキルである。）
の化合物又はその塩。
[23-1]　式(26) (Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, and R 5 is C 1-6 alkyl.)
Or a salt thereof.
[23-1] Equation (26)
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
の化合物又はその塩。
[24]　式（１８） Or a salt thereof.
[24] Formula (18)
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
の化合物又はその塩を製造する方法であって、
式[XX] A method for producing a compound or a salt thereof, comprising:
Formula [XX]
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
（式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVII] (Wherein R 2 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, or C 1-4 alkyl.)
Or a salt thereof with 3-chloro-2-fluorobenzylamine to give a compound of the formula [XVII]
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
（式中、Ｒ２は前記の通りである。）
の化合物又はその塩を得る工程；及び
式[XVII]の化合物又はその塩と、酸とを反応させ、式（１８）の化合物又はその塩を得る工程を含む方法。
[24-1]　Ｒ２がベンジルである［24］記載の方法。
[25]　式（９） (Wherein R 2 is as described above.)
And a step of obtaining a compound of the formula (18) or a salt thereof by reacting a compound of the formula [XVII] or a salt thereof with an acid.
[24-1] The method according to [24], wherein R 2 is benzyl.
[25] Equation (9)
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
の化合物又はその塩と、式[XV] Or a salt thereof and the formula [XV]
Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［24］に記載の通りである。）
の化合物又はその塩とを、有機塩基の存在下で反応させ、式[XX]の化合物又はその塩を得る工程をさらに含む［24］記載の方法。
[25-1]　Ｒ２がベンジルである［25］記載の方法。
[26]　式（１８） (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [24].)
The method according to [24], further comprising a step of reacting the compound of the formula (I) or a salt thereof in the presence of an organic base to obtain the compound of the formula [XX] or a salt thereof.
[25-1] The method described in [25], wherein R 2 is benzyl.
[26] Equation (18)
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124
の化合物又はその塩を製造する方法であって、
式（９） A method for producing a compound or a salt thereof, comprising:
Formula (9)
Figure JPOXMLDOC01-appb-C000125
Figure JPOXMLDOC01-appb-C000125
の化合物又はその塩と、式[XVI] Or a salt thereof and the formula [XVI]
Figure JPOXMLDOC01-appb-C000126
Figure JPOXMLDOC01-appb-C000126
（式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルであり、Ｒ３はＣ１－４アルキルである。）
の化合物を有機塩基の存在下で反応させ、式[XVII] Wherein R 2 is unsubstituted or halogen, C 1-4 alkyl or benzyl substituted with C 1-4 alkoxy, or C 1-4 alkyl, and R 3 is C 1-4 alkyl. )
Is reacted in the presence of an organic base to produce a compound of formula [XVII]
Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127
（式中、Ｒ２は前記の通りである。）
の化合物又はその塩を得る工程；及び
式[XVII]の化合物又はその塩と、酸とを反応させ、式（１８）の化合物又はその塩を得る工程を含む方法。
[26-1]　Ｒ２がベンジルである［26］記載の方法。
[27]　式[XV] (Wherein R 2 is as described above.)
And a step of obtaining a compound of the formula (18) or a salt thereof by reacting a compound of the formula [XVII] or a salt thereof with an acid.
[26-1] The method according to [26], wherein R 2 is benzyl.
[27] Formula [XV]
Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128
（式中、Ｒ２及びＲ３は［26］に記載の通りである。）
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVI]の化合物を得る工程をさらに含む［26］記載の方法。
[27-1]　Ｒ２がベンジルである［27］記載の方法。
[28]　式[XIV] (Wherein R 2 and R 3 are as described in [26].)
The method according to [26], further comprising a step of reacting a compound of the above or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula [XVI].
[27-1] The method according to [27], wherein R 2 is benzyl.
[28] Formula [XIV]
Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［26］に記載の通りである。）
の化合物と、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸とを反応させ、式[XV]の化合物又はその塩を得る工程をさらに含む［25］又は［27］記載の方法。
[28-1]　Ｒ２がベンジルである［28］記載の方法。
[29]　式[XII] (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [26].)
The method according to [25] or [27], further comprising a step of reacting a compound of the above with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of the formula [XV] or a salt thereof.
[28-1] The method according to [28], wherein R 2 is benzyl.
[29] Formula [XII]
Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130
（式中、Ｒ２は［26］に記載の通りである。）
の化合物又はその塩と、式[XIII] (Wherein R 2 is as described in [26].)
Or a salt thereof and the formula [XIII]
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
（式中、Ｒ３は［26］に記載の通りである。）
の化合物とを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XIV]の化合物を得る工程をさらに含む［28］記載の方法。
[29-1]　Ｒ２がベンジルである［29］記載の方法。
[30]　式（１０） (Wherein R 3 is as described in [26].)
The method according to [28], further comprising the step of reacting the compound of formula (XIV) with a compound of formula [XIV] in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide. .
[29-1] The method according to [29], wherein R 2 is benzyl.
[30] Formula (10)
Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132
の化合物又はその塩と式[XI] Or a salt thereof and the formula [XI]
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
（式中、Ｒ２は［26］に記載の通りである。）
の化合物を有機塩基の存在下で反応させ、式[XII]の化合物又はその塩を得る工程をさらに含む［29］記載の方法。
[30-1]　Ｒ２がベンジルである［29］記載の方法。
[31]　プロピオル酸tert-ブチルと、ジエチルアミンとを反応させ、式（１０）の化合物又はその塩を得る工程をさらに含む［30］記載の方法。
[32]　式[XX] (Wherein R 2 is as described in [26].)
[29] The method according to [29], further comprising a step of reacting the compound in the presence of an organic base to obtain a compound of the formula [XII] or a salt thereof.
[30-1] The method according to [29], wherein R 2 is benzyl.
[31] The method according to [30], further comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of the formula (10) or a salt thereof.
[32] Formula [XX]
Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134
（式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩。
[32-1]　Ｒ２がベンジルである［32］記載の化合物又はその塩。
[33]　式（１８） Wherein R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy. Benzyl, or C 1-4 alkyl).
Or a salt thereof.
[32-1] The compound or a salt thereof according to [32], wherein R 2 is benzyl.
[33] Equation (18)
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
の化合物又はその塩を製造する方法であって、式（２４） Or a salt thereof, comprising the formula (24)
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式（１８）の化合物又はその塩を得る工程を含む方法。
[34]　式[XXIII] A method comprising a step of reacting a compound of the formula (I) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula (18) or a salt thereof.
[34] Formula [XXIII]
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
（式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩と、水酸化ナトリウム水溶液とを反応させ、式（２４）の化合物又はその塩を得る工程をさらに含む［33］記載の方法。
[34-1]　Ｒ４がベンジルである［34］記載の方法。
[35]　式（９） Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
[33] The method according to [33], further comprising a step of reacting the compound or a salt thereof with an aqueous sodium hydroxide solution to obtain a compound of the formula (24) or a salt thereof.
[34-1] The method according to [34], wherein R 4 is benzyl.
[35] Equation (9)
Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138
の化合物又はその塩と、式[XXII] Or a salt thereof and the formula [XXII]
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
（式中、Ｒ４は［34］に記載の通りである。）
の化合物を、有機塩基の存在下で反応させ、式[XXIII]の化合物又はその塩を得る工程をさらに含む［34］記載の方法。
[35-1]　Ｒ４がベンジルである［35］記載の方法。
[36]　式[XXI] (Wherein R 4 is as described in [34].)
The method according to [34], further comprising a step of reacting the compound of: in the presence of an organic base to obtain a compound of the formula [XXIII] or a salt thereof.
[35-1] The method described in [35], wherein R 4 is benzyl.
[36] Formula [XXI]
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
（式中、Ｒ４は［34］に記載の通りである。）
の化合物又はその塩と、シュウ酸ジメチルとを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XXII]の化合物を得る工程をさらに含む［35］記載の方法。
[36-1]　Ｒ４がベンジルである［36］記載の方法。
[37]　３－（ジメチルアミノ）アクリロニトリルと式[XI'] (Wherein R 4 is as described in [34].)
Or a salt thereof and dimethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide to obtain a compound of formula [XXII]. The method according to [35], further comprising:
[36-1] The method according to [36], wherein R 4 is benzyl.
[37] 3- (Dimethylamino) acrylonitrile and the formula [XI ']
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
（式中、Ｒ４は［34］に記載の通りである。）
の化合物を有機塩基の存在下で反応させ、式[XXI]の化合物又はその塩を得る工程をさらに含む［36］記載の方法。
[37-1]　Ｒ４がベンジルである［36］記載の方法。
[38]　式（２４） (Wherein R 4 is as described in [34].)
The method according to [36], further comprising a step of reacting the compound in the presence of an organic base to obtain a compound of the formula [XXI] or a salt thereof.
[37-1] The method according to [36], wherein R 4 is benzyl.
[38] Formula (24)
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
の化合物又はその塩。
[39]　式[XXIII] Or a salt thereof.
[39] Formula [XXIII]
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
（式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩。
[39-1]　Ｒ４がベンジルである［39］記載の化合物又はその塩。
[40]　式（１９） Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
Or a salt thereof.
[39-1] The compound or a salt thereof according to [39], wherein R 4 is benzyl.
[40] Equation (19)
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
の化合物を製造する方法であって、
式[XX] A process for producing a compound of
Formula [XX]
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
（式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVII] (Wherein R 2 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, or C 1-4 alkyl.)
Or a salt thereof with 3-chloro-2-fluorobenzylamine to give a compound of the formula [XVII]
Figure JPOXMLDOC01-appb-C000146
Figure JPOXMLDOC01-appb-C000146
（式中、Ｒ２は前記の通りである。）
の化合物又はその塩を得る工程；
式[XVII]の化合物と、酸とを反応させ、式（１８） (Wherein R 2 is as described above.)
Obtaining a compound of or a salt thereof;
A compound of formula [XVII] is reacted with an acid to give a compound of formula (18)
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
の化合物を得る工程；及び
式（１８）の化合物と、水酸化ナトリウムとを反応させ、式（１９）の化合物を得る工程を含む方法。
[40-1]　Ｒ２がベンジルである［40］記載の方法。
[41]　式（９） And a step of reacting a compound of formula (18) with sodium hydroxide to obtain a compound of formula (19).
[40-1] The method according to [40], wherein R 2 is benzyl.
[41] Equation (9)
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
の化合物又はその塩と、式[XV] Or a salt thereof and the formula [XV]
Figure JPOXMLDOC01-appb-C000149
Figure JPOXMLDOC01-appb-C000149
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［40］に記載の通りである。）
の化合物又はその塩とを、有機塩基の存在下で反応させ、式[XX]の化合物又はその塩を得る工程をさらに含む［40］記載の方法。
[41-1]　Ｒ２がベンジルである［41］記載の方法。
[42]　式（１９） (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [40].)
The method according to [40], further comprising a step of reacting the compound or a salt thereof in the presence of an organic base to obtain a compound of the formula [XX] or a salt thereof.
[41-1] The method according to [41], wherein R 2 is benzyl.
[42] Formula (19)
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150
の化合物を製造する方法であって、
式（９） A process for producing a compound of
Formula (9)
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151
の化合物又はその塩と、式[XVI] Or a salt thereof and the formula [XVI]
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152
（式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルであり、Ｒ３はＣ１－４アルキルである。）
の化合物を有機塩基の存在下で反応させ、式[XVII] Wherein R 2 is unsubstituted or halogen, C 1-4 alkyl or benzyl substituted with C 1-4 alkoxy, or C 1-4 alkyl, and R 3 is C 1-4 alkyl. )
Is reacted in the presence of an organic base to produce a compound of formula [XVII]
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153
（式中、Ｒ２は前記の通りである。）
の化合物又はその塩を得る工程；
式[XVII]の化合物又はその塩と、酸とを反応させ、式（１８） (Wherein R 2 is as described above.)
Obtaining a compound of or a salt thereof;
A compound of formula [XVII] or a salt thereof is reacted with an acid to give a compound of formula (18)
Figure JPOXMLDOC01-appb-C000154
Figure JPOXMLDOC01-appb-C000154
の化合物を得る工程；及び
式（１８）の化合物と、水酸化ナトリウム水溶液とを反応させ、式（１９）の化合物を得る工程を含む方法。
[42-1]　Ｒ２がベンジルである［42］記載の方法。
[43]　式[XV] And a step of reacting a compound of formula (18) with an aqueous sodium hydroxide solution to obtain a compound of formula (19).
[42-1] The method according to [42], wherein R 2 is benzyl.
[43] Formula [XV]
Figure JPOXMLDOC01-appb-C000155
Figure JPOXMLDOC01-appb-C000155
（式中、Ｒ２及びＲ３は［42］に記載の通りである。）
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVI]の化合物を得る工程をさらに含む［42］記載の方法。
[43-1]　Ｒ２がベンジルである［43］記載の方法。
[44]　式[XIV] (Wherein R 2 and R 3 are as described in [42].)
[42] The method according to [42], further comprising a step of reacting a compound of the above or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula [XVI].
[43-1] The method described in [43], wherein R 2 is benzyl.
[44] Formula [XIV]
Figure JPOXMLDOC01-appb-C000156
Figure JPOXMLDOC01-appb-C000156
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［40］に記載の通りである。）
の化合物と、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸とを反応させ、式[XV]の化合物又はその塩を得る工程をさらに含む［41］又は［43］記載の方法。
[44-1]　Ｒ２がベンジルである［44］記載の方法。
[45]　式[XII] (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [40].)
The method according to [41] or [43], further comprising a step of reacting a compound of the above with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of the formula [XV] or a salt thereof.
[44-1] The method described in [44], wherein R 2 is benzyl.
[45] Formula [XII]
Figure JPOXMLDOC01-appb-C000157
Figure JPOXMLDOC01-appb-C000157
（式中、Ｒ２は［40］に記載の通りである。）
の化合物又はその塩と、式[XIII] (Wherein R 2 is as described in [40].)
Or a salt thereof and the formula [XIII]
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158
（式中、Ｒ３はＣ１－４アルキルである。）
の化合物とを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XIV]の化合物を得る工程をさらに含む［44］記載の方法。
[45-1]　Ｒ２がベンジルである［45］記載の方法。
[46]　式（１０） Wherein R 3 is C 1-4 alkyl.
The method according to [44], further comprising the step of reacting the compound of formula (XIV) with a compound of formula [XIV] in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide. .
[45-1] The method according to [45], wherein R 2 is benzyl.
[46] Formula (10)
Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159
の化合物又はその塩と式[XI] Or a salt thereof and the formula [XI]
Figure JPOXMLDOC01-appb-C000160
Figure JPOXMLDOC01-appb-C000160
（式中、Ｒ２は［40］に記載の通りである。）
の化合物を有機塩基の存在下で反応させ、式[XII]の化合物又はその塩を得る工程をさらに含む［45］記載の方法。
[46-1]　Ｒ２がベンジルである［46］記載の方法。
[47]　プロピオル酸tert-ブチルと、ジエチルアミンとを反応させ、式（１０）の化合物又はその塩を得る工程をさらに含む［46］記載の方法。
[48]　式（１９） (Wherein R 2 is as described in [40].)
The method according to [45], further comprising a step of reacting the compound of formula (XII) in the presence of an organic base to obtain a compound of formula [XII] or a salt thereof.
[46-1] The method according to [46], wherein R 2 is benzyl.
[47] The method according to [46], further comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of formula (10) or a salt thereof.
[48] Formula (19)
Figure JPOXMLDOC01-appb-C000161
Figure JPOXMLDOC01-appb-C000161
の化合物を製造する方法であって、
式（２４） A process for producing a compound of
Formula (24)
Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式（１８） Or a salt thereof with 3-chloro-2-fluorobenzylamine to give a compound of formula (18)
Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163
の化合物を得る工程；及び
式（１８）の化合物と、水酸化ナトリウム水溶液とを反応させ、式（１９）の化合物を得る工程を含む方法。
[49]　式[XXIII] And a step of reacting a compound of formula (18) with an aqueous sodium hydroxide solution to obtain a compound of formula (19).
[49] Formula [XXIII]
Figure JPOXMLDOC01-appb-C000164
Figure JPOXMLDOC01-appb-C000164
（式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩と、水酸化ナトリウム水溶液とを反応させ、式（２４）の化合物又はその塩を得る工程をさらに含む［48］記載の方法。
[49-1]　Ｒ４がベンジルである［49］記載の方法。
[50]　式（９） Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
The method according to [48], further comprising a step of reacting the compound or a salt thereof with an aqueous sodium hydroxide solution to obtain a compound of the formula (24) or a salt thereof.
[49-1] The method according to [49], wherein R 4 is benzyl.
[50] Formula (9)
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165
の化合物又はその塩と、式[XXII] Or a salt thereof and the formula [XXII]
Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166
（式中、Ｒ４は［49］に記載の通りである。）
の化合物とを、有機塩基の存在下で反応させ、式[XXIII]の化合物又はその塩を得る工程をさらに含む［49］記載の方法。
[50-1]　Ｒ４がベンジルである［50］記載の方法。
[51]　式[XXI] (Wherein R 4 is as described in [49].)
The method according to [49], further comprising a step of reacting the compound of formula (XXIII) in the presence of an organic base to obtain a compound of the formula [XXIII] or a salt thereof.
[50-1] The method according to [50], wherein R 4 is benzyl.
[51] Formula [XXI]
Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167
（式中、Ｒ４は［49］に記載の通りである。）
の化合物又はその塩と、シュウ酸ジメチルとを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XXII]の化合物を得る工程をさらに含む［50］記載の方法。
[51-1]　Ｒ４がベンジルである［51］記載の方法。
[52]　３－（ジメチルアミノ）アクリロニトリルと式[XI'] (Wherein R 4 is as described in [49].)
Or a salt thereof and dimethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide to obtain a compound of formula [XXII]. The method according to [50], further comprising:
[51-1] The method according to [51], wherein R 4 is benzyl.
[52] 3- (Dimethylamino) acrylonitrile and the formula [XI ']
Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168
（式中、Ｒ４は［49］に記載の通りである。）
の化合物を有機塩基の存在下で反応させ、式[XXI]の化合物又はその塩を得る工程をさらに含む［51］記載の方法。
[52-1]　Ｒ４がベンジルである［52］記載の方法。
[53]　式（１９） (Wherein R 4 is as described in [49].)
The method according to [51], further comprising a step of reacting the compound in the presence of an organic base to obtain a compound of the formula [XXI] or a salt thereof.
[52-1] The method described in [52], wherein R 4 is benzyl.
[53] Equation (19)
Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169
の化合物を製造する方法であって、式[XVII] Wherein the compound of formula [XVII]
Figure JPOXMLDOC01-appb-C000170
Figure JPOXMLDOC01-appb-C000170
（式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩と、水酸化ナトリウムとを反応させ、式（１９）の化合物を得る工程を含む方法。
[53-1]　Ｒ２がベンジルである［53］記載の方法。
[54]　式[XX] Wherein R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy. Benzyl, or C 1-4 alkyl).
A method comprising a step of reacting a compound of the formula (I) or a salt thereof with sodium hydroxide to obtain a compound of the formula (19).
[53-1] The method according to [53], wherein R 2 is benzyl.
[54] Formula [XX]
Figure JPOXMLDOC01-appb-C000171
Figure JPOXMLDOC01-appb-C000171
（式中、Ｒ２は［53］に記載の通りである。）
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVII]の化合物又はその塩を得る工程をさらに含む［53］記載の方法。
[54-1]　Ｒ２がベンジルである［54］記載の方法。
[55]　式（９） (Wherein R 2 is as described in [53].)
The method according to [53], further comprising a step of reacting a compound of the formula:
[54-1] The method described in [54], wherein R 2 is benzyl.
[55] Equation (9)
Figure JPOXMLDOC01-appb-C000172
Figure JPOXMLDOC01-appb-C000172
の化合物又はその塩と、式[XV] Or a salt thereof and the formula [XV]
Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［53］に記載の通りである。）
の化合物又はその塩とを、有機塩基の存在下で反応させ、式[XX]の化合物又はその塩を得る工程をさらに含む［54］記載の方法。
[55-1]　Ｒ２がベンジルである［55］記載の方法。
[56]　式（９） (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [53].)
The method according to [54], further comprising a step of reacting the compound of the formula: or a salt thereof in the presence of an organic base to obtain a compound of the formula [XX]:
[55-1] The method according to [55], wherein R 2 is benzyl.
[56] Equation (9)
Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174
の化合物又はその塩と、式[XVI] Or a salt thereof and the formula [XVI]
Figure JPOXMLDOC01-appb-C000175
Figure JPOXMLDOC01-appb-C000175
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［53］に記載の通りである。）
の化合物を有機塩基の存在下で反応させ、式[XVII]の化合物又はその塩を得る工程をさらに含む［53］記載の方法。
[56-1]　Ｒ２がベンジルである［56］記載の方法。
[57]　式[XV] (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [53].)
The method according to [53], further comprising a step of reacting the compound of formula (XVII) to obtain a compound of the formula [XVII] or a salt thereof.
[56-1] The method described in [56], wherein R 2 is benzyl.
[57] Formula [XV]
Figure JPOXMLDOC01-appb-C000176
Figure JPOXMLDOC01-appb-C000176
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［53］に記載の通りである。）
の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVI]の化合物又はその塩を得る工程をさらに含む［56］記載の方法。
[57-1]　Ｒ２がベンジルである［57］記載の方法。
[58]　式[XIV] (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [53].)
The method according to [56], further comprising a step of reacting a compound of the formula: or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula [XVI]:
[57-1] The method according to [57], wherein R 2 is benzyl.
[58] Formula [XIV]
Figure JPOXMLDOC01-appb-C000177
Figure JPOXMLDOC01-appb-C000177
（式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は［53］に記載の通りである。）
の化合物と、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸とを反応させ、式[XV]の化合物又はその塩を得る工程をさらに含む［55］又は［57］記載の方法。
[58-1]　Ｒ２がベンジルである［58］記載の方法。
[59]　式[XII] (Wherein R 3 is C 1-4 alkyl and R 2 is as described in [53].)
The method according to [55] or [57], further comprising a step of reacting a compound of the above with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of the formula [XV] or a salt thereof.
[58-1] The method described in [58], wherein R 2 is benzyl.
[59] Formula [XII]
Figure JPOXMLDOC01-appb-C000178
Figure JPOXMLDOC01-appb-C000178
（式中、Ｒ２は［53］に記載の通りである。）
の化合物又はその塩と、式[XIII] (Wherein R 2 is as described in [53].)
Or a salt thereof and the formula [XIII]
Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179
（式中、Ｒ３はＣ１－４アルキルである。）
の化合物とを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XIV]の化合物を得る工程をさらに含む［58］記載の方法。
[59-1]　Ｒ２がベンジルである［59］記載の方法。
[60]　式（１０） Wherein R 3 is C 1-4 alkyl.
The method according to [58], further comprising the step of reacting the compound of formula (XIV) with a compound of formula [XIV] in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide. .
[59-1] The method according to [59], wherein R 2 is benzyl.
[60] Formula (10)
Figure JPOXMLDOC01-appb-C000180
Figure JPOXMLDOC01-appb-C000180
の化合物又はその塩と式[XI] Or a salt thereof and the formula [XI]
Figure JPOXMLDOC01-appb-C000181
Figure JPOXMLDOC01-appb-C000181
（式中、Ｒ２は［53］に記載の通りである。）
の化合物を有機塩基の存在下で反応させ、式[XII]の化合物又はその塩を得る工程をさらに含む［59］記載の方法。
[60-1]　Ｒ２がベンジルである［60］記載の方法。
[61]　プロピオル酸tert-ブチルと、ジエチルアミンとを反応させ、式（１０）の化合物又はその塩を得る工程をさらに含む［60］記載の方法。
[62]　式[XXII] (Wherein R 2 is as described in [53].)
The method according to [59], further comprising a step of reacting the compound of: in the presence of an organic base to obtain a compound of the formula [XII] or a salt thereof.
[60-1] The method according to [60], wherein R 2 is benzyl.
[61] The method according to [60], further comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of the formula (10) or a salt thereof.
[62] Formula [XXII]
Figure JPOXMLDOC01-appb-C000182
Figure JPOXMLDOC01-appb-C000182
（式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物。
[62-1]　Ｒ４がベンジルである［62］記載の化合物又はその塩。
[63]　式[XXI] Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
Compound.
[62-1] The compound or a salt thereof according to [62], wherein R 4 is benzyl.
[63] Formula [XXI]
Figure JPOXMLDOC01-appb-C000183
Figure JPOXMLDOC01-appb-C000183
（式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
の化合物又はその塩。
[63-1]　Ｒ４がベンジルである［63］記載の化合物又はその塩。
　本発明の別の態様は下記に示す通りである。各式の構造は後記に示す。
[64]　式（１８）の化合物と、水酸化ナトリウムとを反応させ、式（１９）の化合物を得る工程を含む、式（１９）の化合物を製造する方法。
[65]　式（１７）の化合物又はその塩と、酸とを反応させ、式（１８）の化合物又はその塩を得る工程を含む、式（１８）の化合物又はその塩を製造する方法。
[66]　式（２０）の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式（１７）の化合物又はその塩を得る工程を含む、式（１７）の化合物又はその塩を製造する方法。
[67]　式（９）の化合物又はその塩と、式（１５）の化合物又はその塩とを、有機塩基の存在下で反応させ、式（２０）の化合物又はその塩を得る工程を含む、式（２０）の化合物又はその塩を製造する方法。
[68]　式（８）の化合物又はその塩を接触水素還元反応に付し、式（９）の化合物又はその塩を得る工程を含む、式（９）の化合物又はその塩を製造する方法。
[69]　式（７）の化合物又はその塩と、ヒドロキシアミン又はその塩とを反応させ、式（８）の化合物又はその塩を得る工程を含む、式（８）の化合物又はその塩を製造する方法。
[70]　式（６）の化合物と、アルミニウム系還元剤とを反応させ、式（７）の化合物又はその塩を得る工程を含む、式（７）の化合物又はその塩を製造する方法。
[71]　式（５）の化合物と、メチル化剤を反応させ、式（６）の化合物を得る工程を含む、式（６）の化合物を製造する方法。
[72]　式（４）の化合物又はその塩と、ボラン系還元剤とを反応させ、式（５）の化合物を得る工程を含む、式（５）の化合物を製造する方法。
[73]　式（３）の化合物を、アルカリ加水分解に付し、式（４）の化合物又はその塩を得る工程を含む、式（４）の化合物又はその塩を製造する方法。
[74]　式（２）の化合物と、４－メトキシベンジル化剤とを反応させ、式（３）の化合物を得る工程を含む、式（３）の化合物を製造する方法。
[75]　式（１）の化合物又はその塩と、メチル化剤とを反応させ、再結晶により式（２）の化合物を得る工程を含む、式（２）の化合物を製造する方法。
[76]　式（１４）の化合物と、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸とを反応させ、式（１５）の化合物又はその塩を得る工程を含む、式（１５）の化合物又はその塩を製造する方法。
[77]　式（１２）の化合物又はその塩と、シュウ酸ジエチルとを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式（１４）の化合物を得る工程を含む、式（１４）の化合物を製造する方法。
[78]　式（１０）の化合物又はその塩とベンジルオキシアセチルクロリドを有機塩基の存在下で反応させ、式（１２）の化合物又はその塩を得る工程を含む、式（１２）の化合物又はその塩を製造する方法。
[79]　プロピオル酸tert-ブチルと、ジエチルアミンとを反応させ、式（１０）の化合物又はその塩を得る工程を含む、式（１０）の化合物又はその塩を製造する方法。
[80]　式（２４）の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式（１８）の化合物又はその塩を得る工程を含む、式（１８）の化合物又はその塩を製造する方法。
[81]　式（２３）の化合物又はその塩と、水酸化ナトリウム水溶液とを反応させ、式（２４）の化合物又はその塩を得る工程を含む、式（２４）の化合物又はその塩を製造する方法。
[82]　式（９）の化合物又はその塩と、式（２２）の化合物を、有機塩基の存在下で反応させ、式（２３）の化合物又はその塩を得る工程を含む、式（２３）の化合物又はその塩を製造する方法。
[83]　式（２１）の化合物又はその塩と、シュウ酸ジメチルとを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式（２２）の化合物を得る工程を含む、式（２２）の化合物を製造する方法。
[84]　３－（ジメチルアミノ）アクリロニトリルとベンジルオキシアセチルクロリドを有機塩基の存在下で反応させ、式（２１）の化合物又はその塩を得る工程を含む、式（２１）の化合物又はその塩を製造する方法。
[85]　式（１７）の化合物又はその塩と、水酸化ナトリウムとを反応させ、式（１９）の化合物を得る工程を含む、式（１９）の化合物を製造する方法。
[86]　式（９）の化合物又はその塩と、式（１６）の化合物を有機塩基の存在下で反応させ、式（１７）の化合物又はその塩を得る工程を含む、式（１７）の化合物又はその塩を製造する方法。
[87]　式（１５）の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式（１６）の化合物を得る工程を含む、式（１６）の化合物を製造する方法。 Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
Or a salt thereof.
[63-1] The compound according to [63] or a salt thereof, wherein R 4 is benzyl.
Another embodiment of the present invention is as follows. The structure of each formula is shown below.
[64] A method for producing a compound of formula (19), comprising a step of reacting a compound of formula (18) with sodium hydroxide to obtain a compound of formula (19).
[65] A method for producing a compound of formula (18) or a salt thereof, comprising a step of reacting a compound of formula (17) or a salt thereof with an acid to obtain a compound of formula (18) or a salt thereof.
[66] A compound of formula (17) comprising a step of reacting a compound of formula (20) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of formula (17) or a salt thereof A method for producing the salt.
[67] a step of reacting a compound of the formula (9) or a salt thereof with a compound of the formula (15) or a salt thereof in the presence of an organic base to obtain a compound of the formula (20) or a salt thereof. A method for producing a compound of the formula (20) or a salt thereof.
[68] A method for producing a compound of the formula (9) or a salt thereof, comprising a step of subjecting the compound of the formula (8) or a salt thereof to a catalytic hydrogen reduction reaction to obtain a compound of the formula (9) or a salt thereof.
[69] Production of a compound of formula (8) or a salt thereof comprising a step of reacting a compound of formula (7) or a salt thereof with hydroxyamine or a salt thereof to obtain a compound of formula (8) or a salt thereof how to.
[70] A method for producing a compound of formula (7) or a salt thereof, comprising a step of reacting a compound of formula (6) with an aluminum reducing agent to obtain a compound of formula (7) or a salt thereof.
[71] A method for producing a compound of formula (6), comprising a step of reacting a compound of formula (5) with a methylating agent to obtain a compound of formula (6).
[72] A method for producing a compound of formula (5), comprising a step of reacting a compound of formula (4) or a salt thereof with a borane reducing agent to obtain a compound of formula (5).
[73] A method for producing a compound of formula (4) or a salt thereof, comprising a step of subjecting the compound of formula (3) to alkaline hydrolysis to obtain a compound of formula (4) or a salt thereof.
[74] A method for producing a compound of formula (3), comprising a step of reacting a compound of formula (2) with a 4-methoxybenzylating agent to obtain a compound of formula (3).
[75] A method for producing a compound of formula (2), comprising a step of reacting a compound of formula (1) or a salt thereof with a methylating agent to obtain a compound of formula (2) by recrystallization.
[76] A compound of formula (15) or a salt thereof, comprising a step of reacting a compound of formula (14) with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of formula (15) or a salt thereof. How to manufacture.
[77] A compound of the formula (12) or a salt thereof and diethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide, The method of manufacturing the compound of Formula (14) including the process of obtaining the compound of).
[78] A compound of formula (12) or a salt thereof, comprising a step of reacting a compound of formula (10) or a salt thereof with benzyloxyacetyl chloride in the presence of an organic base to obtain a compound of formula (12) or a salt thereof. A method for producing a salt.
[79] A method for producing a compound of the formula (10) or a salt thereof, comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of the formula (10) or a salt thereof.
[80] A compound of formula (18) comprising a step of reacting a compound of formula (24) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of formula (18) or a salt thereof A method for producing the salt.
[81] A compound of formula (24) or a salt thereof is produced, which comprises a step of reacting a compound of formula (23) or a salt thereof with an aqueous sodium hydroxide solution to obtain a compound of formula (24) or a salt thereof. Method.
[82] The method comprising reacting the compound of the formula (9) or a salt thereof with the compound of the formula (22) in the presence of an organic base to obtain a compound of the formula (23) or a salt thereof. Or a salt thereof.
[83] A compound of the formula (21) or a salt thereof and dimethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide to obtain a compound of the formula (22 The method of manufacturing the compound of Formula (22) including the process of obtaining the compound of).
[84] reacting 3- (dimethylamino) acrylonitrile and benzyloxyacetyl chloride in the presence of an organic base to obtain a compound of the formula (21) or a salt thereof; How to manufacture.
[85] A method for producing a compound of formula (19), comprising a step of reacting a compound of formula (17) or a salt thereof with sodium hydroxide to obtain a compound of formula (19).
[86] The method comprising the step of reacting the compound of the formula (9) or a salt thereof with the compound of the formula (16) in the presence of an organic base to obtain a compound of the formula (17) or a salt thereof. A method for producing a compound or a salt thereof.
[87] A process for producing a compound of formula (16), comprising a step of reacting a compound of formula (15) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of formula (16) .
Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000184
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000185
Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000186
Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000187
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000188
Figure JPOXMLDOC01-appb-C000189
Figure JPOXMLDOC01-appb-C000189
　本明細書において使用する各置換基及び各部位の定義は、次の通りである。 The definitions of each substituent and each site used in this specification are as follows.
　「ハロゲン」とは、フッ素、塩素、臭素又はヨウ素である。好ましい「ハロゲン」の態様は、フッ素又は塩素である。
　「Ｃ１－６アルキル」とは、炭素数１乃至６の直鎖又は分岐鎖アルキルを表す。例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、１，１－ジメチルプロピル、１，２－ジメチルプロピル、２，２－ジメチルプロピル、１－エチルプロピル、ヘキシル、１，１－ジメチルブチル、１－エチル－１－メチルプロピル等が含まれる。好ましくは「Ｃ１－４アルキル」である。
　「Ｃ１－４アルキル」とは、炭素数１から４の直鎖又は分岐鎖アルキルを表す。例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル又はｔｅｒｔ－ブチル等が含まれる。
　Ｒ２の好ましい「Ｃ１－４アルキル」の態様は、メチルである。
　Ｒ３の好ましい「Ｃ１－４アルキル」の態様は、メチル又はエチルである。 “Halogen” is fluorine, chlorine, bromine or iodine. Preferred “halogen” embodiments are fluorine or chlorine.
“C 1-6 alkyl” represents linear or branched alkyl having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyl Propyl, hexyl, 1,1-dimethylbutyl, 1-ethyl-1-methylpropyl and the like. Preferred is “C 1-4 alkyl”.
“C 1-4 alkyl” represents linear or branched alkyl having 1 to 4 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like are included.
A preferred “C 1-4 alkyl” embodiment for R 2 is methyl.
A preferred “C 1-4 alkyl” embodiment of R 3 is methyl or ethyl.
　「Ｃ１－４アルコキシ」とは、炭素数１から４の直鎖又は分岐鎖アルコキシである。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブチルオキシ、ｔｅｒｔ－ブチルオキシ等が含まれる。好ましい「Ｃ１－４アルコキシ」の態様は、メトキシである。
　本発明化合物の塩とは、本発明化合物と無毒の塩を形成するものであればいかなる塩でもよく、例えば、無機酸との塩、有機酸との塩、無機塩基との塩、有機塩基との塩、アミノ酸との塩等が挙げられる。
　無機酸との塩として、例えば、塩酸、硝酸、硫酸、リン酸、臭化水素酸等との塩が挙げられる。
　有機酸との塩として、例えば、シュウ酸、マロン酸、マレイン酸、クエン酸、フマル酸、乳酸、リンゴ酸、コハク酸、酒石酸、酢酸、トリフルオロ酢酸、グルコン酸、アスコルビン酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等との塩が挙げられる。
　無機塩基との塩として、例えば、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩等が挙げられる。好ましくは、ナトリウム塩である。
　有機塩基との塩として、例えば、メチルアミン、ジエチルアミン、トリメチルアミン、ｎ－プロピルアミン、ｎ－ブチルアミン、ｔ－ブチルアミン、シクロヘキルアミン、ジシクロヘキルアミン、フェネチルアミン、（S）－フェネチルアミン、（R）－フェネチルアミン、トリエチルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、エチレンジアミン、トリス（ヒドロキシメチル）メチルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ’－ジベンジルエチレンジアミン、グアニジン、ピリジン、ピコリン、コリン、シンコニン、メグルミン等との塩が挙げられる。
　アミノ酸との塩として、例えば、リジン、アルギニン、アスパラギン酸、グルタミン酸等との塩が挙げられる。 “C 1-4 alkoxy” is straight-chain or branched alkoxy having 1 to 4 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, tert-butyloxy and the like are included. A preferred “C 1-4 alkoxy” embodiment is methoxy.
The salt of the compound of the present invention may be any salt as long as it forms a non-toxic salt with the compound of the present invention. For example, a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base, and an organic base And salts with amino acids.
Examples of the salt with an inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
Examples of salts with organic acids include oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, Examples thereof include salts with benzenesulfonic acid, p-toluenesulfonic acid and the like.
Examples of the salt with an inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like. Preferably, it is a sodium salt.
Examples of salts with organic bases include methylamine, diethylamine, trimethylamine, n-propylamine, n-butylamine, t-butylamine, cyclohexylamine, dicyclohexylamine, phenethylamine, (S) -phenethylamine, (R) -phenethylamine, Examples include salts with triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine, etc. It is done.
Examples of the salt with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid and the like.
　公知の方法に従って、本発明化合物と、無機塩基、有機塩基、無機酸、有機酸又はアミノ酸とを反応させることにより、そのような塩を得ることができる。 According to a known method, such a salt can be obtained by reacting the compound of the present invention with an inorganic base, organic base, inorganic acid, organic acid or amino acid.
　本発明において、本発明化合物の塩として、塩酸との塩（例、１塩酸塩、２塩酸塩）、臭化水素酸との塩（例、１臭化水素酸塩、２臭化水素酸塩）、硫酸との塩、ｐ－トルエンスルホン酸との塩、ナトリウム塩、カリウム塩、カルシウム塩が好ましい態様である。 In the present invention, as a salt of the compound of the present invention, a salt with hydrochloric acid (eg, monohydrochloride, dihydrochloride), a salt with hydrobromic acid (eg, monohydrobromide, dihydrobromide) ), A salt with sulfuric acid, a salt with p-toluenesulfonic acid, a sodium salt, a potassium salt, and a calcium salt are preferred embodiments.
　本発明化合物又はその塩は、溶媒和物として存在することもある。 The compound of the present invention or a salt thereof may exist as a solvate.
　「溶媒和物」とは、本発明化合物又はその塩に、溶媒の分子が配位したものであり、水和物（含水物ともいう。）も包含される。溶媒和物は、製薬上許容される溶媒和物が好ましく、例えば、本発明化合物の０．４から０．８水和物、１水和物、１／２水和物、２水和物、ナトリウム塩の０．４から０．８水和物、ナトリウム塩の１水和物、１メタノール和物、１エタノール和物、１アセトニトリル和物、２塩酸塩の１／２エタノール和物等が挙げられる。本発明化合物の溶媒和物の好ましい態様は、０．５から０．７水和物、１水和物、１／２水和物、０．６水和物、２水和物、ナトリウム塩の０．５から０．７水和物、ナトリウム塩の１水和物、ナトリウム塩の０．６水和物、ナトリウム塩の０．５水和物、ナトリウム塩の２水和物である。 The “solvate” is a compound in which a solvent molecule is coordinated to the compound of the present invention or a salt thereof, and also includes a hydrate (also referred to as a hydrate). The solvate is preferably a pharmaceutically acceptable solvate, for example, 0.4 to 0.8 hydrate, 1 hydrate, 1/2 hydrate, 2 hydrate of the compound of the present invention, Sodium salt 0.4 to 0.8 hydrate, sodium salt monohydrate, 1 methanol hydrate, 1 ethanol hydrate, 1 acetonitrile hydrate, 2 hydrochloride ½ ethanol hydrate, etc. Be A preferred embodiment of the solvate of the compound of the present invention is 0.5 to 0.7 hydrate, monohydrate, 1/2 hydrate, 0.6 hydrate, dihydrate, sodium salt 0.5 to 0.7 hydrate, sodium salt monohydrate, sodium salt 0.6 hydrate, sodium salt 0.5 hydrate, sodium salt dihydrate.
　公知の方法に従って、本発明化合物又はその塩の溶媒和物を得ることができる。 According to a known method, a solvate of the compound of the present invention or a salt thereof can be obtained.
　本発明化合物は、互変異性体として存在する場合がある。その場合、本発明化合物は、個々の互変異性体又は互変異性体の混合物として存在し得る。
　本発明化合物は、炭素二重結合を有する場合がある。その場合、本発明化合物は、E体、Z体、又はE体とZ体の混合物として存在し得る。
　本発明化合物は、シス／トランス異性体として認識すべき立体異性体が存在する場合がある。その場合、本発明化合物は、シス体、トランス体、又はシス体とトランス体の混合物として存在し得る。
　本発明化合物は、上記の異性体を生じさせる構造上の特徴を同時に複数含むことがある。また、本発明化合物は、上記の異性体をあらゆる比率で含み得る。 The compounds of the present invention may exist as tautomers. In that case, the compounds of the invention may exist as individual tautomers or mixtures of tautomers.
The compound of the present invention may have a carbon double bond. In that case, the compound of the present invention may exist as E-form, Z-form, or a mixture of E-form and Z-form.
The compound of the present invention may have a stereoisomer to be recognized as a cis / trans isomer. In that case, the compound of the present invention may exist as a cis form, a trans form, or a mixture of a cis form and a trans form.
The compound of the present invention may contain a plurality of structural features that give rise to the above isomers simultaneously. In addition, the compound of the present invention can contain the above isomers in any ratio.
　本願明細書に立体化学を特定せずに表記した式、化学構造もしくは化合物名は、他に注釈等の言及がない限り、存在しうる上記の異性体すべてを含む。 In the present specification, formulas, chemical structures or compound names expressed without specifying stereochemistry include all the above-mentioned isomers that may exist unless otherwise noted.
　ジアステレオマー混合物は、クロマトグラフィーや結晶化などの慣用されている方法によって、それぞれのジアステレオマーに分離することができる。また、立体化学的に単一である出発物質を用いることにより、又は立体選択的な反応を用いる合成方法によりそれぞれのジアステレオマーを作ることもできる。 The diastereomer mixture can be separated into each diastereomer by a conventional method such as chromatography or crystallization. Each diastereomer can also be made by using a stereochemically single starting material or by a synthetic method using a stereoselective reaction.
　本願に記載している立体配置は、化合物（１８）の単結晶のＸ線構造解析に基づいて特定することができる。 The steric configuration described in the present application can be specified based on the X-ray structural analysis of the single crystal of the compound (18).
　本発明化合物のある実施態様として、本発明化合物は結晶或いは非晶質（アモルファス）であってもよい。 As an embodiment of the compound of the present invention, the compound of the present invention may be crystalline or amorphous.
　本発明化合物のある実施態様として、本発明化合物は同位元素（例えば、３Ｈ、１４Ｃ、３５Ｓ等）で標識されていてもよい。 As an embodiment of the compound of the present invention, the compound of the present invention may be labeled with an isotope (eg, 3 H, 14 C, 35 S etc.).
　本発明化合物又はその塩の好ましい態様は、実質的に精製された、本発明化合物又はその塩である。さらに好ましい実施態様は、８０％以上の純度に精製された、本発明化合物又はその塩である。 A preferred embodiment of the compound of the present invention or a salt thereof is a substantially purified compound of the present invention or a salt thereof. A further preferred embodiment is the compound of the present invention or a salt thereof purified to a purity of 80% or more.
　次に、本発明の製造方法を具体的に説明する。
　各工程において、反応は溶媒中で行う。
　各工程において、反応後の処理は、特に記載していない場合は当業者が通常行う方法で行うことができる。例えば、蒸留、結晶化、再結晶化、カラムクロマトグラフィー、分取ＨＰＬＣ等の方法を適宜選択し、またはこれらの方法を組み合わせて反応後の処理を行えばよい。
　また、場合によっては、単離精製せず次の工程に進むことができる。
　本明細書において、「室温」とは、１５℃から３０℃を意味する。
　具体的な反応温度については±５℃、好ましくは±２℃まで許容される。 Next, the production method of the present invention will be specifically described.
In each step, the reaction is performed in a solvent.
In each step, the treatment after the reaction can be carried out by a method usually performed by those skilled in the art unless otherwise specified. For example, a method such as distillation, crystallization, recrystallization, column chromatography, preparative HPLC or the like may be appropriately selected, or these methods may be combined to carry out the treatment after the reaction.
In some cases, the next step can be carried out without isolation and purification.
In this specification, “room temperature” means 15 ° C. to 30 ° C.
The specific reaction temperature is allowed to be ± 5 ° C., preferably ± 2 ° C.
製造方法１：式（９）の化合物又はその塩の製造方法 Production method 1: Production method of compound of formula (9) or salt thereof
製造方法１－１ Manufacturing method 1-1
Figure JPOXMLDOC01-appb-C000190
Figure JPOXMLDOC01-appb-C000190
工程１ Process 1
Figure JPOXMLDOC01-appb-C000191
Figure JPOXMLDOC01-appb-C000191
　式（１）の化合物は、３－オキソシクロブタンカルボン酸から、Bucherer-Bergs反応（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ　３３　（１９９０）　２９０５－２９１５、あるいはＳｙｎｌｅｔｔ　１１　（２００９）　１８２７－１８２９）により製造することができる。
　溶媒は、メタノール、エタノール、１－プロパノール、２－プロパノール、ＤＭＦ（Ｎ，Ｎ－ジメチルホルムアミド）、ＤＭＡ（Ｎ，Ｎ－ジメチルアセトアミド）、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は水である。
　シアン化カリウムの量は、３－オキソシクロブタンカルボン酸に対し０．９から１．０当量であり、好ましくは０．９５当量である。
　炭酸アンモニウムの量は、３－オキソシクロブタンカルボン酸に対し１．５から２．５当量であり、好ましくは２．０当量である。
　塩化アンモニウムの量は、３－オキソシクロブタンカルボン酸に対し０．２から１．０当量であり、好ましくは１．０当量である。
　反応開始前の溶液は、２８％アンモニア水によりｐＨを中性付近にする必要がある。好ましい溶液のｐＨは、６．５から９．０である。
　反応温度は、５０℃から６０℃であり、好ましくは５５℃から６０℃である。
　反応時間は、１時間から２０時間であり、好ましくは４時間から２０時間である。
　試薬添加の順序は、シアン化カリウムを最後に加えるのが好ましい。 Compounds of formula (1) can be prepared from 3-oxocyclobutanecarboxylic acid by the Bucherer-Bergs reaction (Journal of Medicinal Chemistry 33 (1990) 2905-2915, or Synlett 11 (2009) 1827-1829).
Examples of the solvent include methanol, ethanol, 1-propanol, 2-propanol, DMF (N, N-dimethylformamide), DMA (N, N-dimethylacetamide), water alone or a mixed solvent. A preferred solvent is water.
The amount of potassium cyanide is 0.9 to 1.0 equivalent, preferably 0.95 equivalent, relative to 3-oxocyclobutanecarboxylic acid.
The amount of ammonium carbonate is 1.5 to 2.5 equivalents, preferably 2.0 equivalents, relative to 3-oxocyclobutanecarboxylic acid.
The amount of ammonium chloride is 0.2 to 1.0 equivalent, preferably 1.0 equivalent, based on 3-oxocyclobutanecarboxylic acid.
The solution before the start of the reaction needs to have a pH close to neutral with 28% aqueous ammonia. The pH of the preferred solution is 6.5 to 9.0.
The reaction temperature is 50 ° C to 60 ° C, preferably 55 ° C to 60 ° C.
The reaction time is 1 to 20 hours, preferably 4 to 20 hours.
The order of reagent addition is preferably to add potassium cyanide last.
工程２ Process 2
Figure JPOXMLDOC01-appb-C000192
Figure JPOXMLDOC01-appb-C000192
　式（２）の化合物又はその塩は、式（１）の化合物又はその塩とメチル化剤とを反応させ、式（２）の化合物又はその塩とそのトランス異性体の混合物を得た後、その混合物を再結晶することにより製造することができる。式（１）の化合物又はその塩とメチル化剤との反応は、塩基の存在下で行う。
　溶媒は、ＤＭＦ、ＤＭＳＯ（ジメチルスルホキシド）、ＤＭＡ、ＤＭＩ（１，３－ジメチル－２－イミダゾリジノン）等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＤＭＦである。
　メチル化剤としては、ヨウ化メチル、硫酸ジメチル、ｐ－トルエンスルホン酸メチル等が例示される。好ましいメチル化剤は、ヨウ化メチルである。
　塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等が例示される。好ましい塩基は、炭酸カリウムである。
　式（１）の化合物又はその塩とメチル化剤との反応を円滑に進めるには、塩基およびメチル化剤の必要量を分割して添加することが好ましい。
　式（１）の化合物はカッターミル等で解砕したものを使用するのが好ましい。
　反応温度は、０℃から室温であり、好ましくは室温である。
　再結晶に用いる溶媒は、アルコール（メタノール、エタノール、１－プロパノール、２－プロパノール等）が例示される。好ましい溶媒は、メタノールである。 The compound of formula (2) or a salt thereof is reacted with a compound of formula (1) or a salt thereof and a methylating agent to obtain a mixture of the compound of formula (2) or a salt thereof and a trans isomer thereof, It can be produced by recrystallizing the mixture. The reaction of the compound of formula (1) or a salt thereof and the methylating agent is carried out in the presence of a base.
Examples of the solvent include DMF, DMSO (dimethyl sulfoxide), DMA, DMI (1,3-dimethyl-2-imidazolidinone) and the like alone or as a mixed solvent. A preferred solvent is DMF.
Examples of the methylating agent include methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, and the like. A preferred methylating agent is methyl iodide.
Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate and the like. A preferred base is potassium carbonate.
In order to facilitate the reaction between the compound of formula (1) or a salt thereof and the methylating agent, it is preferable to add the necessary amounts of the base and the methylating agent in divided portions.
The compound of formula (1) is preferably used after being crushed with a cutter mill or the like.
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
Examples of the solvent used for recrystallization include alcohols (methanol, ethanol, 1-propanol, 2-propanol, etc.). A preferred solvent is methanol.
工程３ Process 3
Figure JPOXMLDOC01-appb-C000193
Figure JPOXMLDOC01-appb-C000193
（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、好ましくは無置換のベンジル又は４－メトキシベンジルであり、さらに好ましくは無置換のベンジル（単にベンジルとも言う。）である。）
　式[ＩＩＩ]の化合物は、式（２）の化合物又はその塩とベンジル化剤とを反応させることにより製造することができる。式（２）の化合物とベンジル化剤との反応は、塩基の存在下で行う。
　溶媒は、ＭｅＣＮ（アセトニトリル）、ＤＭＦ、ＤＭＳＯ、ＤＭＡ、ＤＭＩ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＤＭＦである。
　ベンジル化剤としては、式Ｒ１－Ｘ（式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、Ｘは、塩素原子、臭素原子等の脱離基である。）の化合物であり、ベンジルクロリド、ベンジルブロミド、３－クロロベンジルクロリド、３－クロロベンジルブロミド、４－クロロベンジルクロリド、４－クロロベンジルブロミド、３－メチルベンジルクロリド、３－メチルベンジルブロミド、４－メチルベンジルクロリド、４－メチルベンジルブロミド、３－メトキシベンジルクロリド、３－メトキシベンジルブロミド、４－メトキシベンジルクロリド、４－メトキシベンジルブロミドが例示される。好ましいベンジル化剤は、４－メトキシベンジルクロリドなどの４－メトキシベンジル化剤、又はベンジルクロリド、ベンジルブロミドなどのベンジル化剤である。
　塩基としては、炭酸セシウム、水素化ナトリウム、カリウムtert-ブトキシド等が例示される。好ましい塩基は、炭酸セシウムである。
　反応温度は、０℃から室温であり、好ましくは０℃から５℃である。 (Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, preferably unsubstituted benzyl or 4-methoxybenzyl, more preferably Substituted benzyl (also referred to simply as benzyl).)
The compound of the formula [III] can be produced by reacting the compound of the formula (2) or a salt thereof with a benzylating agent. The reaction between the compound of formula (2) and the benzylating agent is carried out in the presence of a base.
Examples of the solvent include MeCN (acetonitrile), DMF, DMSO, DMA, DMI and the like alone or in combination. A preferred solvent is DMF.
As the benzylating agent, a compound of formula R 1 -X (wherein R 1 is benzyl which is unsubstituted or substituted by halogen, C 1-4 alkyl or C 1-4 alkoxy, and X is a chlorine atom, bromine A benzyl chloride, benzyl bromide, 3-chlorobenzyl chloride, 3-chlorobenzyl bromide, 4-chlorobenzyl chloride, 4-chlorobenzyl bromide, 3-methylbenzyl chloride. , 3-methylbenzyl bromide, 4-methylbenzyl chloride, 4-methylbenzyl bromide, 3-methoxybenzyl chloride, 3-methoxybenzyl bromide, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide. Preferred benzylating agents are 4-methoxybenzylating agents such as 4-methoxybenzyl chloride or benzylating agents such as benzyl chloride and benzyl bromide.
Examples of the base include cesium carbonate, sodium hydride, potassium tert-butoxide and the like. A preferred base is cesium carbonate.
The reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
工程４ Process 4
Figure JPOXMLDOC01-appb-C000194
Figure JPOXMLDOC01-appb-C000194
（式中の記号は、前記の通りである。）
　式[ＩＶ－ａ]の化合物又はその塩は、式[ＩＩＩ]の化合物の加水分解反応により製造することができる。式[ＩＩＩ]の化合物の加水分解反応は、アルカリ加水分解が好ましい。
　溶媒は、メタノール、水、トルエン、ＴＨＦ（テトラヒドロフラン）等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＴＨＦである。
　塩基としては、水酸化ナトリウム、水酸化カリウム等が例示される。好ましい塩基は、水酸化ナトリウムである。
　反応温度は、０℃から室温であり、好ましくは０℃から５℃である。 (The symbols in the formula are as described above.)
The compound of formula [IV-a] or a salt thereof can be produced by hydrolysis reaction of the compound of formula [III]. The hydrolysis reaction of the compound of formula [III] is preferably alkaline hydrolysis.
Examples of the solvent include methanol, water, toluene, THF (tetrahydrofuran) and the like alone or as a mixed solvent. A preferred solvent is THF.
Examples of the base include sodium hydroxide and potassium hydroxide. A preferred base is sodium hydroxide.
The reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
工程５ Process 5
Figure JPOXMLDOC01-appb-C000195
Figure JPOXMLDOC01-appb-C000195
（式中の記号は、前記の通りである。）
　式[Ｖ]の化合物又はその塩は、式[ＩＶ－ａ]の化合物又はその塩をボラン系還元剤と反応させることにより製造することができる。式[ＩＶ－ａ]の化合物又はその塩とボラン系還元剤との反応は、添加剤の存在下で行ってもよい。
　溶媒は、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＴＨＦである。
　ボラン系還元剤としては、水素化ホウ素ナトリウムと添加剤、ボラン-テトラヒドロフラン錯体等が例示される。好ましいボラン系還元剤は、水素化ホウ素ナトリウムと添加剤である。
　水素化ホウ素ナトリウムの量は式[ＩＶ－ａ]の化合物に対し１．００当量から２．００当量が例示され、好ましくは１．１０当量である。
　添加剤としては、三フッ化ホウ素ジエチルエーテラート（三フッ化ホウ素－ジエチルエーテル錯体）、ヨウ素、硫酸等が例示される。好ましい添加剤は、三フッ化ホウ素ジエチルエーテラートである。
三フッ化ホウ素ジエチルエーテラートの量は式[ＩＶ－ａ]の化合物に対し０．９５当量から１．５０当量が例示され、好ましくは０．９９５当量である。
　反応温度は、０℃から室温であり、好ましくは０℃から５℃である。
　また、式[Ｖ]の化合物又はその塩は、式[ＩＶ－ａ]の化合物又はその塩を塩基の存在下でクロロ炭酸イソブチル等のクロロ炭酸Ｃ１－４アルキルと反応させ、活性エステルに変換した後、水素化ホウ素ナトリウムと反応させることにより製造することもできる。
　溶媒は、ＴＨＦ、１，４－ジオキサン、１，２－ジメトキシエタン、メタノール、エタノール、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＴＨＦと水の混合溶媒である。
　反応温度は、０℃から室温であり、好ましくは０℃から５℃である。 (The symbols in the formula are as described above.)
The compound of the formula [V] or a salt thereof can be produced by reacting the compound of the formula [IV-a] or a salt thereof with a borane reducing agent. The reaction of the compound of the formula [IV-a] or a salt thereof and the borane reducing agent may be performed in the presence of an additive.
Examples of the solvent include THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane and the like alone or in a mixed solvent. A preferred solvent is THF.
Examples of the borane-based reducing agent include sodium borohydride and additives, borane-tetrahydrofuran complex, and the like. Preferred borane reducing agents are sodium borohydride and additives.
The amount of sodium borohydride is, for example, 1.00 to 2.00 equivalents, preferably 1.10 equivalents, relative to the compound of formula [IV-a].
Examples of the additive include boron trifluoride diethyl etherate (boron trifluoride-diethyl ether complex), iodine, sulfuric acid and the like. A preferred additive is boron trifluoride diethyl etherate.
The amount of boron trifluoride diethyl etherate is 0.95 equivalents to 1.50 equivalents, preferably 0.995 equivalents, relative to the compound of formula [IV-a].
The reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
Further, the compound of the formula [V] or a salt thereof is converted into an active ester by reacting the compound of the formula [IV-a] or a salt thereof with a C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base. And then reacting with sodium borohydride.
Examples of the solvent include THF, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, water and the like alone or as a mixed solvent. A preferred solvent is a mixed solvent of THF and water.
The reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
工程６ Step 6
Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196
（式中の記号は、前記の通りである。）
　式[ＶＩ]の化合物は、式[Ｖ]の化合物又はその塩をメチル化剤と反応させることにより製造することができる。式[Ｖ]の化合物又はその塩とメチル化剤との反応は、塩基の存在下で行う。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ＤＭＦ、ＤＭＡ、ＤＭＩ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＴＨＦである。
　メチル化剤としては、ヨウ化メチル、硫酸ジメチル、ｐ－トルエンスルホン酸メチル等が例示される。好ましいメチル化剤は、ヨウ化メチルである。
　塩基としては、水素化ナトリウム、カリウムtert-ブトキシド、ナトリウムtert-ブトキシド、リチウムtert-ブトキシド等が例示される。好ましい塩基は、カリウムtert-ブトキシドである。
　反応温度は、０℃から室温であり、好ましくは０℃から５℃である。 (The symbols in the formula are as described above.)
The compound of the formula [VI] can be produced by reacting the compound of the formula [V] or a salt thereof with a methylating agent. The reaction of the compound of formula [V] or a salt thereof and the methylating agent is carried out in the presence of a base.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, DMF, DMA, DMI and the like alone or in combination. A preferred solvent is THF.
Examples of the methylating agent include methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, and the like. A preferred methylating agent is methyl iodide.
Examples of the base include sodium hydride, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide and the like. A preferred base is potassium tert-butoxide.
The reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
工程７ Step 7
Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197
（式中の記号は、前記の通りである。）
　式[ＶＩＩ]の化合物又はその塩は、式[ＶＩ]の化合物をアルミニウム系還元剤と反応させることにより製造することができる。
　溶媒は、トルエン、キシレン、エチルベンゼン、クロロベンゼン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン等の単独あるいは混合溶媒が例示される。好ましい溶媒は、トルエンである。
　アルミニウム系還元剤としては、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウム、水素化アルミニウムリチウム等が例示される。好ましい還元剤は、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウムである。
　反応温度は、室温から７５℃であり、好ましくは６５℃から７５℃である。 (The symbols in the formula are as described above.)
The compound of formula [VII] or a salt thereof can be produced by reacting the compound of formula [VI] with an aluminum-based reducing agent.
Examples of the solvent include toluene, xylene, ethylbenzene, chlorobenzene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane and the like alone or in a mixed solvent. A preferred solvent is toluene.
Examples of the aluminum reducing agent include bis (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride and the like. A preferred reducing agent is sodium bis (2-methoxyethoxy) aluminum hydride.
The reaction temperature is from room temperature to 75 ° C, preferably from 65 ° C to 75 ° C.
工程８ Process 8
Figure JPOXMLDOC01-appb-C000198
Figure JPOXMLDOC01-appb-C000198
（式中の記号は、前記の通りである。）
　式[ＶＩＩＩ]の化合物又はその塩は、式[ＶＩＩ]の化合物又はその塩からJ. AM. CHEM. SOC. 2003, 125, 11836-11837記載の方法により製造することができる。具体的には、式[ＶＩＩ]の化合物又はその塩とヒドロキシアミン又はその塩とを反応させることにより製造することができる。式[ＶＩＩ]の化合物又はその塩とヒドロキシアミン又はその塩との反応は、酸性溶液中で行う。
　酸性溶液としては、濃度2 mol/L以下の塩酸水溶液が好ましい。
　反応温度は、０℃から室温であり、好ましくは５℃から室温である。
　式[ＶＩＩＩ]の化合物は、塩酸塩として固体として得ることができる。式[ＶＩＩＩ]の塩酸塩の調製方法は、非水系又は非アルコール系溶媒において塩酸塩を調製する方法を用いればよい。
　塩酸塩としては、１塩酸塩又は２塩酸塩が例示される。好ましい塩酸塩は、２塩酸塩である。 (The symbols in the formula are as described above.)
The compound of formula [VIII] or a salt thereof can be produced from the compound of formula [VII] or a salt thereof by the method described in J. AM. CHEM. SOC. 2003, 125, 11836-11837. Specifically, it can be produced by reacting a compound of the formula [VII] or a salt thereof with hydroxyamine or a salt thereof. The reaction of the compound of formula [VII] or a salt thereof and hydroxyamine or a salt thereof is carried out in an acidic solution.
As the acidic solution, an aqueous hydrochloric acid solution having a concentration of 2 mol / L or less is preferable.
The reaction temperature is 0 ° C. to room temperature, preferably 5 ° C. to room temperature.
The compound of formula [VIII] can be obtained as a hydrochloride as a solid. The method for preparing the hydrochloride of the formula [VIII] may be a method for preparing the hydrochloride in a non-aqueous or non-alcoholic solvent.
Examples of the hydrochloride include monohydrochloride and dihydrochloride. A preferred hydrochloride salt is the dihydrochloride salt.
工程９ Step 9
Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199
（式中の記号は、前記の通りである。）
　式（９）の化合物又はその塩は、式[ＶＩＩＩ]の化合物又はその塩を接触水素還元反応に付すことにより製造することができる。式[ＶＩＩＩ]の塩を用いる場合には、酢酸ナトリウム等の添加剤を加えてもよい。
　溶媒は、アルコール（メタノール、エタノール、１－プロパノール、２－プロパノール等）の単独、あるいはアルコールと芳香族炭化水素溶媒（トルエン、ベンゼン等）、エーテル溶媒（テトラヒドロフラン、ジエチルエーテル等）、エステル溶媒（酢酸エチル等）等との混合溶媒が例示される。好ましい溶媒は、メタノールである。
　パラジウム触媒としては、パラジウム炭素、パラジウム黒、水酸化パラジウム炭素等が例示される。好ましいパラジウム触媒は、１０％パラジウム炭素である。
　水素圧は０．１から１．０ＭＰａ、好ましい水素圧は０．３から０．４ＭＰａである。
　反応温度は０℃から５０℃、好ましくは１５℃から３０℃である。 (The symbols in the formula are as described above.)
The compound of formula (9) or a salt thereof can be produced by subjecting the compound of formula [VIII] or a salt thereof to a catalytic hydrogen reduction reaction. When the salt of the formula [VIII] is used, an additive such as sodium acetate may be added.
Solvents are alcohol (methanol, ethanol, 1-propanol, 2-propanol, etc.) alone, or alcohol and aromatic hydrocarbon solvents (toluene, benzene, etc.), ether solvents (tetrahydrofuran, diethyl ether, etc.), ester solvents (acetic acid, etc.) And a mixed solvent with ethyl and the like. A preferred solvent is methanol.
Examples of the palladium catalyst include palladium carbon, palladium black, palladium hydroxide carbon, and the like. A preferred palladium catalyst is 10% palladium on carbon.
The hydrogen pressure is 0.1 to 1.0 MPa, and the preferred hydrogen pressure is 0.3 to 0.4 MPa.
The reaction temperature is 0 ° C to 50 ° C, preferably 15 ° C to 30 ° C.
製造方法１－２ Manufacturing method 1-2
Figure JPOXMLDOC01-appb-C000200
Figure JPOXMLDOC01-appb-C000200
工程１ Process 1
Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201
（式中、Ｒ５は、Ｃ１－６アルキルであり、好ましくはＣ１－4アルキルであり、さらに好ましくはイソプロピルである。）
　式[ＸＸＶ]の化合物は、３－オキソシクロブタンカルボン酸と式Ｒ５－ＯＨのアルコールを触媒量の酸の存在下で反応させることにより製造することができる。
　式Ｒ５－ＯＨのアルコールは溶媒として使用することができる。溶媒は、メタノール、エタノール、１－プロパノール、２－プロパノールが例示される。好ましい溶媒は２－プロパノールである。
　触媒量の酸は、濃塩酸、濃硫酸、メタンスルホン酸、ｐ－トルエンスルホン酸等が例示される。好ましくは、濃硫酸である。
　触媒量は、３－オキソシクロブタンカルボン酸の重量に対し０．５００％から１０．０％が例示される。好ましい触媒量は、１．００％である。
　反応温度は、室温から還流温度が例示される。好ましい反応温度は、還流温度である。 (In the formula, R 5 is C 1-6 alkyl, preferably C 1-4 alkyl, and more preferably isopropyl.)
A compound of formula [XXV] can be prepared by reacting 3-oxocyclobutanecarboxylic acid with an alcohol of formula R 5 —OH in the presence of a catalytic amount of acid.
Alcohols of the formula R 5 —OH can be used as solvents. Examples of the solvent include methanol, ethanol, 1-propanol, and 2-propanol. A preferred solvent is 2-propanol.
Examples of the catalytic amount of acid include concentrated hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. Preferably, it is concentrated sulfuric acid.
The amount of the catalyst is exemplified by 0.500% to 10.0% based on the weight of 3-oxocyclobutanecarboxylic acid. A preferred amount of catalyst is 1.00%.
Examples of the reaction temperature include room temperature to reflux temperature. A preferred reaction temperature is the reflux temperature.
工程２ Process 2
Figure JPOXMLDOC01-appb-C000202
Figure JPOXMLDOC01-appb-C000202
（式中の記号は、前記の通りである。）
　式[ＸＸＶＩ]の化合物は、式[ＸＸＶ]の化合物と式Ｒ１－ＮＨ２の化合物を縮合し、続いてシアノ化剤とを反応させることにより製造することができる（ＴＥＴＲＡＨＥＤＲＯＮ　ＡＳＹＭＭＥＴＲＹ　１４（２００３）　４９７－５０２）。
　式[ＸＸＶ]の化合物と式Ｒ１－ＮＨ２の化合物の縮合反応において、式Ｒ１－ＮＨ2の化合物は、ベンジルアミン、３－クロロベンジルアミン、４－クロロベンジルアミン、３－メチルベンジルアミン、４－メチルベンジルアミン、３－メトキシベンジルアミン、４－メトキシベンジルアミンが例示される。好ましい式Ｒ１－ＮＨ２の化合物は、４－メトキシベンジルアミン又はベンジルアミンであり、さらに好ましくはベンジルアミンでる。
式Ｒ１－ＮＨ２の化合物の量は、式[ＸＸＶ]の化合物に対し１．００当量から２．００当量であり、好ましくは１．０５当量である。
　溶媒は、アルコール（メタノール、エタノール、２－プロパノール等）、エーテル（ジエチルエーテル、テトラヒドロフラン、シクロペンチルメチルエーテル等）、トルエン、水等の単独、あるいは混合溶媒が例示される。好ましい溶媒はトルエンである。
　シアノ化剤は、アセトンシアノヒドリン、トリメチルシリルシアニド、エチルシアノホルメート、シアン化ナトリウム、シアン化カリウムが例示される。好ましいシアノ化剤はアセトンシアノヒドリンである。
　反応温度は、室温から還流温度が例示される。好ましい反応温度は還流温度である。
　続くシアノ化剤との反応において、シアノ化剤の量は、式[ＸＸＶ]の化合物に対し１．００当量から３．００当量であり、好ましくは１．５０当量である。
　塩基としてトリエチルアミン、ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ピリジンが例示される。好ましい塩基はトリエチルアミンである。
　塩基の量は式[ＸＸＶ]の化合物に対し０．５００当量から３．００当量であり、好ましくは１．５０当量である。
　反応温度は、０℃から室温が例示される。好ましい反応温度は０℃である。 (The symbols in the formula are as described above.)
A compound of formula [XXVI] can be prepared by condensing a compound of formula [XXV] and a compound of formula R 1 —NH 2 followed by reaction with a cyanating agent (TETRAHEDRON ASYMMETRY 14 (2003)). 497-502).
In the condensation reaction of the compound of formula [XXV] and the compound of formula R 1 —NH 2 , the compound of formula R 1 —NH 2 is benzylamine, 3-chlorobenzylamine, 4-chlorobenzylamine, 3-methylbenzylamine , 4-methylbenzylamine, 3-methoxybenzylamine, 4-methoxybenzylamine. A preferred compound of formula R 1 —NH 2 is 4-methoxybenzylamine or benzylamine, more preferably benzylamine.
The amount of the compound of formula R 1 —NH 2 is from 1.00 equivalents to 2.00 equivalents, preferably 1.05 equivalents, relative to the compound of formula [XXV].
Examples of the solvent include alcohols (methanol, ethanol, 2-propanol, etc.), ethers (diethyl ether, tetrahydrofuran, cyclopentylmethyl ether, etc.), toluene, water and the like alone or a mixed solvent. A preferred solvent is toluene.
Examples of the cyanating agent include acetone cyanohydrin, trimethylsilyl cyanide, ethyl cyanoformate, sodium cyanide, and potassium cyanide. A preferred cyanating agent is acetone cyanohydrin.
Examples of the reaction temperature include room temperature to reflux temperature. The preferred reaction temperature is the reflux temperature.
In the subsequent reaction with the cyanating agent, the amount of the cyanating agent is 1.00 to 3.00 equivalents, preferably 1.50 equivalents, relative to the compound of formula [XXV].
Examples of the base include triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine. A preferred base is triethylamine.
The amount of the base is 0.500 equivalents to 3.00 equivalents, preferably 1.50 equivalents, relative to the compound of formula [XXV].
The reaction temperature is exemplified by 0 ° C. to room temperature. The preferred reaction temperature is 0 ° C.
工程３ Process 3
Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203
（式中の記号は、前記の通りである。）
　式[ＸＸＶＩＩ]の化合物は、式[ＸＸＶＩ]の化合物又はその塩とシアン酸カリウム又はシアン酸ナトリウムとを反応させることにより製造することができる。
　シアン酸カリウム又はシアン酸ナトリウムの量は、式[ＸＸＶＩ]の化合物に対し１．００当量から３．００当量が例示され、好ましくは１．１０当量である。
　溶媒は、アルコール（メタノール、エタノール、２－プロパノール等）、ＤＭＦ、ＤＭＳＯ（ジメチルスルホキシド）、酢酸、水等の単独、あるいは混合溶媒が例示される。好ましい溶媒は、酢酸－水の混合溶媒である。
　反応温度は、０℃から室温が例示される。好ましい反応温度は室温である。
　環化後、アミジンの酸加水分解において使用される酸として、塩酸、リン酸水溶液、硫酸水溶液が例示される。好ましい酸は、塩酸である。反応温度は、１０℃から４０℃が例示される。好ましい反応温度は室温である。 (The symbols in the formula are as described above.)
The compound of the formula [XXVII] can be produced by reacting the compound of the formula [XXVI] or a salt thereof with potassium cyanate or sodium cyanate.
The amount of potassium cyanate or sodium cyanate is, for example, 1.00 equivalent to 3.00 equivalent, preferably 1.10 equivalent, relative to the compound of formula [XXVI].
Examples of the solvent include alcohols (methanol, ethanol, 2-propanol, etc.), DMF, DMSO (dimethyl sulfoxide), acetic acid, water and the like alone or as a mixed solvent. A preferred solvent is a mixed solvent of acetic acid and water.
The reaction temperature is exemplified by 0 ° C. to room temperature. The preferred reaction temperature is room temperature.
Examples of the acid used in the acid hydrolysis of amidine after cyclization include hydrochloric acid, phosphoric acid aqueous solution, and sulfuric acid aqueous solution. A preferred acid is hydrochloric acid. The reaction temperature is exemplified by 10 ° C to 40 ° C. The preferred reaction temperature is room temperature.
工程４ Process 4
Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204
（式中の記号は、前記の通りである。）
　式[ＸＸＶＩＩＩ]の化合物は、式[ＸＸＶＩＩ]の化合物又はその塩とメチル化剤とを反応させることにより製造することができる。
　溶媒は、ＤＭＦ、ＤＭＳＯ（ジメチルスルホキシド）、ＤＭＡ、ＤＭＩ（１，３－ジメチル－２－イミダゾリジノン）等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＤＭＦである。
　メチル化剤としては、ヨウ化メチル、硫酸ジメチル、ｐ－トルエンスルホン酸メチル等が例示される。好ましいメチル化剤は、ヨウ化メチルである。
　メチル化剤の量は、式[ＸＸＶＩＩ]の化合物に対し１．００当量から２．００当量が例示され、好ましくは１．００当量である。
　塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等が例示される。好ましい塩基は、炭酸カリウムである。
　塩基の量は、式[ＸＸＶＩＩ]の化合物に対し１．００当量から２．００当量が例示され、好ましくは１．００当量である。
　反応温度は、０℃から室温であり、好ましくは室温である。 (The symbols in the formula are as described above.)
A compound of formula [XXVIII] can be produced by reacting a compound of formula [XXVII] or a salt thereof with a methylating agent.
Examples of the solvent include DMF, DMSO (dimethyl sulfoxide), DMA, DMI (1,3-dimethyl-2-imidazolidinone) and the like alone or as a mixed solvent. A preferred solvent is DMF.
Examples of the methylating agent include methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, and the like. A preferred methylating agent is methyl iodide.
The amount of the methylating agent is, for example, 1.00 equivalent to 2.00 equivalent, preferably 1.00 equivalent, relative to the compound of the formula [XXVII].
Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate and the like. A preferred base is potassium carbonate.
The amount of the base is, for example, 1.00 equivalent to 2.00 equivalent, preferably 1.00 equivalent, relative to the compound of the formula [XXVII].
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
工程５ Process 5
Figure JPOXMLDOC01-appb-C000205
Figure JPOXMLDOC01-appb-C000205
（式中の記号は、前記の通りである。）
　式[ＩＶ]の化合物又はその塩は、式[ＸＸＶＩＩＩ]の化合物の加水分解反応により製造することができる。式[ＸＸＶＩＩＩ]の化合物の加水分解反応は、アルカリ加水分解が好ましい。
　溶媒は、アルコール（メタノール、エタノール、２－プロパノール等）、水、トルエン、ＴＨＦ（テトラヒドロフラン）等の単独あるいは混合溶媒が例示される。好ましい溶媒は、２－プロパノールである。
　塩基としては、水酸化ナトリウム、水酸化カリウム等が例示される。好ましい塩基は、水酸化ナトリウムである。
　塩基の量は、式[ＸＸＶＩＩＩ]の化合物に対し１．００当量から２．００当量が例示され、好ましくは１．００当量である。
　反応温度は、０℃から室温であり、好ましくは０℃から５℃である。
　式[ＩＶ]の化合物は、式[ＩＶ－ａ]の化合物 (The symbols in the formula are as described above.)
The compound of formula [IV] or a salt thereof can be produced by hydrolysis reaction of the compound of formula [XXVIII]. The hydrolysis reaction of the compound of the formula [XXVIII] is preferably alkaline hydrolysis.
Examples of the solvent include alcohols (methanol, ethanol, 2-propanol and the like), water, toluene, THF (tetrahydrofuran) and the like alone or as a mixed solvent. A preferred solvent is 2-propanol.
Examples of the base include sodium hydroxide and potassium hydroxide. A preferred base is sodium hydroxide.
The amount of the base is, for example, 1.00 equivalent to 2.00 equivalent, preferably 1.00 equivalent, relative to the compound of the formula [XXVIII].
The reaction temperature is 0 ° C to room temperature, preferably 0 ° C to 5 ° C.
The compound of formula [IV] is a compound of formula [IV-a]
Figure JPOXMLDOC01-appb-C000206
Figure JPOXMLDOC01-appb-C000206
及び式[ＩＶ－ｂ]の化合物 And a compound of formula [IV-b]
Figure JPOXMLDOC01-appb-C000207
Figure JPOXMLDOC01-appb-C000207
を含む。式[ＩＶ－ａ]の化合物は、式[ＩＶ]の化合物から塩を形成することにより製造することができる。さらに再結晶などの精製により純度を向上させることができる。 including. A compound of formula [IV-a] can be prepared by forming a salt from a compound of formula [IV]. Furthermore, the purity can be improved by purification such as recrystallization.
　塩は、無機塩基との塩又は有機塩基との塩が例示される。好ましい塩はｎ－プロピルアミン、ｎ－ブチルアミン、ｔ－ブチルアミン、シクロヘキルアミン、ジシクロヘキルアミン、フェネチルアミン、（S）－フェネチルアミン、（R）－フェネチルアミン等の有機塩基との塩である。さらに好ましい塩は、ｎ－プロピルアミン塩である。
　無機塩基又は有機塩基の量は、式[ＩＶ]の化合物に対し０．９５０当量から１．５０当量が例示され、好ましくは０．９９５当量である。
　塩の形成及び再結晶で使用される溶媒は、メタノール、アセトニトリル、酢酸エチル、酢酸イソプロピル、トルエン等の単独あるいは混合溶媒が例示される。好ましい溶媒は、酢酸エチル－酢酸イソプロピルの混合溶媒である。
　反応温度は、０℃から７０℃が例示される。好ましい反応温度は室温である。
　式[ＩＶ－ａ]の化合物は、一般的な方法によって式[ＩＶ－ａ]の化合物の塩を中和又は酸性にすることにより製造することができる。一例としては、濃塩酸又は濃硫酸等の酸を用いて中和又は酸性にすることにより製造することができる。 Examples of the salt include a salt with an inorganic base or a salt with an organic base. Preferred salts are salts with organic bases such as n-propylamine, n-butylamine, t-butylamine, cyclohexylamine, dicyclohexylamine, phenethylamine, (S) -phenethylamine, (R) -phenethylamine. A more preferred salt is n-propylamine salt.
The amount of the inorganic base or the organic base is, for example, 0.950 equivalent to 1.50 equivalent, preferably 0.995 equivalent, relative to the compound of the formula [IV].
Examples of the solvent used for salt formation and recrystallization include methanol, acetonitrile, ethyl acetate, isopropyl acetate, toluene and the like alone or as a mixed solvent. A preferred solvent is a mixed solvent of ethyl acetate-isopropyl acetate.
The reaction temperature is exemplified by 0 ° C to 70 ° C. The preferred reaction temperature is room temperature.
The compound of the formula [IV-a] can be produced by neutralizing or acidifying the salt of the compound of the formula [IV-a] by a general method. As an example, it can manufacture by neutralizing or acidifying using acids, such as concentrated hydrochloric acid or concentrated sulfuric acid.
　式[ＩＶ－ａ]の化合物又はその塩から式（９）の化合物又はその塩への製造は、製造方法１－１工程５から工程９に準じて製造することができる。 Production of the compound of formula [IV-a] or a salt thereof to the compound of formula (9) or a salt thereof can be carried out according to Production Method 1-1, Step 5 to Step 9.
　製造方法１－２においては、工程２において３－オキソシクロブタンカルボン酸に比べそのエステルである式[ＸＸＶ]の化合物を用いることにより、式[ＸＸＶＩ]の化合物の立体選択性を向上させることができる。
　さらに、前記立体選択性が向上した式[ＸＸＶＩ]の化合物から工程３－５を経て製造した式[ＸＸＩＸ]の化合物は、その塩として有機塩基との塩を選択することにより、結晶化による目的物のロスを最小限にして高純度の式[ＩＶ－ａ]の化合物又はその塩を効率よく得ることができる。 In the production method 1-2, the stereoselectivity of the compound of the formula [XXVI] can be improved by using the compound of the formula [XXV] which is an ester compared to 3-oxocyclobutanecarboxylic acid in the step 2. .
Further, the compound of the formula [XXIX] produced from the compound of the formula [XXVI] having improved stereoselectivity through the step 3-5 is obtained by selecting a salt with an organic base as a salt thereof, thereby achieving the purpose of crystallization. A highly pure compound of the formula [IV-a] or a salt thereof can be obtained efficiently with a minimum of product loss.
製造方法２：式[ＸＶ]の化合物の製造方法 Production method 2: Method for producing compound of formula [XV]
Figure JPOXMLDOC01-appb-C000208
Figure JPOXMLDOC01-appb-C000208
（式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルであり、好ましくは無置換のベンジル又は４－メトキシベンジルであり、さらに好ましくは無置換のベンジル（単にベンジルとも言う。）である。Ｒ３はＣ１－４アルキルであり、好ましくはメチル又はエチルである。） Wherein R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy. Benzyl, or C 1-4 alkyl, preferably unsubstituted benzyl or 4-methoxybenzyl, more preferably unsubstituted benzyl (also simply referred to as benzyl) R 3 is C 1- 4 alkyl, preferably methyl or ethyl.)
工程１ Process 1
Figure JPOXMLDOC01-appb-C000209
Figure JPOXMLDOC01-appb-C000209
　式（１０）の化合物又はその塩は、プロピオル酸tert-ブチルとジエチルアミンとを反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＭｅＣＮである。
　反応温度は、０℃から室温であり、好ましくは室温である。 The compound of the formula (10) or a salt thereof can be produced by reacting tert-butyl propiolate with diethylamine.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, MeCN and the like alone or in combination. . A preferred solvent is MeCN.
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
工程２ Process 2
Figure JPOXMLDOC01-appb-C000210
Figure JPOXMLDOC01-appb-C000210
（式中の記号は、前記の通りである。）
　式[ＸＩＩ]の化合物又はその塩は、式（１０）の化合物又はその塩を塩基の存在下、式[ＸＩ]の化合物と反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＩ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＭｅＣＮである。
　塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等の有機塩基、又は炭酸水素カリウム等の無機塩基が例示される。好ましい塩基は、ピリジンである。
　反応温度は、０℃から室温であり、好ましくは０℃である。 (The symbols in the formula are as described above.)
A compound of formula [XII] or a salt thereof can be produced by reacting a compound of formula (10) or a salt thereof with a compound of formula [XI] in the presence of a base.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMI, MeCN and the like alone or in combination. A preferred solvent is MeCN.
Examples of the base include organic bases such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium hydrogen carbonate. A preferred base is pyridine.
The reaction temperature is from 0 ° C. to room temperature, preferably 0 ° C.
工程３ Process 3
Figure JPOXMLDOC01-appb-C000211
Figure JPOXMLDOC01-appb-C000211
（式中の記号は、前記の通りである。）
　式[ＸＩＶ]の化合物は、式[ＸＩＩ]の化合物又はその塩と式[ＸＩＩＩ]のシュウ酸ジ（Ｃ１－４アルキル）（例、シュウ酸ジエチル、シュウ酸ジメチル）とを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセンと無水リチウムブロミドの存在下で反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＭｅＣＮである。
　反応温度は、室温から８５℃であり、好ましくは７０℃である。 (The symbols in the formula are as described above.)
The compound of the formula [XIV] is a compound of the formula [XII] or a salt thereof and di (C 1-4 alkyl) oxalate of the formula [XIII] (eg, diethyl oxalate, dimethyl oxalate) -It can be produced by reacting diazabicyclo [5.4.0] -7-undecene with anhydrous lithium bromide.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, DMF, DMA, DMSO, DMI, MeCN and the like alone or in combination. A preferred solvent is MeCN.
The reaction temperature is from room temperature to 85 ° C, preferably 70 ° C.
工程４ Process 4
Figure JPOXMLDOC01-appb-C000212
Figure JPOXMLDOC01-appb-C000212
（式中の記号は、前記の通りである。）
　式[ＸＶ]の化合物又はその塩は、式[ＸＩＶ]の化合物を酸と反応させることにより製造することができる。
　溶媒は、ヘキサン、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は、酢酸エチルである。
　酸としては、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸等が例示される。好ましい酸は、4 mol/L 塩化水素の酢酸エチル溶液である。
　反応温度は、０℃から室温であり、好ましくは室温である。 (The symbols in the formula are as described above.)
The compound of the formula [XV] or a salt thereof can be produced by reacting the compound of the formula [XIV] with an acid.
Examples of the solvent include hexane, toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, water and the like alone or in a mixed solvent. Is done. A preferred solvent is ethyl acetate.
Examples of the acid include an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid. A preferred acid is 4 mol / L hydrogen chloride in ethyl acetate.
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
製造方法３
式［ＸＶＩＩ］の化合物の製造方法 Manufacturing method 3
Process for producing compound of formula [XVII]
Figure JPOXMLDOC01-appb-C000213
Figure JPOXMLDOC01-appb-C000213
　式［ＸＶＩＩ］の化合物は製造方法３－１又は製造方法３－２により製造することができる。 The compound of the formula [XVII] can be produced by the production method 3-1 or the production method 3-2.
製造方法３－１
工程１ Manufacturing method 3-1
Process 1
Figure JPOXMLDOC01-appb-C000214
Figure JPOXMLDOC01-appb-C000214
（式中の記号は、前記の通りである。）
　式［ＸＸ］の化合物又はその塩は、式（９）の化合物又はその塩と式［ＸＶ］の化合物又はその塩とを反応させることにより製造することができる。式（９）の化合物又はその塩と式［ＸＶ］の化合物又はその塩との反応は、有機塩基の存在下で行ってもよい。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、メタノール、エタノール、１－プロパノール、２－プロパノール、ＭｅＣＮ、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は、メタノールである。
　有機塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が例示される。好ましい塩基は、トリエチルアミンである。
　反応温度は、０℃から室温であり、好ましくは室温である。
　反応不純物を低減させるためには、式[ＸＶ]の化合物を反応進行に合わせて連続的にまたは分割して添加することが好ましい。 (The symbols in the formula are as described above.)
A compound of formula [XX] or a salt thereof can be produced by reacting a compound of formula (9) or a salt thereof with a compound of formula [XV] or a salt thereof. The reaction between the compound of formula (9) or a salt thereof and the compound of formula [XV] or a salt thereof may be performed in the presence of an organic base.
Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol , MeCN, water alone or a mixed solvent. A preferred solvent is methanol.
Examples of the organic base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is triethylamine.
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
In order to reduce reaction impurities, it is preferable to add the compound of the formula [XV] continuously or dividedly according to the progress of the reaction.
工程２ Process 2
Figure JPOXMLDOC01-appb-C000215
Figure JPOXMLDOC01-appb-C000215
（式中の記号は、前記の通りである。）
　式［ＸＶＩＩ］の化合物又はその塩は、式［ＸＸ］の化合物又はその塩を３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することができる。
　一の実施態様として、式[ＸＶＩＩ]の化合物又はその塩は、式[ＸＸ]の化合物又はその塩を塩基の存在下でクロロ炭酸イソブチル等のクロロ炭酸Ｃ１－４アルキルと反応させ、活性エステルに変換した後、３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、ＮＭＰ（１－メチル－２－ピロリドン）、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が例示される。好ましい塩基はジイソプロピルエチルアミンである。
　反応温度は、－５０℃から室温であり、好ましくは０℃である。
　他の実施態様として、式［ＸＶＩＩ］の化合物又はその塩は、式［ＸＸ］の化合物又はその塩を１，１’－カルボニルジイミダゾールと反応させ活性化した後、３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、ＮＭＰ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　反応温度は、０℃から室温であり、好ましくは室温である。
　他の実施態様として、式［ＸＶＩＩ］の化合物又はその塩は、式［ＸＸ］の化合物又はその塩を塩素化剤と反応させ、酸塩化物に変換した後、塩基の存在下で３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することもできる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、ＤＭＦ、ＮＭＰ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　塩素化剤としては、塩化チオニル、二塩化オキサリル等が例示される。好ましい塩素化剤は、塩化チオニルである。
　反応温度は、０℃から５０℃であり、好ましくは室温である。
　酸塩化物と３－クロロ－２－フルオロベンジルアミンとの反応は、塩基の存在下で行う。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、ＤＭＦ、ＮＭＰ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が例示される。好ましい塩基は、トリエチルアミンである。
　反応温度は、０℃から５０℃であり、好ましくは室温である。
　好ましい反応は、式[ＸＸ]の化合物又はその塩を塩基の存在下でクロロ炭酸イソブチル等のクロロ炭酸Ｃ１－４アルキルと反応させ、活性エステルに変換した後、３－クロロ－２－フルオロベンジルアミンと反応させることにより製造する方法である。 (The symbols in the formula are as described above.)
A compound of formula [XVII] or a salt thereof can be produced by reacting a compound of formula [XX] or a salt thereof with 3-chloro-2-fluorobenzylamine.
In one embodiment, a compound of formula [XVII] or a salt thereof is obtained by reacting a compound of formula [XX] or a salt thereof with a C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base. Can be prepared by reacting with 3-chloro-2-fluorobenzylamine.
Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP (1-methyl-2-pyrrolidone), Examples thereof include single or mixed solvents such as MeCN. A preferred solvent is NMP.
Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is diisopropylethylamine.
The reaction temperature is from −50 ° C. to room temperature, preferably 0 ° C.
In another embodiment, the compound of formula [XVII] or a salt thereof is activated by reacting the compound of formula [XX] or a salt thereof with 1,1′-carbonyldiimidazole, and then activating 3-chloro-2-fluoro It can be produced by reacting with benzylamine.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP, MeCN, etc., alone or in combination. Is done. A preferred solvent is NMP.
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
In another embodiment, the compound of formula [XVII] or a salt thereof is obtained by reacting a compound of formula [XX] or a salt thereof with a chlorinating agent to convert it to an acid chloride, and then in the presence of a base with 3-chloro It can also be produced by reacting with -2-fluorobenzylamine.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent. A preferred solvent is NMP.
Examples of the chlorinating agent include thionyl chloride and oxalyl dichloride. A preferred chlorinating agent is thionyl chloride.
The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
The reaction between the acid chloride and 3-chloro-2-fluorobenzylamine is carried out in the presence of a base.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent. A preferred solvent is NMP.
Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is triethylamine.
The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
A preferred reaction is to react a compound of formula [XX] or a salt thereof with a C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base, convert it to an active ester, and then 3-chloro-2-fluorobenzyl. It is a method of producing by reacting with an amine.
製造方法３－２
工程１ Manufacturing method 3-2
Process 1
Figure JPOXMLDOC01-appb-C000216
Figure JPOXMLDOC01-appb-C000216
（式中の記号は、前記の通りである。）
　式［ＸＶＩ］の化合物又はその塩は、式［ＸＶ］の化合物又はその塩を３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することができる。
　式［ＸＶＩ］の化合物又はその塩は、式［ＸＶ］の化合物又はその塩を塩素化剤と反応させ酸塩化物に変換した後、酸塩化物を塩基の存在下で３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することもできる。
　式［ＸＶ］の化合物又はその塩と塩素化剤との反応は、塩基の存在下で行ってもよい。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、ＤＭＦ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、トルエンとＤＭＦの混合溶媒である。
　塩素化剤としては、塩化チオニル、二塩化オキサリル等が例示される。好ましい塩素化剤は、塩化チオニルである。
　反応温度は、０℃から室温であり、好ましくは室温である。
　酸塩化物と３－クロロ－２－フルオロベンジルアミンとの反応は、塩基の存在下で行う。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、ＤＭＦ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、トルエンとＤＭＦの混合溶媒である。
　塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が例示される。好ましい塩基は、トリエチルアミンである。
　反応温度は、－７８℃から０℃であり、好ましくは－５０℃である。 (The symbols in the formula are as described above.)
The compound of formula [XVI] or a salt thereof can be produced by reacting the compound of formula [XV] or a salt thereof with 3-chloro-2-fluorobenzylamine.
The compound of the formula [XVI] or a salt thereof is converted into an acid chloride by reacting the compound of the formula [XV] or a salt thereof with a chlorinating agent, and then the acid chloride is converted into 3-chloro-2- It can also be produced by reacting with fluorobenzylamine.
The reaction of the compound of the formula [XV] or a salt thereof and the chlorinating agent may be performed in the presence of a base.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF and the like alone or in a mixed solvent. A preferred solvent is a mixed solvent of toluene and DMF.
Examples of the chlorinating agent include thionyl chloride and oxalyl dichloride. A preferred chlorinating agent is thionyl chloride.
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
The reaction between the acid chloride and 3-chloro-2-fluorobenzylamine is carried out in the presence of a base.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF and the like alone or in a mixed solvent. A preferred solvent is a mixed solvent of toluene and DMF.
Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is triethylamine.
The reaction temperature is -78 ° C to 0 ° C, preferably -50 ° C.
工程２ Process 2
Figure JPOXMLDOC01-appb-C000217
Figure JPOXMLDOC01-appb-C000217
（式中の記号は、前記の通りである。）
　式［ＸＶＩＩ］の化合物又はその塩は、式（９）の化合物又はその塩と式［ＸＶＩ］の化合物又はその塩とを塩基の存在下で反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、メタノール、エタノール、１－プロパノール、２－プロパノール、ＭｅＣＮ、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は、メタノールである。
　塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン等の有機塩基が例示される。好ましい有機塩基は、トリエチルアミンである。
　反応温度は、室温から８０℃であり、好ましくは５５℃から６０℃である。
　反応不純物を低減させるためには、式[ＸＶＩ]の化合物を反応進行に合わせて連続的にまたは分割して添加することが好ましい。 (The symbols in the formula are as described above.)
A compound of formula [XVII] or a salt thereof can be produced by reacting a compound of formula (9) or a salt thereof with a compound of formula [XVI] or a salt thereof in the presence of a base.
Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol, MeCN And a single or mixed solvent such as water. A preferred solvent is methanol.
Examples of the base include organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene. A preferred organic base is triethylamine.
The reaction temperature is from room temperature to 80 ° C, preferably from 55 ° C to 60 ° C.
In order to reduce reaction impurities, it is preferable to add the compound of the formula [XVI] continuously or divided according to the progress of the reaction.
製造方法４：式（１８）の化合物の製造方法 Production method 4: Production method of compound of formula (18)
Figure JPOXMLDOC01-appb-C000218
Figure JPOXMLDOC01-appb-C000218
　式（１８）の化合物は、製造方法４－１又は製造方法４－２により製造することができる。
製造方法４－１
工程１ The compound of formula (18) can be produced by production method 4-1, or production method 4-2.
Manufacturing method 4-1
Process 1
Figure JPOXMLDOC01-appb-C000219
Figure JPOXMLDOC01-appb-C000219
（式中、Ｒ２は、前記の通りである。ただし、無置換又はハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニルは除く。）
　式（１８）の化合物又はその塩は、式［ＸＶＩＩ］の化合物又はその塩を酸と反応させることにより製造することができる。
　残存Pdを低減する場合には、式［ＸＶＩＩ］の化合物又はその塩の溶液をカルボラフィン(登録商標)などの活性炭で処理するのが好ましい。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、メタノール、エタノール、１－プロパノール、２－プロパノール、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は、トルエンである。
　酸としては、トリフルオロ酢酸、塩酸、塩化マグネシウム等が例示される。好ましい酸は、トリフルオロ酢酸である。
　反応温度は、０℃から５０℃であり、好ましくは５℃から室温である。 (Wherein R 2 is as defined above, except for phenyl which is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro.)
The compound of the formula (18) or a salt thereof can be produced by reacting the compound of the formula [XVII] or a salt thereof with an acid.
When reducing the residual Pd, it is preferable to treat the solution of the compound of the formula [XVII] or a salt thereof with activated carbon such as Carborafine (registered trademark).
Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol, water Examples thereof include single or mixed solvents. A preferred solvent is toluene.
Examples of the acid include trifluoroacetic acid, hydrochloric acid, magnesium chloride and the like. A preferred acid is trifluoroacetic acid.
The reaction temperature is 0 ° C. to 50 ° C., preferably 5 ° C. to room temperature.
製造方法４－２
工程１ Manufacturing method 4-2
Process 1
Figure JPOXMLDOC01-appb-C000220
Figure JPOXMLDOC01-appb-C000220
（式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルであり、好ましくは無置換ベンジル又は４－メトキシベンジルであり、さらに好ましくは無置換のベンジル（単にベンジルとも言う。）である。）
　式［ＸＸＩ］の化合物又はその塩は、３－（ジメチルアミノ）アクリロニトリルを塩基の存在下、式[ＸＩ']の化合物と反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＩ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＭｅＣＮである。
　塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等の有機塩基、又は炭酸水素カリウム等の無機塩基が例示される。好ましい塩基は、ピリジンである。
　反応温度は、－２０℃から室温であり、好ましくは０℃である。 Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl, preferably unsubstituted benzyl or 4-methoxybenzyl, more preferably unsubstituted benzyl (also simply referred to as benzyl).
A compound of the formula [XXI] or a salt thereof can be produced by reacting 3- (dimethylamino) acrylonitrile with a compound of the formula [XI ′] in the presence of a base.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMI, MeCN and the like alone or in combination. A preferred solvent is MeCN.
Examples of the base include organic bases such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium hydrogen carbonate. A preferred base is pyridine.
The reaction temperature is from −20 ° C. to room temperature, preferably 0 ° C.
式[XXI]の化合物又はその塩は、製造方法２工程２で得られる式[ＸＩＩ]の化合物又はその塩に比べ、結晶性が良いため不純物の除去に有利であり、単離が容易である。 The compound of the formula [XXI] or a salt thereof is advantageous in removing impurities because of its good crystallinity compared to the compound of the formula [XII] obtained in Step 2 of the production method 2 or a salt thereof, and is easily isolated. .
工程２ Process 2
Figure JPOXMLDOC01-appb-C000221
Figure JPOXMLDOC01-appb-C000221
（式中の記号は、前記の通りである。）
　式［ＸＸＩＩ］の化合物又はその塩は、［ＸＸＩ］の化合物又はその塩とシュウ酸ジメチルとを、塩基の存在下で反応させることにより製造することができる。塩基が、１，８－ジアザビシクロ［５．４．０］－７－ウンデセンである場合、無水リチウムブロミドを加える。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＭｅＣＮである。
　塩基としては、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン、ナトリウムtert-ブトキシド、カリウムtert-ブトキシド等が例示される。好ましい塩基は、１，８－ジアザビシクロ［５．４．０］－７－ウンデセンである。
　反応温度は、０℃から７０℃であり、好ましくは室温である。 (The symbols in the formula are as described above.)
The compound of formula [XXII] or a salt thereof can be produced by reacting the compound of [XXI] or a salt thereof with dimethyl oxalate in the presence of a base. When the base is 1,8-diazabicyclo [5.4.0] -7-undecene, anhydrous lithium bromide is added.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, DMF, DMA, DMSO, DMI, MeCN and the like alone or in combination. A preferred solvent is MeCN.
Examples of the base include 1,8-diazabicyclo [5.4.0] -7-undecene, sodium tert-butoxide, potassium tert-butoxide and the like. A preferred base is 1,8-diazabicyclo [5.4.0] -7-undecene.
The reaction temperature is 0 ° C. to 70 ° C., preferably room temperature.
式[XXII]の化合物は、製造方法２工程３で得られる式[ＸＩＶ]の化合物に比べ、結晶性が良いため不純物の除去に有利であり、単離が容易である。また、本反応は、製造方法２工程３に比べて低温で行うことができる。 The compound of the formula [XXII] is advantageous in removing impurities and easy to isolate because it has better crystallinity than the compound of the formula [XIV] obtained in the production method 2 step 3. Moreover, this reaction can be performed at low temperature compared with the manufacturing method 2 process 3. FIG.
工程３ Process 3
Figure JPOXMLDOC01-appb-C000222
Figure JPOXMLDOC01-appb-C000222
（式中の記号は、前記の通りである。）
　式［ＸＸＩＩＩ］の化合物又はその塩は、式（９）の化合物又はその塩と式［ＸＸＩＩ］の化合物又はその塩とを反応させることにより製造することができる。式（９）の化合物又はその塩と式［ＸＸＩＩ］の化合物又はその塩との反応は、有機塩基の存在下で行ってもよい。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、メタノール、エタノール、１－プロパノール、２－プロパノール、ＭｅＣＮ、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は、メタノールである。
　有機塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が例示される。好ましい有機塩基は、トリエチルアミンである。
　反応温度は、０℃から６０℃であり、好ましくは室温である。
　反応不純物を低減させるためには、式[ＸＸＩＩ]の化合物を反応進行に合わせて連続的にまたは分割して添加することが好ましい。 (The symbols in the formula are as described above.)
The compound of formula [XXIII] or a salt thereof can be produced by reacting the compound of formula (9) or a salt thereof with the compound of formula [XXII] or a salt thereof. The reaction between the compound of formula (9) or a salt thereof and the compound of formula [XXII] or a salt thereof may be performed in the presence of an organic base.
Solvents are toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, methanol, ethanol, 1-propanol, 2-propanol , MeCN, water alone or a mixed solvent. A preferred solvent is methanol.
Examples of the organic base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred organic base is triethylamine.
The reaction temperature is 0 ° C. to 60 ° C., preferably room temperature.
In order to reduce reaction impurities, it is preferable to add the compound of the formula [XXII] continuously or dividedly according to the progress of the reaction.
工程４ Process 4
Figure JPOXMLDOC01-appb-C000223
Figure JPOXMLDOC01-appb-C000223
（式中の記号は、前記の通りである。）
　式（２４）の化合物又はその塩は、式［ＸＸＩＩＩ］の化合物又はその塩をアルカリ水溶液と反応させることにより製造することができる。
　アルカリ水溶液としては、水酸化ナトリウム水溶液、水酸化カリウム水溶液等が例示される。好ましいアルカリ水溶液は、25 %水酸化ナトリウム水溶液である。
　溶媒は、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、tert－ブタノール、２－メチルプロピルアルコール、２－メチル－２－ブタノール、エチレングリコール、プロピレングリコール、ＤＭＩ、ＮＭＰ、ＤＭＳＯ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＤＭＳＯである。
　反応温度は７０℃から１４０℃であり、好ましくは９５℃である。 (The symbols in the formula are as described above.)
The compound of the formula (24) or a salt thereof can be produced by reacting the compound of the formula [XXIII] or a salt thereof with an alkaline aqueous solution.
Examples of the alkaline aqueous solution include a sodium hydroxide aqueous solution and a potassium hydroxide aqueous solution. A preferred aqueous alkaline solution is a 25% aqueous sodium hydroxide solution.
Solvents are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, 2-methylpropyl alcohol, 2-methyl-2-butanol, ethylene glycol, propylene glycol, DMI, NMP And a single or mixed solvent such as DMSO. A preferred solvent is DMSO.
The reaction temperature is 70 ° C to 140 ° C, preferably 95 ° C.
工程５ Process 5
Figure JPOXMLDOC01-appb-C000224
Figure JPOXMLDOC01-appb-C000224
　式（１８）の化合物又はその塩は、式（２４）の化合物又はその塩を３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することができる。
　一の実施態様として、式（１８）の化合物又はその塩は、式（２４）の化合物又はその塩を塩基の存在下、クロロ炭酸イソブチル等のクロロ炭酸Ｃ１－４アルキルと反応させ、活性エステルに変換した後、３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、ＮＭＰ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が例示される。好ましい塩基は、ジイソプロピルエチルアミンである。
　反応温度は、－５０℃から室温であり、好ましくは０℃である。
　他の実施態様として、式（１８）の化合物又はその塩は、式（２４）の化合物又はその塩をカルボジイミダゾールと反応させ活性化した後、３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することができる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、酢酸エチル、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、ＤＭＩ、ＮＭＰ、ＭｅＣＮ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　反応温度は、０℃から室温であり、好ましくは室温である。
　他の実施態様として、式（１８）の化合物又はその塩は、式（２４）の化合物又はその塩を塩素化剤と反応させ、酸塩化物に変換した後、塩基の存在下で３－クロロ－２－フルオロベンジルアミンと反応させることにより製造することもできる。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、ＤＭＦ、ＮＭＰ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　塩素化剤としては、塩化チオニル、二塩化オキサリル等が例示される。好ましい塩素化剤は、塩化チオニルである。
　反応温度は、－５℃から室温であり、好ましくは０℃から１０℃である。
　酸塩化物と３－クロロ－２－フルオロベンジルアミンとの反応は、塩基の存在下で行う。
　溶媒は、トルエン、ＴＨＦ、１，２－ジメトキシエタン、シクロペンチルメチルエーテル、１，４－ジオキサン、ジクロロメタン、クロロホルム、ＤＭＦ、ＮＭＰ等の単独あるいは混合溶媒が例示される。好ましい溶媒は、ＮＭＰである。
　塩基としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等が例示される。好ましい塩基は、トリエチルアミンである。
　反応温度は、－５℃から室温であり、好ましくは室温である。
　好ましい反応は、式（２４）の化合物又はその塩を塩基の存在下、クロロ炭酸イソブチル等のクロロ炭酸Ｃ１－４アルキルと反応させ、活性エステルに変換した後、３－クロロ－２－フルオロベンジルアミンと反応させることにより製造する方法である。 The compound of formula (18) or a salt thereof can be produced by reacting the compound of formula (24) or a salt thereof with 3-chloro-2-fluorobenzylamine.
In one embodiment, the compound of formula (18) or a salt thereof is obtained by reacting a compound of formula (24) or a salt thereof with C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base. Can be prepared by reacting with 3-chloro-2-fluorobenzylamine.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP, MeCN, etc., alone or in combination. Is done. A preferred solvent is NMP.
Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is diisopropylethylamine.
The reaction temperature is from −50 ° C. to room temperature, preferably 0 ° C.
In another embodiment, the compound of formula (18) or a salt thereof is activated by reacting the compound of formula (24) or a salt thereof with carbodiimidazole and then reacting with 3-chloro-2-fluorobenzylamine. Can be manufactured.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentyl methyl ether, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, DMF, DMA, DMSO, DMI, NMP, MeCN, etc., alone or in combination. Is done. A preferred solvent is NMP.
The reaction temperature is from 0 ° C. to room temperature, preferably room temperature.
In another embodiment, the compound of formula (18) or a salt thereof is obtained by reacting a compound of formula (24) or a salt thereof with a chlorinating agent to convert to an acid chloride, and then in the presence of a base with 3-chloro It can also be produced by reacting with -2-fluorobenzylamine.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent. A preferred solvent is NMP.
Examples of the chlorinating agent include thionyl chloride and oxalyl dichloride. A preferred chlorinating agent is thionyl chloride.
The reaction temperature is −5 ° C. to room temperature, preferably 0 ° C. to 10 ° C.
The reaction between the acid chloride and 3-chloro-2-fluorobenzylamine is carried out in the presence of a base.
Examples of the solvent include toluene, THF, 1,2-dimethoxyethane, cyclopentylmethyl ether, 1,4-dioxane, dichloromethane, chloroform, DMF, NMP and the like alone or as a mixed solvent. A preferred solvent is NMP.
Examples of the base include pyridine, triethylamine, diisopropylethylamine and the like. A preferred base is triethylamine.
The reaction temperature is from −5 ° C. to room temperature, preferably room temperature.
A preferred reaction is that the compound of formula (24) or a salt thereof is reacted with C 1-4 alkyl chlorocarbonate such as isobutyl chlorocarbonate in the presence of a base, converted to an active ester, and then 3-chloro-2-fluorobenzyl It is a method of producing by reacting with an amine.
製造方法５：式（１９）の化合物の製造方法
　式（１９）の化合物は、製造方法５－１又は製造方法５－２により製造することができる。
製造方法５－１
工程１ Production Method 5: Production Method of Compound of Formula (19) The compound of formula (19) can be produced by production method 5-1 or production method 5-2.
Manufacturing method 5-1
Process 1
Figure JPOXMLDOC01-appb-C000225
Figure JPOXMLDOC01-appb-C000225
　式（１９）の化合物は、式（１８）の化合物に塩基を加えて造塩した後、再結晶することにより製造することができる。
　溶媒は、ＴＨＦ、１，２－ジメトキシエタン、１，４－ジオキサン、アセトン、ＭＥＫ（メチルエチルケトン）、ＭＩＢＫ（メチルイソブチルケトン）、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、tert-ブタノール、１－ペンタノール、ＭｅＣＮ、プロピオニトリル、水等の単独あるいは混合溶媒が例示される。好ましい溶媒は、水とエタノールの混合溶媒である。
　塩基としては、水酸化ナトリウム、ナトリウムtert-ブトキシド等が例示される。好ましい塩基は、水酸化ナトリウムである。
　反応温度は、０℃から７０℃であり、好ましくは室温である。 The compound of formula (19) can be produced by adding a base to the compound of formula (18) to form a salt, and then recrystallizing.
Solvents are THF, 1,2-dimethoxyethane, 1,4-dioxane, acetone, MEK (methyl ethyl ketone), MIBK (methyl isobutyl ketone), DMF, DMA, DMSO, methanol, ethanol, 1-propanol, 2-propanol, Examples thereof include 1-butanol, 2-butanol, tert-butanol, 1-pentanol, MeCN, propionitrile, water and the like alone or in a mixed solvent. A preferred solvent is a mixed solvent of water and ethanol.
Examples of the base include sodium hydroxide, sodium tert-butoxide and the like. A preferred base is sodium hydroxide.
The reaction temperature is 0 ° C. to 70 ° C., preferably room temperature.
製造方法５-２
工程１ Manufacturing method 5-2
Process 1
Figure JPOXMLDOC01-appb-C000226
Figure JPOXMLDOC01-appb-C000226
（式中の記号は、前記の通りである。）
　式（１９）の化合物は、式［ＸＶＩＩ］の化合物又はその塩と塩基とを反応させることにより製造することができる。
　溶媒は、ＤＭＦ、ＤＭＡ、ＤＭＳＯ、メタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、２－ブタノール、tert-ブタノール、１－ペンタノール、ＭｅＣＮ、プロピオニトリル等と水の混合溶媒が例示される。好ましい溶媒は、ＤＭＳＯと水の混合溶媒である。
　塩基としては、水酸化ナトリウム、ナトリウムtert-ブトキシド等が例示される。好ましい塩基は、4 mol/L水酸化ナトリウム水溶液である。
　反応温度は、室温から９０℃であり、好ましくは８０℃である。 (The symbols in the formula are as described above.)
The compound of the formula (19) can be produced by reacting the compound of the formula [XVII] or a salt thereof with a base.
The solvent is a mixed solvent of DMF, DMA, DMSO, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, 1-pentanol, MeCN, propionitrile, etc. and water. Illustrated. A preferred solvent is a mixed solvent of DMSO and water.
Examples of the base include sodium hydroxide, sodium tert-butoxide and the like. A preferred base is a 4 mol / L aqueous sodium hydroxide solution.
The reaction temperature is from room temperature to 90 ° C, preferably 80 ° C.
　次に、本発明化合物の製造方法を、実施例によって具体的に説明する。しかしながら、本発明はこれらの実施例によって限定されるものではない。
　化合物（８’）の製造（実施例１工程８）、化合物（１７）の製造（実施例３工程２、実施例４工程２）、化合物（１８）の製造（実施例３工程３）および化合物（２０）の製造（実施例４工程１）において種晶が用いられているが、これらの化合物については種晶を用いなくても実施例記載の方法に準じて目的物の結晶が得られた。
　ここで、本明細書において用いられる略号の意味を以下に示す。
ＭｅＣＮ：アセトニトリル
ＴＨＦ：テトラヒドロフラン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＭＳＯ：ジメチルスルホキシド
ＴＦＡ：トリフルオロ酢酸
　また、以下の１Ｈ－ＮＭＲ値は、分解能４００ＭＨｚで測定した。 Next, the manufacturing method of this invention compound is demonstrated concretely by an Example. However, the present invention is not limited to these examples.
Production of Compound (8 ′) (Example 1 Step 8), Production of Compound (17) (Example 3 Step 2, Example 4 Step 2), Production of Compound (18) (Example 3 Step 3) and Compound Seed crystals were used in the production of (20) (Example 4, Step 1), but for these compounds, crystals of the target product were obtained according to the method described in the Examples without using seed crystals. .
Here, the meanings of the abbreviations used in this specification are shown below.
MeCN: acetonitrile THF: tetrahydrofuran DMF: N, N-dimethylformamide DMSO: dimethylsulfoxide TFA: trifluoroacetic acid The following 1 H-NMR values were measured at a resolution of 400 MHz.
実施例１
シス-3-(メトキシメチル)-1-[(メチルアミノ)メチル]シクロブチルアミン（９）の製造 Example 1
Production of cis-3- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine (9)
工程１ Process 1
Figure JPOXMLDOC01-appb-C000227
Figure JPOXMLDOC01-appb-C000227
　3-オキソシクロブタンカルボン酸（20.0 g, 175 mmol）の水（130 mL）溶液に28%アンモニア水（12.60 g, 207 mmol）を滴下し、溶液のpHを8.3に調整した。この溶液に塩化アンモニウム（9.36 g, 175 mmol）、炭酸アンモニウム（33.6 g, 350 mmol）及びシアン化カリウム（10.8 g 166 mmol）を添加した。この混合液を55℃にて18時間撹拌した。反応終了後、この溶液を室温に冷却した。室温にて濃塩酸を滴下し、溶液のpHを4.4に調整した。得られた懸濁液を2時間30分撹拌後、濃塩酸を滴下し、溶液のpHを0.2に調整した。これを室温で1時間撹拌した後、75℃で2時間撹拌した。この懸濁液を室温に戻した後、さらに氷冷下で冷却し、2時間撹拌した。析出した結晶を濾取し、結晶を洗液のpHが2.5以上になるまで、冷却した水（120 mL）で洗浄した。得られた湿結晶を減圧乾燥することで6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸（１）（23.13 g, 126 mmol）を収率72.0%で得た。
　上記の方法に準じて、3-オキソシクロブタンカルボン酸（71.2 kg, 624 mol）を使用し反応を行った。
　3-オキソシクロブタンカルボン酸（71.2 kg, 624 mol）の水（462.8 L）溶液に28%アンモニア水（40.44 kg, 665 mol）を滴下し、溶液のpHを8.7に調整した。この溶液に塩化アンモニウム（33.4 kg, 624 mol）、炭酸アンモニウム（119.9 kg, 1248 mol）及びシアン化カリウム（38.6 kg, 593 mol）を添加した。この混合液を55℃にて22.5時間撹拌した。反応終了後、この溶液を室温に冷却した。室温にて濃塩酸を滴下し、溶液のpHを4.0に調整した。得られた懸濁液を2時間撹拌後、濃塩酸を滴下し、溶液のpHを0.4に調整した。これを室温で15時間撹拌した後、70℃で2時間撹拌した。この懸濁液を室温に戻した後、さらに氷冷下で冷却し、17時間撹拌した。析出した結晶を濾取し、結晶を洗液のpHが2.5以上になるまで、冷却した水（427 L）で洗浄した。得られた湿結晶を減圧乾燥することで6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸（１）（85.9 kg, 466 mol）を収率74.7%で得た。
　上記の方法に準じて合成した化合物（１）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 12.35 (brs, 1.00H), 10.60 (brs, 1.00H), 8.47 (s, 0.33H), 8.23 (s, 0.67H), 3.18-3.09 (m, 0.33H), 3.01-2.92 (m, 0.67H), 2.70-2.65 (m, 0.67H), 2.56-2.49 (m, 1.33H), 2.44-2.30 (m, 2.00H).
MS: m/z = 183 [M-H]- 28% aqueous ammonia (12.60 g, 207 mmol) was added dropwise to a solution of 3-oxocyclobutanecarboxylic acid (20.0 g, 175 mmol) in water (130 mL) to adjust the pH of the solution to 8.3. To this solution was added ammonium chloride (9.36 g, 175 mmol), ammonium carbonate (33.6 g, 350 mmol) and potassium cyanide (10.8 g 166 mmol). The mixture was stirred at 55 ° C. for 18 hours. After completion of the reaction, the solution was cooled to room temperature. Concentrated hydrochloric acid was added dropwise at room temperature to adjust the pH of the solution to 4.4. The resulting suspension was stirred for 2 hours and 30 minutes, and concentrated hydrochloric acid was added dropwise to adjust the pH of the solution to 0.2. This was stirred at room temperature for 1 hour and then stirred at 75 ° C. for 2 hours. The suspension was returned to room temperature, further cooled under ice cooling, and stirred for 2 hours. The precipitated crystals were collected by filtration, and the crystals were washed with cooled water (120 mL) until the pH of the washing solution reached 2.5 or higher. The obtained wet crystals were dried under reduced pressure to obtain 6,8-dioxo-5,7-diazaspiro [3.4] octane-2-carboxylic acid (1) (23.13 g, 126 mmol) in a yield of 72.0%.
According to the above method, the reaction was carried out using 3-oxocyclobutanecarboxylic acid (71.2 kg, 624 mol).
To a solution of 3-oxocyclobutanecarboxylic acid (71.2 kg, 624 mol) in water (462.8 L), 28% aqueous ammonia (40.44 kg, 665 mol) was added dropwise to adjust the pH of the solution to 8.7. To this solution, ammonium chloride (33.4 kg, 624 mol), ammonium carbonate (119.9 kg, 1248 mol) and potassium cyanide (38.6 kg, 593 mol) were added. The mixture was stirred at 55 ° C. for 22.5 hours. After completion of the reaction, the solution was cooled to room temperature. Concentrated hydrochloric acid was added dropwise at room temperature to adjust the pH of the solution to 4.0. After stirring the resulting suspension for 2 hours, concentrated hydrochloric acid was added dropwise to adjust the pH of the solution to 0.4. This was stirred at room temperature for 15 hours and then stirred at 70 ° C. for 2 hours. The suspension was returned to room temperature, further cooled under ice cooling, and stirred for 17 hours. The precipitated crystals were collected by filtration, and the crystals were washed with cooled water (427 L) until the pH of the washing solution reached 2.5 or higher. The obtained wet crystals were dried under reduced pressure to obtain 6,8-dioxo-5,7-diazaspiro [3.4] octane-2-carboxylic acid (1) (85.9 kg, 466 mol) in a yield of 74.7%.
NMR and MS were measured for the compound (1) synthesized according to the above method.
1 H-NMR (DMSO-d 6 ) δ: 12.35 (brs, 1.00H), 10.60 (brs, 1.00H), 8.47 (s, 0.33H), 8.23 (s, 0.67H), 3.18-3.09 (m, 0.33H), 3.01-2.92 (m, 0.67H), 2.70-2.65 (m, 0.67H), 2.56-2.49 (m, 1.33H), 2.44-2.30 (m, 2.00H).
MS: m / z = 183 [MH] -
工程２ Process 2
Figure JPOXMLDOC01-appb-C000228
Figure JPOXMLDOC01-appb-C000228
　カッターミルにより粉砕した6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸（１）（50.75 kg, 275 mol）のN,N-ジメチルホルムアミド（152 L）懸濁液を、アルゴン気流下、45℃で撹拌し、塊を消失させた後、室温に冷却した。この懸濁液に室温にて炭酸カリウム（16.8 kg, 121 mol, 0.44 eq.）を添加し、30分撹拌した後、ヨウ化メチル（17.2 kg, 121 mol, 0.44 eq.）を滴下し、2時間以上撹拌した。上記炭酸カリウムの添加及びヨウ化メチルの滴下操作をあと4回繰り返し、合計で炭酸カリウム（84.0 kg, 605 mol, 2.2 eq.）及びヨウ化メチル（86.0 kg, 605 mol, 2.2 eq.）を反応混合液に加えた。この混合液を最後の試薬添加終了から27℃で25時間撹拌した。反応終了後、この混合液を10℃に冷却し、水（508 L）を滴下した。水の滴下終了後、得られた懸濁液を5℃で18時間撹拌した。析出した結晶を濾取し、結晶を洗液のpHが7になるまで、冷却した水（305 L）で洗浄した。得られた湿結晶を減圧乾燥することで7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸メチル（２）とそのトランス異性体の混合物の粗結晶（28.1 kg, 132 mol）を収率48.0%で得た。
　得られた化合物（２）とそのトランス異性体の混合物の粗結晶（28.1 kg, 132 mol）のメタノール（197 L）懸濁液をアルゴン気流下、66℃で還流し、固体を溶解させた。この溶液を57℃に冷却し、30分撹拌した後、7℃まで冷却し、2時間撹拌した。析出した結晶を濾取し、結晶を冷却したメタノール（56 L）で洗浄した。得られた湿結晶を減圧乾燥することで7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸メチル（２）（24.2 kg, 114 mol）を収率86.3%で得た。
　上記の方法に準じて合成した化合物（２）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 8.56 (s, 1H), 3.63 (s, 3H), 3.15-3.06 (m, 1H), 2.81 (s, 3H), 2.61-2.43 (m, 4H).
MS: m/z = 213 [M+H]+
　得られた化合物（２）は以下の分析条件でcis体：trans体＝99：1であった。
HPLC分析条件
カラム：Atlantis(登録商標) T3 : 3 μm、4.6 mm×50 mm (Waters)
カラム温度：40℃付近の一定温度
移動相：移動相A：0.01%TFA水溶液
　　　　移動相B：MeCN
グラジエント条件：
時間（分）    0    5  15  20   25
A(%)　　　  100  100  50   0  100
B(%)　　　    0    0  50  95    0
流速：1.0 mL/分
検出方法：UV 220 nm
参考；保持時間：cis体（約12.9分）、trans体（約12.6分） A suspension of N, N-dimethylformamide (152 L) of 6,8-dioxo-5,7-diazaspiro [3.4] octane-2-carboxylic acid (1) (50.75 kg, 275 mol) pulverized by a cutter mill The mixture was stirred at 45 ° C. under an argon stream, and the mass was disappeared, followed by cooling to room temperature. To this suspension, potassium carbonate (16.8 kg, 121 mol, 0.44 eq.) Was added at room temperature, stirred for 30 minutes, and methyl iodide (17.2 kg, 121 mol, 0.44 eq.) Was added dropwise. Stir for more than an hour. The above potassium carbonate addition and methyl iodide dropping operation were repeated four more times, for a total reaction of potassium carbonate (84.0 kg, 605 mol, 2.2 eq.) And methyl iodide (86.0 kg, 605 mol, 2.2 eq.) Added to the mixture. The mixture was stirred at 27 ° C. for 25 hours after the last reagent addition. After completion of the reaction, the mixture was cooled to 10 ° C. and water (508 L) was added dropwise. After the dropwise addition of water, the resulting suspension was stirred at 5 ° C. for 18 hours. The precipitated crystals were collected by filtration, and the crystals were washed with cooled water (305 L) until the pH of the washing solution became 7. The resulting wet crystals were dried under reduced pressure to give a crude mixture of methyl 7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylate (2) and its trans isomer. Crystals (28.1 kg, 132 mol) were obtained with a yield of 48.0%.
A suspension of crude crystals (28.1 kg, 132 mol) of a mixture of the obtained compound (2) and its trans isomer in methanol (197 L) was refluxed at 66 ° C. under an argon stream to dissolve the solid. The solution was cooled to 57 ° C. and stirred for 30 minutes, then cooled to 7 ° C. and stirred for 2 hours. The precipitated crystals were collected by filtration and washed with cooled methanol (56 L). The obtained wet crystals were dried under reduced pressure to obtain methyl 7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylate (2) (24.2 kg, 114 mol). Obtained at a rate of 86.3%.
About compound (2) synthesize | combined according to said method, NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 8.56 (s, 1H), 3.63 (s, 3H), 3.15-3.06 (m, 1H), 2.81 (s, 3H), 2.61-2.43 (m, 4H) .
MS: m / z = 213 [M + H] +
The obtained compound (2) was cis: trans = 99: 1 under the following analysis conditions.
HPLC analysis condition column: Atlantis (registered trademark) T3: 3 μm, 4.6 mm × 50 mm (Waters)
Column temperature: Constant temperature around 40 ° C Mobile phase: Mobile phase A: 0.01% TFA aqueous solution Mobile phase B: MeCN
Gradient condition:
Time (minutes) 0 5 15 20 25
A (%) 100 100 50 0 100
B (%) 0 0 50 95 0
Flow rate: 1.0 mL / min Detection method: UV 220 nm
Reference; Retention time: cis form (about 12.9 minutes), trans form (about 12.6 minutes)
工程３ Process 3
Figure JPOXMLDOC01-appb-C000229
Figure JPOXMLDOC01-appb-C000229
　アルゴン気流下、7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸メチル（２）（42.7 kg, 201 mol）のN,N-ジメチルホルムアミド（171 mL）懸濁液に炭酸セシウム（78.7 kg, 241 mol）及び4-メトキシベンジルクロリド（37.8 kg, 241 mol）を、反応温度が10℃を超えない速度で添加した。この混合液を5℃で7時間30分撹拌した後、室温で14時間撹拌した。反応終了後、この混合液に室温でトルエン（256 L）を添加した後、5℃に冷却し、水（342 L）を滴下し、抽出した。得られた有機層を室温にて5%食塩水（85 L）で2回洗浄し、減圧下溶媒を留去することで5-(4-メトキシベンジル)-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸メチル（３）の粗生成物（201 mol相当）を得た。得られた化合物（３）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（３）の粗生成物を濃縮乾固し、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.22 (d, 2H, J = 9.0 Hz), 6.90 (d, 2H, J = 9.0 Hz), 4.58 (s, 2H), 3.74 (s, 3H), 3.61 (s, 3H), 3.10 (ｍ, 1H,), 2.90 (s, 3H), 2.59-2.49 (m, 2H), 2.43-2.38 (m, 2H).
MS: m/z = 333 [M+H]+ 7-Methyl-6,8-dioxo-5,7-diazaspiro [3.4] methyl octane-cis-2-carboxylate (2) (42.7 kg, 201 mol) in N, N-dimethylformamide (171 To the suspension, cesium carbonate (78.7 kg, 241 mol) and 4-methoxybenzyl chloride (37.8 kg, 241 mol) were added at a rate such that the reaction temperature did not exceed 10 ° C. The mixture was stirred at 5 ° C. for 7 hours 30 minutes, and then stirred at room temperature for 14 hours. After completion of the reaction, toluene (256 L) was added to the mixture at room temperature, and then cooled to 5 ° C., and water (342 L) was added dropwise for extraction. The obtained organic layer was washed twice with 5% brine (85 L) at room temperature, and the solvent was distilled off under reduced pressure to give 5- (4-methoxybenzyl) -7-methyl-6,8-dioxo. A crude product (corresponding to 201 mol) of methyl -5,7-diazaspiro [3.4] octane-cis-2-carboxylate (3) was obtained. The obtained crude product of compound (3) was used in the next step with a yield of 100%.
The crude product of compound (3) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.22 (d, 2H, J = 9.0 Hz), 6.90 (d, 2H, J = 9.0 Hz), 4.58 (s, 2H), 3.74 (s, 3H), 3.61 (s, 3H), 3.10 (m, 1H,), 2.90 (s, 3H), 2.59-2.49 (m, 2H), 2.43-2.38 (m, 2H).
MS: m / z = 333 [M + H] +
工程４ Process 4
Figure JPOXMLDOC01-appb-C000230
Figure JPOXMLDOC01-appb-C000230
　5-(4-メトキシベンジル)-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸メチル（３）の粗生成物（201 mol相当）のテトラヒドロフラン（214 L）溶液を5℃に冷却し、アルゴン気流下で2 mol/L水酸化ナトリウム水溶液（131 kg, 241 mol）を滴下した。この溶液を5℃で4時間撹拌した。反応終了後、この溶液に7℃にてトルエン（128 L）を添加した。この混合液を6℃にて分層し、得られた水層に2 mol/L塩酸（125 kg, 241 mol）を7℃にて滴下した。この混合液に酢酸エチル（256 L）を添加し、抽出した。得られた有機層を10%食塩水（128 L）で2回洗浄し、減圧下溶媒を留去した。この残渣に酢酸エチル（214 L）を添加し、減圧下溶媒を留去した。この残渣に酢酸エチルを添加し、液量を149 Lに調整した。このとき析出していた固体を61℃にて溶解後、40℃に冷却し、2時間撹拌した。得られた懸濁液にn-ヘプタン（214 L）を35℃にて滴下し、同温で1時間撹拌した。この懸濁液を室温に冷却し、16時間撹拌した。析出した結晶を濾取し、結晶を酢酸エチル（43 L）とn-ヘプタン（128 L）の混合溶媒で洗浄した。得られた湿結晶を減圧乾燥することで5-(4-メトキシベンジル)-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸（４）（59.4 kg, 187 mol）を収率93.0%で得た。
　上記の方法に準じて合成した化合物（４）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 12.38 (s, 1H), 7.21 (d, 2H, J = 8.8 Hz), 6.89 (d, 2H, J = 8.8 Hz), 4.57 (s, 2H), 3.73 (s, 3H), 3.07-2.98 (m, 1H), 2.90 (s, 3H), 2.56-2.49 (m, 2H), 2.40-2.35 (m, 2H).
MS: m/z = 317 [M-H]- Tetrahydrofuran of crude product (corresponding to 201 mol) of methyl 5- (4-methoxybenzyl) -7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylate (3) The (214 L) solution was cooled to 5 ° C., and 2 mol / L aqueous sodium hydroxide solution (131 kg, 241 mol) was added dropwise under an argon stream. The solution was stirred at 5 ° C. for 4 hours. After completion of the reaction, toluene (128 L) was added to this solution at 7 ° C. The mixture was separated at 6 ° C., and 2 mol / L hydrochloric acid (125 kg, 241 mol) was added dropwise at 7 ° C. to the obtained aqueous layer. Ethyl acetate (256 L) was added to the mixture and extracted. The obtained organic layer was washed twice with 10% brine (128 L), and the solvent was distilled off under reduced pressure. Ethyl acetate (214 L) was added to the residue, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue to adjust the liquid volume to 149 L. The solid precipitated at this time was dissolved at 61 ° C., cooled to 40 ° C., and stirred for 2 hours. N-Heptane (214 L) was added dropwise to the obtained suspension at 35 ° C., and the mixture was stirred at the same temperature for 1 hour. The suspension was cooled to room temperature and stirred for 16 hours. The precipitated crystals were collected by filtration, and the crystals were washed with a mixed solvent of ethyl acetate (43 L) and n-heptane (128 L). The obtained wet crystals were dried under reduced pressure to give 5- (4-methoxybenzyl) -7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylic acid (4) ( 59.4 kg, 187 mol) was obtained with a yield of 93.0%.
About compound (4) synthesize | combined according to said method, NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 12.38 (s, 1H), 7.21 (d, 2H, J = 8.8 Hz), 6.89 (d, 2H, J = 8.8 Hz), 4.57 (s, 2H), 3.73 (s, 3H), 3.07-2.98 (m, 1H), 2.90 (s, 3H), 2.56-2.49 (m, 2H), 2.40-2.35 (m, 2H).
MS: m / z = 317 [MH] -
工程５ Process 5
Figure JPOXMLDOC01-appb-C000231
Figure JPOXMLDOC01-appb-C000231
　窒素気流下で水素化ホウ素ナトリウム（5.49 kg, 145 mol）のTHF（84 L）懸濁液を5℃に冷却した。この懸濁液に5-(4-メトキシベンジル)-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸（４）（42.0 kg, 131 mol）のTHF（126 L）溶液を5℃で滴下した。この溶液を5℃で30分間撹拌後、三フッ化ホウ素－ジエチルエーテル錯体（18.7 kg, 132 mol）を5℃で滴下した。この反応液を5℃で1時間撹拌した。反応終了後、この溶液を5%重曹水（84 L）と10%食塩水（84 L）の混合溶液に5℃で滴下し、反応容器をTHF(42 L)で洗い込んだ。この混合溶液を室温にて30分間撹拌した後、酢酸エチル（168 L）とトルエン（168 L）の混合溶液で抽出した。有機層を5%重曹水（126 L）で2回、10%食塩水(126 L)で1回洗浄した。減圧下50℃以下で有機層の溶媒を留去した。残渣にトルエン（84 L）を添加し、減圧下50℃以下で溶媒を留去した。再び残渣にトルエン(84 L)を添加し、減圧下50℃以下で溶媒を留去することで、シス-2-(ヒドロキシメチル)-5-(4-メトキシベンジル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（５）の粗生成物（84.0 kg, 131 mol相当）を得た。得られた化合物（５）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（５）の粗生成物を濃縮乾固し、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.24 (d, 2H, J = 8.3 Hz), 6.89 (d, 2H, J = 8.3 Hz), 4.62 (t, 1H, J = 5.3 Hz), 4.56 (s, 2H), 3.73 (s, 3H), 3.32 (dd, 2H, J = 5.3, 5.3 Hz), 2.90 (s, 3H), 2.48-2.39 (m, 1H), 2.25-2.20 (m, 2H), 2.15-2.09 (m, 2H).
MS: m/z = 303 [M-H]- Under a nitrogen stream, a suspension of sodium borohydride (5.49 kg, 145 mol) in THF (84 L) was cooled to 5 ° C. To this suspension, 5- (4-methoxybenzyl) -7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylic acid (4) (42.0 kg, 131 mol) Of THF (126 L) was added dropwise at 5 ° C. The solution was stirred at 5 ° C. for 30 minutes, and boron trifluoride-diethyl ether complex (18.7 kg, 132 mol) was added dropwise at 5 ° C. The reaction was stirred at 5 ° C. for 1 hour. After completion of the reaction, this solution was added dropwise to a mixed solution of 5% aqueous sodium bicarbonate (84 L) and 10% brine (84 L) at 5 ° C., and the reaction vessel was washed with THF (42 L). The mixed solution was stirred at room temperature for 30 minutes, and then extracted with a mixed solution of ethyl acetate (168 L) and toluene (168 L). The organic layer was washed twice with 5% aqueous sodium bicarbonate (126 L) and once with 10% brine (126 L). The solvent of the organic layer was distilled off at 50 ° C. or lower under reduced pressure. Toluene (84 L) was added to the residue, and the solvent was distilled off at 50 ° C. or lower under reduced pressure. Toluene (84 L) was again added to the residue, and the solvent was distilled off at 50 ° C. or lower under reduced pressure to obtain cis-2- (hydroxymethyl) -5- (4-methoxybenzyl) -7-methyl-5, A crude product (equivalent to 84.0 kg, 131 mol) of 7-diazaspiro [3.4] octane-6,8-dione (5) was obtained. The obtained crude product of compound (5) was used in the next step with a yield of 100%.
The crude product of compound (5) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.24 (d, 2H, J = 8.3 Hz), 6.89 (d, 2H, J = 8.3 Hz), 4.62 (t, 1H, J = 5.3 Hz), 4.56 ( s, 2H), 3.73 (s, 3H), 3.32 (dd, 2H, J = 5.3, 5.3 Hz), 2.90 (s, 3H), 2.48-2.39 (m, 1H), 2.25-2.20 (m, 2H) , 2.15-2.09 (m, 2H).
MS: m / z = 303 [MH] -
工程６ Step 6
Figure JPOXMLDOC01-appb-C000232
Figure JPOXMLDOC01-appb-C000232
　窒素気流下、シス-2-(ヒドロキシメチル)-5-(4-メトキシベンジル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（５）の粗生成物（84.0 kg, 131 mol相当）とヨウ化メチル（46.8 kg, 330 mol）のTHF（210 L）溶液を5℃に冷却した。この溶液にカリウムtert-ブトキシド（37.0 kg, 330 mol）のDMF（84 L）溶液を5℃で滴下した。この反応液を5℃で1時間撹拌した。反応終了後、この溶液に水（210 L）を5℃で滴下した。この溶液をトルエン（210 L）で抽出後、有機層を10%食塩水（126 L）で2回洗浄した。減圧下50℃以下で有機層の溶媒を留去した。残渣にトルエン（84 L）を添加し、減圧下50℃以下で溶媒を留去した。再び残渣にトルエン(84 L)を添加し、減圧下50℃以下で溶媒を留去することで5-(4-メトキシベンジル)-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（６）の粗生成物（64.6 kg, 131 mol相当）を得た。得られた化合物（６）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（６）の粗生成物を濃縮乾固し、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.24 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 4.57 (s, 2H), 3.74 (s, 3H), 3.24 (d, 2H, J = 5.7 Hz), 3.23 (s, 3H), 2.90 (s, 3H), 2.55-2.46 (m, 1H), 2.22-2.13 (m, 4H).
MS: m/z = 319 [M+H]+ Crude product of cis-2- (hydroxymethyl) -5- (4-methoxybenzyl) -7-methyl-5,7-diazaspiro [3.4] octane-6,8-dione (5) under nitrogen flow (84.0 kg, 131 mol) and methyl iodide (46.8 kg, 330 mol) in THF (210 L) were cooled to 5 ° C. To this solution, a solution of potassium tert-butoxide (37.0 kg, 330 mol) in DMF (84 L) was added dropwise at 5 ° C. The reaction was stirred at 5 ° C. for 1 hour. After completion of the reaction, water (210 L) was added dropwise to this solution at 5 ° C. This solution was extracted with toluene (210 L), and the organic layer was washed twice with 10% brine (126 L). The solvent of the organic layer was distilled off at 50 ° C. or lower under reduced pressure. Toluene (84 L) was added to the residue, and the solvent was distilled off at 50 ° C. or lower under reduced pressure. Toluene (84 L) was added to the residue again, and the solvent was distilled off under reduced pressure at 50 ° C. or lower to give 5- (4-methoxybenzyl) -cis-2- (methoxymethyl) -7-methyl-5,7 -Diazaspiro [3.4] octane-6,8-dione (6) crude product (64.6 kg, equivalent to 131 mol) was obtained. The obtained crude product of compound (6) was used in the next step with a yield of 100%.
The crude product of compound (6) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.24 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 4.57 (s, 2H), 3.74 (s, 3H), 3.24 (d, 2H, J = 5.7 Hz), 3.23 (s, 3H), 2.90 (s, 3H), 2.55-2.46 (m, 1H), 2.22-2.13 (m, 4H).
MS: m / z = 319 [M + H] +
工程７ Step 7
Figure JPOXMLDOC01-appb-C000233
Figure JPOXMLDOC01-appb-C000233
　窒素気流下、70%水素化ビス(2-メトキシエトキシ)アルミニウムナトリウム（152 kg, 528 mol）のトルエン（84 L）溶液を70℃に加温した。この溶液に5-(4-メトキシベンジル)-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（６）の粗生成物（64.6 kg, 131 mol相当）のトルエン（123 L）溶液を65～75℃で2時間かけて滴下した。この反応液を70℃で5時間撹拌した。反応終了後、この溶液を室温に冷却した。この溶液を（＋）－酒石酸ナトリウムカリウム四水和物（168 kg, 594 mol）の水（336
L）溶液に5℃で滴下し、反応容器をトルエン(42 L)で洗浄した。この混合溶液を室温で1時間撹拌した。この溶液を有機層と水層に分液した。有機層を10%食塩水（126 L）で洗浄し、5-(4-メトキシベンジル)-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン（７）のトルエン溶液（306 kg, 131 mol相当）を得た。得られた化合物（７）のトルエン溶液を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（７）のトルエン溶液を濃縮乾固し、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.21 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 3.73 (s, 3H), 3.62 (s, 2H), 3.26 (d, 2H, 6.2 Hz), 3.21 (s, 3H), 3.19 (s, 2H), 2.81 (s, 2H), 2.21 (s, 3H), 2.19-2.08 (m, 1H), 2.02-1.97 (m, 2H), 1.90-1.85 (m, 2H).
MS: m/z = 291 [M+H]+ Under a nitrogen stream, a solution of 70% sodium bis (2-methoxyethoxy) aluminum hydride (152 kg, 528 mol) in toluene (84 L) was heated to 70 ° C. To this solution was added a crude product (64.6 kg) of 5- (4-methoxybenzyl) -cis-2- (methoxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane-6,8-dione (6) , 131 mol) in toluene (123 L) was added dropwise at 65 to 75 ° C. over 2 hours. The reaction was stirred at 70 ° C. for 5 hours. After completion of the reaction, the solution was cooled to room temperature. This solution was added to (+)-potassium sodium tartrate tetrahydrate (168 kg, 594 mol) in water (336
L) The solution was added dropwise at 5 ° C., and the reaction vessel was washed with toluene (42 L). The mixed solution was stirred at room temperature for 1 hour. This solution was separated into an organic layer and an aqueous layer. The organic layer was washed with 10% brine (126 L) to give 5- (4-methoxybenzyl) -cis-2- (methoxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane (7). A toluene solution (306 kg, equivalent to 131 mol) was obtained. The toluene solution of the obtained compound (7) was used in the next step with a yield of 100%.
A toluene solution of the compound (7) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.21 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 3.73 (s, 3H), 3.62 (s, 2H), 3.26 (d, 2H, 6.2 Hz), 3.21 (s, 3H), 3.19 (s, 2H), 2.81 (s, 2H), 2.21 (s, 3H), 2.19-2.08 (m, 1H), 2.02-1.97 (m, 2H), 1.90-1.85 (m, 2H).
MS: m / z = 291 [M + H] +
工程８ Process 8
Figure JPOXMLDOC01-appb-C000234
Figure JPOXMLDOC01-appb-C000234
　窒素気流下、5-(4-メトキシベンジル)-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン（７）のトルエン溶液（306 kg, 131 mol相当）に2 mol/L塩酸（168 L）を加えて、水層を分離した。得られた水層に塩化ヒドロキシルアンモニウム（18.3 kg, 264 mol）を室温で添加した。この反応液を室温にて3時間撹拌した。反応終了後、この溶液に4 mol/L水酸化ナトリウム水溶液（159 L）を室温で滴下した。この混合溶液を酢酸エチル（210 L）で抽出し、有機層を10%食塩水（126 L）で洗浄した。減圧下50℃以下で有機層の溶媒を留去した。残渣に酢酸エチル（231 L）とエタノール（126 L）を添加した。この溶液に4 mol/L 塩化水素の酢酸エチル溶液（36.3 L, 145 mol）を室温で滴下した。この混合溶液にN-(4-メトキシベンジル)-シス-2-(メトキシメチル)-1-[(メチルアミノ)メチル]シクロブチルアミン 2塩酸塩（８’）の種晶（4.2 g）を添加して、室温で1時間撹拌した。4 mol/L 塩化水素の酢酸エチル溶液（29.7 L, 119 mol）を室温で滴下し、同温で2時間撹拌した。析出した固体を濾取し、この濾取した固体を酢酸エチル（126 L）とエタノール（42 L）の混合溶液で洗浄した。減圧下50℃以下で湿固体を12時間乾燥することで化合物（８’）（36.3 kg, 103 mol）を収率78.3%で得た。
　上記の方法に準じて合成した化合物（８’）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 9.88 (brs, 1H), 9.48 (br s, 1H), 7.61 (d, 2H, J = 8.6 Hz), 6.98 (d, 2H, J = 8.6 Hz), 4.12 (brs, 2H), 3.77 (s, 3H), 3.58 (brs, 2H), 3.38 (d,2H, J = 6.6 Hz), 3.23 (s, 3H), 2.67 (br s, 3H), 2.51-2.42 (m, 1H), 2.42-2.37 (m, 2H), 2.27-2.22 (m, 2H).
MS: m/z = 279 [M-H-2Cl]+
　Cl含量は、イオンクロマトグラフィーを用いて測定し、２塩酸塩であることを確認した。
Cl含量: 20.3% Toluene solution (corresponding to 306 kg, 131 mol) of 5- (4-methoxybenzyl) -cis-2- (methoxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane (7) under nitrogen flow 2 mol / L hydrochloric acid (168 L) was added and the aqueous layer was separated. Hydroxyl ammonium chloride (18.3 kg, 264 mol) was added to the obtained aqueous layer at room temperature. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, 4 mol / L aqueous sodium hydroxide solution (159 L) was added dropwise to this solution at room temperature. This mixed solution was extracted with ethyl acetate (210 L), and the organic layer was washed with 10% brine (126 L). The solvent of the organic layer was distilled off at 50 ° C. or lower under reduced pressure. To the residue was added ethyl acetate (231 L) and ethanol (126 L). To this solution, 4 mol / L hydrogen chloride in ethyl acetate (36.3 L, 145 mol) was added dropwise at room temperature. To this mixed solution was added N- (4-methoxybenzyl) -cis-2- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine dihydrochloride (8 ') seed crystals (4.2 g). And stirred at room temperature for 1 hour. 4 mol / L Hydrogen chloride in ethyl acetate (29.7 L, 119 mol) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 2 hours. The precipitated solid was collected by filtration, and the collected solid was washed with a mixed solution of ethyl acetate (126 L) and ethanol (42 L). The wet solid was dried under reduced pressure at 50 ° C. or lower for 12 hours to obtain Compound (8 ′) (36.3 kg, 103 mol) in a yield of 78.3%.
NMR and MS of the compound (8 ′) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 9.88 (brs, 1H), 9.48 (br s, 1H), 7.61 (d, 2H, J = 8.6 Hz), 6.98 (d, 2H, J = 8.6 Hz) , 4.12 (brs, 2H), 3.77 (s, 3H), 3.58 (brs, 2H), 3.38 (d, 2H, J = 6.6 Hz), 3.23 (s, 3H), 2.67 (br s, 3H), 2.51 -2.42 (m, 1H), 2.42-2.37 (m, 2H), 2.27-2.22 (m, 2H).
MS: m / z = 279 [MH-2Cl] +
The Cl content was measured using ion chromatography and confirmed to be dihydrochloride.
Cl content: 20.3%
工程９ Step 9
Figure JPOXMLDOC01-appb-C000235
Figure JPOXMLDOC01-appb-C000235
　窒素雰囲気下、N-(4-メトキシベンジル)-シス-2-(メトキシメチル)-1-[(メチルアミノ)メチル]シクロブチルアミン 2塩酸塩（８’）（36.2 kg, 103 mol）のメタノール（253 L）溶液に酢酸ナトリウム（16.9 kg, 206 mol）、酢酸（12.4 kg, 206 mol）及び10%パラジウム炭素（N.E. CHEMCAT社製PEタイプ, 56.76%含水, 4.18 kg）を室温で添加した。反応容器を水素で置換し、水素ガス圧0.4 MPaで室温にて45時間撹拌した。反応終了後、反応容器を窒素で置換し、不溶物を濾過で除去した。反応容器と不溶物をメタノール(72.3 L)で洗い込み、シス-3-(メトキシメチル)-1-[(メチルアミノ)メチル]シクロブチルアミン（９）のメタノール溶液(103 mol相当)を得た。得られた化合物（９）のメタノール溶液を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（９）を蒸留し、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 3.28 (d, 2H, J = 6.0 Hz), 3.20 (s, 3H), 2.42 (s, 2H), 2.31 (s, 3H), 2.10-1.98 (m, 3H), 1.59 (br s, 2H), 1.46-1.41 (m, 2H).
MS: m/z = 159 [M+H]+
沸点: 90-95℃ (減圧度 1.5 kPa) Under a nitrogen atmosphere, N- (4-methoxybenzyl) -cis-2- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine dihydrochloride (8 ′) (36.2 kg, 103 mol) in methanol ( 253 L) sodium acetate (16.9 kg, 206 mol), acetic acid (12.4 kg, 206 mol) and 10% palladium carbon (PE type manufactured by NE CHEMCAT, 56.76% water content, 4.18 kg) were added at room temperature. The reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature at a hydrogen gas pressure of 0.4 MPa for 45 hours. After completion of the reaction, the reaction vessel was replaced with nitrogen, and insoluble matters were removed by filtration. The reaction vessel and insoluble matter were washed with methanol (72.3 L) to obtain a methanol solution (corresponding to 103 mol) of cis-3- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine (9). The methanol solution of the obtained compound (9) was used in the next step with a yield of 100%.
The compound (9) synthesized according to the above method was distilled, and NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 3.28 (d, 2H, J = 6.0 Hz), 3.20 (s, 3H), 2.42 (s, 2H), 2.31 (s, 3H), 2.10-1.98 (m , 3H), 1.59 (br s, 2H), 1.46-1.41 (m, 2H).
MS: m / z = 159 [M + H] +
Boiling point: 90-95 ℃ (Decompression degree 1.5 kPa)
実施例２
3-(ベンジルオキシ)-2-(エトキシカルボニル)-4-オキソ-4H-ピラン-5-カルボン酸（１５）の製造
工程１ Example 2
Production process 1 of 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxo-4H-pyran-5-carboxylic acid (15)
Figure JPOXMLDOC01-appb-C000236
Figure JPOXMLDOC01-appb-C000236
　窒素気流下、プロピオル酸tert-ブチル（24.9 kg、197 mol）のアセトニトリル（112.5 L）溶液を0℃に冷却し、ジエチルアミン（15.2 kg、207 mol）を滴下した。この溶液を0℃にて２時間撹拌した。反応終了後、(E)-3-(ジエチルアミノ)アクリル酸tert-ブチル（１０）のアセトニトリル溶液（128.4 kg、197 mol相当）を得た。得られた化合物（１０）のアセトニトリル溶液を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（１０）の粗生成物を濃縮乾固し、NMRとMSを測定した。
1H-NMR (CDCl3) δ: 7.35(d, 1H, J = 13.2 Hz), 4.50(d, 1H, J = 13.2 Hz), 3.15 (q, 4H, J = 7.2 Hz), 1.46 (s, 9H), 1.13 (t, 6H, J = 7.2 Hz).
MS: m/z = 200 [M+H]+ Under a nitrogen stream, a solution of tert-butyl propiolate (24.9 kg, 197 mol) in acetonitrile (112.5 L) was cooled to 0 ° C., and diethylamine (15.2 kg, 207 mol) was added dropwise. The solution was stirred at 0 ° C. for 2 hours. After completion of the reaction, an acetonitrile solution (128.4 kg, corresponding to 197 mol) of tert-butyl (10) (E) -3- (diethylamino) acrylate was obtained. The acetonitrile solution of the obtained compound (10) was used in the next step with a yield of 100%.
The crude product of compound (10) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (CDCl 3 ) δ: 7.35 (d, 1H, J = 13.2 Hz), 4.50 (d, 1H, J = 13.2 Hz), 3.15 (q, 4H, J = 7.2 Hz), 1.46 (s, 9H), 1.13 (t, 6H, J = 7.2 Hz).
MS: m / z = 200 [M + H] +
工程２ Process 2
Figure JPOXMLDOC01-appb-C000237
Figure JPOXMLDOC01-appb-C000237
　窒素気流下、0℃に冷却した(E)-3-(ジエチルアミノ)アクリル酸tert-ブチル（１０）（39.3 kg、197 mol）のアセトニトリル（112.5 L）溶液に、ピリジン（17.2 kg、217 mol）のアセトニトリル（12.5 L）溶液を滴下した。この溶液に0℃にて塩化2-(ベンジルオキシ)アセチル（38.2 kg、207 mol）のアセトニトリル（12.5 L）溶液を2.5時間かけて滴下した。この混合液を0℃にて3時間撹拌した。反応終了後、4-(ベンジルオキシ)-2-[(ジエチルアミノ)メチレン]-3-オキソブタン酸tert-ブチル（１２）のアセトニトリル溶液（203.4 kg、197 mol相当）を得た。得られた化合物（１２）のアセトニトリル溶液を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（１２）の粗生成物を濃縮乾固し、NMRとMSを測定した。
1H-NMR (CDCl3) δ: 7.63 (s, 1H), 7.36-7.25 (m, 5H), 4.58 (s, 2H), 4.37 (s, 2H), 3.38 (q, 4H, J = 7.2 Hz), 1.43 (s, 9H), 1.20-1.00 (m, 6H).
MS: m/z = 348 [M+H]+ To a solution of tert-butyl (E) -3- (diethylamino) acrylate (10) (39.3 kg, 197 mol) in acetonitrile (112.5 L) cooled to 0 ° C. under a nitrogen stream, pyridine (17.2 kg, 217 mol) Of acetonitrile (12.5 L) was added dropwise. To this solution was added dropwise a solution of 2- (benzyloxy) acetyl chloride (38.2 kg, 207 mol) in acetonitrile (12.5 L) at 0 ° C. over 2.5 hours. The mixture was stirred at 0 ° C. for 3 hours. After completion of the reaction, an acetonitrile solution (203.4 kg, corresponding to 197 mol) of tert-butyl 4- (benzyloxy) -2-[(diethylamino) methylene] -3-oxobutanoate (12) was obtained. The resulting acetonitrile solution of compound (12) was used in the next step with a yield of 100%.
The crude product of the compound (12) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (CDCl 3 ) δ: 7.63 (s, 1H), 7.36-7.25 (m, 5H), 4.58 (s, 2H), 4.37 (s, 2H), 3.38 (q, 4H, J = 7.2 Hz ), 1.43 (s, 9H), 1.20-1.00 (m, 6H).
MS: m / z = 348 [M + H] +
工程３ Process 3
　窒素気流下、0℃に冷却した4-(ベンジルオキシ)-2-[(ジエチルアミノ)メチレン]-3-オキソブタン酸tert-ブチル（１２）（68.6 kg、197 mol）のアセトニトリル（137.5 L）溶液に、シュウ酸ジエチル（１３）(72.1 kg、493 mol)を滴下した。この溶液に0℃にて1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(75.1 kg、493 mol)を滴下した。この溶液に、無水リチウムブロミド（31.0 kg、356 mol、本荘ケミカル社製）を添加した。添加終了後、この混合液を70℃にて3時間撹拌した。反応終了後、混合液を0℃に冷却し、同温にて4 mol/L塩酸（200 L）を滴下した。この混合液に酢酸エチル（150 L）を加え抽出した。得られた有機層を食塩水（200 L）で2回洗浄後、濃縮した。この濃縮残渣に酢酸エチル（150 L）を加え、再度濃縮した。得られた濃縮残渣に酢酸エチルを加え、3-(ベンジルオキシ)-4-オキソ-4H-ピラン-2,5-ジカルボン酸2-エチル5-tert-ブチル（１４）の酢酸エチル溶液（250 L、197 mol相当）を得た。得られた化合物（１４）の酢酸エチル溶液を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（１４）の粗生成物を濃縮乾固し、NMRとMSを測定した。
1H-NMR (CDCl3) δ: δ: 8.37 (s, 1H), 7.49-7.47 (m, 2H), 7.39-7.30 (m, 3H), 5.31 (s, 2H), 4.34 (q, 2H, J = 7.2 Hz), 1.56 (s, 9H), 1.30 (t, 3H, J = 7.2 Hz).
MS: m/z = 397 [M+Na]+ To a solution of tert-butyl 4- (benzyloxy) -2-[(diethylamino) methylene] -3-oxobutanoate (12) (68.6 kg, 197 mol) in acetonitrile (137.5 L) cooled to 0 ° C. under a nitrogen stream Diethyl oxalate (13) (72.1 kg, 493 mol) was added dropwise. To this solution, 1,8-diazabicyclo [5.4.0] -7-undecene (75.1 kg, 493 mol) was added dropwise at 0 ° C. To this solution, anhydrous lithium bromide (31.0 kg, 356 mol, manufactured by Honjo Chemical Co., Ltd.) was added. After the addition was complete, the mixture was stirred at 70 ° C. for 3 hours. After completion of the reaction, the mixture was cooled to 0 ° C., and 4 mol / L hydrochloric acid (200 L) was added dropwise at the same temperature. The mixture was extracted with ethyl acetate (150 L). The obtained organic layer was washed twice with brine (200 L) and concentrated. Ethyl acetate (150 L) was added to the concentrated residue and concentrated again. Ethyl acetate was added to the resulting concentrated residue, and ethyl acetate solution of 2-ethyl 5-tert-butyl (14) 3- (benzyloxy) -4-oxo-4H-pyran-2,5-dicarboxylate (250 L) was added. , Equivalent to 197 mol). The ethyl acetate solution of the obtained compound (14) was used in the next step with a yield of 100%.
The crude product of compound (14) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (CDCl 3 ) δ: δ: 8.37 (s, 1H), 7.49-7.47 (m, 2H), 7.39-7.30 (m, 3H), 5.31 (s, 2H), 4.34 (q, 2H, J = 7.2 Hz), 1.56 (s, 9H), 1.30 (t, 3H, J = 7.2 Hz).
MS: m / z = 397 [M + Na] +
工程４ Process 4
Figure JPOXMLDOC01-appb-C000239
Figure JPOXMLDOC01-appb-C000239
　窒素気流下、3-(ベンジルオキシ)-4-オキソ-4H-ピラン-2,5-ジカルボン酸2-エチル5-tert-ブチル（１４）（68.6 kg、197 mol）の酢酸エチル（225 L）溶液に、4 mol/L 塩化水素の酢酸エチル溶液（100 L）を0℃にて滴下した。滴下終了後、この混合液を室温で2時間撹拌した。反応終了後、この懸濁液に0℃にて水（100 L）及び酢酸エチル（625 L）を滴下した。この溶液を室温にて有機層と水層に分液した。得られた有機層を食塩水（100 L）で洗浄後、濃縮した。この濃縮残渣に、室温にてn-ヘプタン（250 L）を加え、同温にて2時間撹拌した。析出した固体を濾取し、得られた固体を酢酸エチル（75 L）とn-ヘプタン(75 L)の混合溶媒で洗浄した。この固体を減圧乾燥することで3-(ベンジルオキシ)-2-(エトキシカルボニル)-4-オキソ-4H-ピラン-5-カルボン酸（１５）（44.5 kg、140 mol）を収率71.0%で得た。
　上記の方法に準じて合成した化合物（１５）について、NMRとMSを測定した。
1H-NMR (CDCl3) δ: 13.00 (brs, 1H), 8.78 (s, 1H), 7.45-7.42 (m, 2H), 7.39-7.32 (m, 3H), 5.36 (s, 2H), 4.38 (q, 2H, J = 7.2 Hz), 1.33 (t, 3H, J = 7.2 Hz).
MS: m/z = 319 [M+H]+ 3- (Benzyloxy) -4-oxo-4H-pyran-2,5-dicarboxylate 2-ethyl 5-tert-butyl (14) (68.6 kg, 197 mol) ethyl acetate (225 L) under nitrogen flow To the solution, 4 mol / L hydrogen chloride in ethyl acetate (100 L) was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (100 L) and ethyl acetate (625 L) were added dropwise to this suspension at 0 ° C. This solution was separated into an organic layer and an aqueous layer at room temperature. The obtained organic layer was washed with brine (100 L) and concentrated. To this concentrated residue, n-heptane (250 L) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The precipitated solid was collected by filtration, and the obtained solid was washed with a mixed solvent of ethyl acetate (75 L) and n-heptane (75 L). The solid was dried under reduced pressure to give 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxo-4H-pyran-5-carboxylic acid (15) (44.5 kg, 140 mol) in a yield of 71.0%. Obtained.
NMR and MS were measured for the compound (15) synthesized according to the above method.
1 H-NMR (CDCl 3 ) δ: 13.00 (brs, 1H), 8.78 (s, 1H), 7.45-7.42 (m, 2H), 7.39-7.32 (m, 3H), 5.36 (s, 2H), 4.38 (q, 2H, J = 7.2 Hz), 1.33 (t, 3H, J = 7.2 Hz).
MS: m / z = 319 [M + H] +
実施例３
7'-{[(3-クロロ-2-フルオロフェニル)メチル]カルバモイル}-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-9'-オレート 1ナトリウム（１９）の製造 Example 3
7 '-{[(3-Chloro-2-fluorophenyl) methyl] carbamoyl} -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ' Of 8,8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -9'-oleate monosodium (19)
工程１ Process 1
Figure JPOXMLDOC01-appb-C000240
Figure JPOXMLDOC01-appb-C000240
　窒素気流下、化合物3-(ベンジルオキシ)-2-(エトキシカルボニル)-4-オキソ-4H-ピラン-5-カルボン酸（１５）（33.0 kg、104 mol）のトルエン（165 L）溶液に室温にてN,N-ジメチルホルムアミド（3.3 L）を加えた後、同温にて塩化チオニル（18.5 kg、156 mol）を滴下した。この混合液を40℃にて2時間撹拌した。反応終了後、この混合液を濃縮した。得られた濃縮残渣にトルエン（230 L）を加え、内温-50℃に冷却した。このトルエン溶液に-50℃にて市販の3-クロロ-2-フルオロベンジルアミン（14.9 kg、93.3 mol）を滴下した。この溶液に-50℃にてトリエチルアミン（15.7 kg、156 mol）のトルエン（16.5 L）溶液を滴下し、同温で2時間撹拌した。反応終了後、この-50℃の混合液を硫酸水素カリウム（16.5 kg）の水（148 L）溶液に3℃で滴下した。この溶液を30℃にて有機層と水層に分液した。得られた有機層を水（165 L）で洗浄し、濃縮した。得られた濃縮残渣にエタノール（50 L）を添加した後、n-ヘプタン（297 L）を加えた。この混合液を6時間撹拌した。析出した固体を濾取した。得られた固体をトルエン(33 L)とn-ヘプタン(66 L)の混合溶媒で洗浄した。この固体を減圧乾燥することで3-(ベンジルオキシ)-5-{[(3-クロロ-2-フルオロフェニル)メチル]カルバモイル}-4-オキソ-4H-ピラン-2-カルボン酸エチル（１６）（30.0 kg、65 mol）を収率62.9%で得た。
　上記の方法に準じて合成した化合物（１６）について、NMRとMSを測定した。
1H-NMR (CDCl3) δ: 9.62-9.47 (m, 1H), 8.77 (s, 1H), 7.46-7.43 (m, 2H), 7.40-7.24(m, 5H), 7.06 (t, 1H, J = 7.9 Hz), 5.26 (s, 2H), 4.68 (d, 2H, J = 6.2 Hz), 4.35(q, 2H, J = 7.2 Hz), 1.31 (t, 3H, J = 7.2 Hz).
MS: m/z = 460 [M+H]+ Under a nitrogen stream, compound 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxo-4H-pyran-5-carboxylic acid (15) (33.0 kg, 104 mol) in toluene (165 L) at room temperature After adding N, N-dimethylformamide (3.3 L), thionyl chloride (18.5 kg, 156 mol) was added dropwise at the same temperature. The mixture was stirred at 40 ° C. for 2 hours. After completion of the reaction, the mixture was concentrated. Toluene (230 L) was added to the obtained concentrated residue, and the internal temperature was cooled to -50 ° C. Commercially available 3-chloro-2-fluorobenzylamine (14.9 kg, 93.3 mol) was added dropwise to the toluene solution at -50 ° C. To this solution, a toluene (16.5 L) solution of triethylamine (15.7 kg, 156 mol) was added dropwise at -50 ° C., and the mixture was stirred at the same temperature for 2 hours. After completion of the reaction, this -50 ° C mixture was added dropwise at 3 ° C to a solution of potassium hydrogen sulfate (16.5 kg) in water (148 L). This solution was separated into an organic layer and an aqueous layer at 30 ° C. The resulting organic layer was washed with water (165 L) and concentrated. Ethanol (50 L) was added to the resulting concentrated residue, followed by n-heptane (297 L). The mixture was stirred for 6 hours. The precipitated solid was collected by filtration. The obtained solid was washed with a mixed solvent of toluene (33 L) and n-heptane (66 L). The solid was dried under reduced pressure to give ethyl 3- (benzyloxy) -5-{[(3-chloro-2-fluorophenyl) methyl] carbamoyl} -4-oxo-4H-pyran-2-carboxylate (16) (30.0 kg, 65 mol) was obtained with a yield of 62.9%.
NMR and MS were measured for the compound (16) synthesized according to the above method.
1 H-NMR (CDCl 3 ) δ: 9.62-9.47 (m, 1H), 8.77 (s, 1H), 7.46-7.43 (m, 2H), 7.40-7.24 (m, 5H), 7.06 (t, 1H, J = 7.9 Hz), 5.26 (s, 2H), 4.68 (d, 2H, J = 6.2 Hz), 4.35 (q, 2H, J = 7.2 Hz), 1.31 (t, 3H, J = 7.2 Hz).
MS: m / z = 460 [M + H] +
工程２ Process 2
Figure JPOXMLDOC01-appb-C000241
Figure JPOXMLDOC01-appb-C000241
　窒素気流下、シス-3-(メトキシメチル)-1-[(メチルアミノ)メチル]シクロブチルアミン（９）のメタノール溶液(103 mol相当)にトリエチルアミン（46.9 kg, 464 mol）を室温で滴下した。この溶液に3-(ベンジルオキシ)-5-{[(3-クロロ-2-フルオロフェニル)メチル]カルバモイル}-4-オキソ-4H-ピラン-2-カルボン酸エチル（１６）（52.1 kg, 113 mol）を5℃で添加した。この混合液を室温にて1時間撹拌後、55℃にて3時間撹拌した。反応終了後、この溶液に9'-(ベンジルオキシ)-N-[(3-クロロ-2-フルオロフェニル)メチル]-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１７）の種晶（3.6 g）を55℃で添加した。この溶液を55℃で1時間撹拌し、室温にて1時間撹拌した。得られた懸濁液に水(145 L)を室温で滴下し、同温にて3時間撹拌した。析出した結晶を濾取し、この濾取した結晶をメタノール（72.4 L）と水（36.2 L）の混合溶液で洗浄した。減圧下50℃以下で湿結晶を14時間乾燥することで化合物（１７）（52.4 kg, 94.5 mol）を収率91.7%で得た。
　上記の方法に準じて合成した化合物（１７）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 10.53 (t, 1H, J = 6.0 Hz), 8.66 (s, 1H), 7.55-7.48 (m, 3H),7.38-7.29 (m, 4H), 7.21 (dd, 1H, J = 7.9, 7.7 Hz), 5.11 (s, 2H), 4.63 (d, 2H, J= 6.0 Hz), 3.80 (s, 2H), 3.42 (d, 2H, J =4.0 Hz), 3.30 (s, 3H), 3.11 (s, 3H), 2.62-2.54 (m, 1H), 2.42-2.37 (m, 2H), 2.26-2.21 (m, 2H).
MS: m/z = 554 [M+H]+ Under a nitrogen stream, triethylamine (46.9 kg, 464 mol) was added dropwise at room temperature to a methanol solution (corresponding to 103 mol) of cis-3- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine (9). To this solution was added ethyl 3- (benzyloxy) -5-{[(3-chloro-2-fluorophenyl) methyl] carbamoyl} -4-oxo-4H-pyran-2-carboxylate (16) (52.1 kg, 113 mol) was added at 5 ° C. The mixture was stirred at room temperature for 1 hour and then stirred at 55 ° C. for 3 hours. After completion of the reaction, 9 '-(benzyloxy) -N-[(3-chloro-2-fluorophenyl) methyl] -cis-3- (methoxymethyl) -2'-methyl-1', 8 ' -Dioxo-1 ', 2', 3 ', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (17) seed crystal (3.6 g) Was added at 55 ° C. The solution was stirred at 55 ° C. for 1 hour and stirred at room temperature for 1 hour. Water (145 L) was added dropwise to the obtained suspension at room temperature, and the mixture was stirred at the same temperature for 3 hours. The precipitated crystals were collected by filtration, and the collected crystals were washed with a mixed solution of methanol (72.4 L) and water (36.2 L). The wet crystals were dried under reduced pressure at 50 ° C. or lower for 14 hours to obtain Compound (17) (52.4 kg, 94.5 mol) in a yield of 91.7%.
NMR and MS were measured for the compound (17) synthesized according to the above method.
1 H-NMR (DMSO-d 6 ) δ: 10.53 (t, 1H, J = 6.0 Hz), 8.66 (s, 1H), 7.55-7.48 (m, 3H), 7.38-7.29 (m, 4H), 7.21 (dd, 1H, J = 7.9, 7.7 Hz), 5.11 (s, 2H), 4.63 (d, 2H, J = 6.0 Hz), 3.80 (s, 2H), 3.42 (d, 2H, J = 4.0 Hz) , 3.30 (s, 3H), 3.11 (s, 3H), 2.62-2.54 (m, 1H), 2.42-2.37 (m, 2H), 2.26-2.21 (m, 2H).
MS: m / z = 554 [M + H] +
工程３ Process 3
Figure JPOXMLDOC01-appb-C000242
Figure JPOXMLDOC01-appb-C000242
　窒素気流下、9'-(ベンジルオキシ)-N-[(3-クロロ-2-フルオロフェニル)メチル]-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１７）（52.2 kg, 94.2 mol）とトルエン(365 L)の懸濁液に活性炭（カルボラフィン(登録商標) 20, 5.22 kg）を室温で添加した。この懸濁液を80℃で3時間撹拌した。この懸濁液中の活性炭を80℃にて濾過で除去し、反応容器と活性炭をトルエン(104 L)で洗い込んだ。減圧下50℃以下で濾液の溶媒を留去した。残渣にトリフルオロ酢酸（53.7 kg, 471 mol）を室温で滴下した。この混合液を室温にて2時間撹拌した。反応終了後、この溶液にエタノール（522 L）及びN-[(3-クロロ-2-フルオロフェニル)メチル]-9'-ヒドロキシ-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１８）の種晶（5.2 g）を室温で添加した。この溶液を室温で2時間撹拌後、0℃で3時間撹拌した。析出した結晶を濾取し、この濾取した結晶をエタノール（261 L）で洗浄した。減圧下50℃以下で湿結晶を11時間乾燥することで化合物（１８）（38.3 kg, 82.6 mol）を収率87.7%で得た。
　他の結晶化条件として、化合物（１８）（5 mg）をアセトニトリル（0.6 mL）に溶解させ、室温静置して単結晶を得た。化合物（１８）の立体配置は、得られた単結晶のＸ線構造解析により決定した。
　上記の方法に準じて合成した化合物（１８）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 12.79 (s, 1H), 10.45 (t, 1H, J = 6.0 Hz), 8.53 (s, 1H), 7.52-7.48 (m, 1H), 7.35-7.31 (m, 1H), 7.23-7.18 (m, 1H), 4.62 (d, 2H, J = 6.0 Hz), 3.90 (s, 2H), 3.39 (d, 2H, J = 5.3 Hz), 3.27 (s, 3H), 3.14 (s, 3H), 2.62-2.54 (m, 1H), 2.38-2.25 (m, 4H).
MS: m/z = 464 [M+H]+ 9 '-(Benzyloxy) -N-[(3-chloro-2-fluorophenyl) methyl] -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo- under nitrogen flow 1 ', 2', 3 ', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (17) (52.2 kg, 94.2 mol) and toluene ( 365 L) was added with activated carbon (Carborafin (registered trademark) 20, 5.22 kg) at room temperature. This suspension was stirred at 80 ° C. for 3 hours. The activated carbon in the suspension was removed by filtration at 80 ° C., and the reaction vessel and the activated carbon were washed with toluene (104 L). The solvent of the filtrate was distilled off at 50 ° C. or lower under reduced pressure. Trifluoroacetic acid (53.7 kg, 471 mol) was added dropwise to the residue at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethanol (522 L) and N-[(3-chloro-2-fluorophenyl) methyl] -9'-hydroxy-cis-3- (methoxymethyl) -2'-methyl-1 'were added to this solution. , 8'-Dioxo-1 ', 2', 3 ', 8'-Tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (18) seed crystal ( 5.2 g) was added at room temperature. The solution was stirred at room temperature for 2 hours and then stirred at 0 ° C. for 3 hours. The precipitated crystals were collected by filtration, and the collected crystals were washed with ethanol (261 L). The wet crystals were dried under reduced pressure at 50 ° C. or lower for 11 hours to obtain Compound (18) (38.3 kg, 82.6 mol) in a yield of 87.7%.
As other crystallization conditions, compound (18) (5 mg) was dissolved in acetonitrile (0.6 mL) and allowed to stand at room temperature to obtain a single crystal. The configuration of compound (18) was determined by X-ray structural analysis of the obtained single crystal.
NMR and MS were measured for the compound (18) synthesized according to the above method.
1 H-NMR (DMSO-d 6 ) δ: 12.79 (s, 1H), 10.45 (t, 1H, J = 6.0 Hz), 8.53 (s, 1H), 7.52-7.48 (m, 1H), 7.35-7.31 (m, 1H), 7.23-7.18 (m, 1H), 4.62 (d, 2H, J = 6.0 Hz), 3.90 (s, 2H), 3.39 (d, 2H, J = 5.3 Hz), 3.27 (s, 3H), 3.14 (s, 3H), 2.62-2.54 (m, 1H), 2.38-2.25 (m, 4H).
MS: m / z = 464 [M + H] +
工程４ Process 4
Figure JPOXMLDOC01-appb-C000243
Figure JPOXMLDOC01-appb-C000243
　窒素気流下、N-[(3-クロロ-2-フルオロフェニル)メチル]-9'-ヒドロキシ-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１８）（38.2 kg, 82.4 mol）、エタノール（649 L）及び水（329 L）の懸濁液に室温にて1 mol/l水酸化ナトリウム溶液（90.6 L）を滴下した。この懸濁液を80℃で1時間撹拌し、固体を溶解させた。この溶液を80℃で除塵濾過し、反応容器と配管を75℃に加温したエタノール（38.2 L）と水(38.2 L)の混合溶液で洗い込んだ。この濾液を75℃で1時間撹拌し、45℃で１時間撹拌した。得られた懸濁液を室温にて１時間撹拌し、5℃で5時間撹拌した。析出した結晶を濾取し、この濾取した結晶を5℃に冷却したエタノール（45.9 L）と水（30.6 L）の混合溶液で洗浄した。減圧下50℃以下で湿結晶を22時間乾燥した。結晶をトレーに広げ、気温約22℃、湿度約37%で60時間静置することで7'-{[(3-クロロ-2-フルオロフェニル)メチル]カルバモイル}-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-9'-オレート 1ナトリウム（１９）（30.7 kg, 63.4 mol）を収率77.0%で得た。
　上記の方法に準じて合成した化合物（１９）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 10.82 (t, 1H, J = 6.0 Hz), 8.04 (s, 1H), 7.48-7.45 (m, 1H),7.33-7.27 (m, 1H), 7.19-7.15 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz), 3.63 (s, 2H), 3.38 (d, 2H, J = 5.0 Hz), 3.27 (s, 3H), 3.05 (s, 3H), 2.61-2.49 (m, 1H), 2.28-2.15 (m, 4H).
MS: m/z = 462 [M-Na]-
水分量: 1.98% (カールフィッシャー法) N-[(3-chloro-2-fluorophenyl) methyl] -9'-hydroxy-cis-3- (methoxymethyl) -2'-methyl-1 ', 8'-dioxo-1', 2 ', 3', 8'-Tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (18) (38.2 kg, 82.4 mol), ethanol (649 L) And 1 mol / l sodium hydroxide solution (90.6 L) was added dropwise to a suspension of water (329 L) at room temperature. This suspension was stirred at 80 ° C. for 1 hour to dissolve the solid. This solution was subjected to dust filtration at 80 ° C., and the reaction vessel and piping were washed with a mixed solution of ethanol (38.2 L) and water (38.2 L) heated to 75 ° C. The filtrate was stirred at 75 ° C. for 1 hour and stirred at 45 ° C. for 1 hour. The resulting suspension was stirred at room temperature for 1 hour and stirred at 5 ° C. for 5 hours. The precipitated crystals were collected by filtration, and the collected crystals were washed with a mixed solution of ethanol (45.9 L) and water (30.6 L) cooled to 5 ° C. The wet crystals were dried under reduced pressure at 50 ° C. or lower for 22 hours. 7 '-{[(3-Chloro-2-fluorophenyl) methyl] carbamoyl} -cis-3- (methoxymethyl) by spreading the crystals on a tray and standing at a temperature of about 22 ° C. and a humidity of about 37% for 60 hours ) -2'-methyl-1 ', 8'-dioxo-1', 2 ', 3', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -9 ' -Orate monosodium (19) (30.7 kg, 63.4 mol) was obtained in a yield of 77.0%.
NMR and MS were measured for the compound (19) synthesized according to the above method.
1 H-NMR (DMSO-d 6 ) δ: 10.82 (t, 1H, J = 6.0 Hz), 8.04 (s, 1H), 7.48-7.45 (m, 1H), 7.33-7.27 (m, 1H), 7.19 -7.15 (m, 1H), 4.59 (d, 2H, J = 6.0 Hz), 3.63 (s, 2H), 3.38 (d, 2H, J = 5.0 Hz), 3.27 (s, 3H), 3.05 (s, 3H), 2.61-2.49 (m, 1H), 2.28-2.15 (m, 4H).
MS: m / z = 462 [M-Na] -
Moisture content: 1.98% (Karl Fischer method)
実施例４
9'-(ベンジルオキシ)-N-[(3-クロロ-2-フルオロフェニル)メチル]-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１７）の製造 Example 4
9 '-(benzyloxy) -N-[(3-chloro-2-fluorophenyl) methyl] -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2 Production of ', 3', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (17)
工程１ Process 1
Figure JPOXMLDOC01-appb-C000244
Figure JPOXMLDOC01-appb-C000244
　窒素下、シス-3-(メトキシメチル)-1-[(メチルアミノ)メチル]シクロブチルアミン（９）のメタノール溶液（126.50 g, 42.6 mmol相当）にトリエチルアミン（19.4 g, 192 mmol）を加えた後、室温で3-(ベンジルオキシ)-2-(エトキシカルボニル)-4-オキソ-4H-ピラン-5-カルボン酸（１５）（14.9 g, 46.8 mmol）を添加した。この際、化合物（１５）は4分割して加え、各分割添加の間隔は30分とした。この混合液を室温で2時間撹拌した。反応終了後、この溶液に9'-(ベンジルオキシ)-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボン酸（２０）の種晶（1.5 mg）を添加し、氷冷下で2時間撹拌した。得られた懸濁液に2 mol/L塩酸（45 mL, 90 mmol）を氷冷下で30分かけて滴下した後、同温で17時間撹拌した。析出した結晶を濾取し、結晶を冷却したメタノール（60 mL）と水（30 mL）の混合溶液で洗浄した。得られた湿結晶を減圧乾燥することで化合物（２０）（11.9 g, 28.9 mmol）を収率67.8%で得た。
　上記の方法に準じて合成した化合物（２０）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 15.59 (s, 1H), 8.70 (s, 1H), 7.54 (d, 2H, J = 1.6 Hz), 7.40-7.31 (m, 3H), 5.15 (s, 2H), 3.84 (s, 2H), 3.44 (d, 2H, J = 5.2 Hz), 3.31 (s, 3H), 3.12 (s, 3H), 2.64-2.45 (m, 3H), 2.28-2.23 (m, 2H).
MS: m/z = 413 [M+H]+ After adding triethylamine (19.4 g, 192 mmol) to a methanol solution of cis-3- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine (9) (equivalent to 126.50 g, 42.6 mmol) under nitrogen 3- (Benzyloxy) -2- (ethoxycarbonyl) -4-oxo-4H-pyran-5-carboxylic acid (15) (14.9 g, 46.8 mmol) was added at room temperature. At this time, the compound (15) was added in four portions, and the interval between each divided addition was 30 minutes. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, 9 '-(benzyloxy) -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ', 8'-tetrahydro Spiro [cyclobutane-1,4′-pyrido [1,2-a] pyrazine] -7′-carboxylic acid (20) seed crystals (1.5 mg) were added, and the mixture was stirred for 2 hours under ice cooling. To the obtained suspension, 2 mol / L hydrochloric acid (45 mL, 90 mmol) was added dropwise over 30 minutes under ice-cooling, followed by stirring at the same temperature for 17 hours. The precipitated crystals were collected by filtration, and washed with a cooled mixed solution of methanol (60 mL) and water (30 mL). The obtained wet crystals were dried under reduced pressure to obtain Compound (20) (11.9 g, 28.9 mmol) in a yield of 67.8%.
NMR and MS were measured for the compound (20) synthesized according to the above method.
1 H-NMR (DMSO-d 6 ) δ: 15.59 (s, 1H), 8.70 (s, 1H), 7.54 (d, 2H, J = 1.6 Hz), 7.40-7.31 (m, 3H), 5.15 (s , 2H), 3.84 (s, 2H), 3.44 (d, 2H, J = 5.2 Hz), 3.31 (s, 3H), 3.12 (s, 3H), 2.64-2.45 (m, 3H), 2.28-2.23 ( m, 2H).
MS: m / z = 413 [M + H] +
工程２ Process 2
Figure JPOXMLDOC01-appb-C000245
Figure JPOXMLDOC01-appb-C000245
　窒素下、9'-(ベンジルオキシ)-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボン酸（２０）（4.00 g, 9.70 mmol）の1-メチル-2-ピロリドン（16 mL）溶液に氷冷下でジイソプロピルエチルアミン（1.50 g, 11.6 mmol）及びクロロ炭酸イソブチル（1.46 g,10.7 mmol）を滴下した。この混合液を氷冷下で1時間30分撹拌した後、3-クロロ-2-フルオロベンジルアミン（1.78 g, 11.2 mmol）の1-メチル-2-ピロリドン（4.0 mL）溶液を同温で滴下した。この混合液を氷冷下で1時間30分撹拌した。反応終了後、この溶液にジイソプロピルエチルアミン（627 mg, 4.85 mmol）と水（2.0 mL）を添加し、室温で30分撹拌した。この溶液にメタノール（8.0 mL）及び9'-(ベンジルオキシ)-N-[(3-クロロ-2-フルオロフェニル)メチル]-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１７）の種晶を加えた後、室温で１時間撹拌した。得られた懸濁液に室温で水（8.0 mL）を添加し、同温で30分撹拌した。さらに氷冷下で、この懸濁液を1時間30分撹拌した。析出した結晶を濾取し、結晶をメタノール（16 mL）及び水（8.0 mL）の混合溶液で洗浄した。得られた湿結晶を減圧乾燥することで化合物（１７）（5.08 g, 9.17 mmol）を収率94.5%で得た。
　上記の方法に準じて合成した化合物（１７）のNMRとMSの測定結果は、実施例３の化合物（１７）の測定結果と一致した。
MS: m/z = 554 [M+H]+ Under nitrogen, 9 '-(benzyloxy) -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ', 8'-tetrahydrospiro [cyclobutane- To a solution of 1,4′-pyrido [1,2-a] pyrazine] -7′-carboxylic acid (20) (4.00 g, 9.70 mmol) in 1-methyl-2-pyrrolidone (16 mL) was added diisopropyl under ice-cooling. Ethylamine (1.50 g, 11.6 mmol) and isobutyl chlorocarbonate (1.46 g, 10.7 mmol) were added dropwise. The mixture was stirred for 1 hour and 30 minutes under ice cooling, and then a solution of 3-chloro-2-fluorobenzylamine (1.78 g, 11.2 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) was added dropwise at the same temperature. did. The mixture was stirred for 1 hour 30 minutes under ice cooling. After completion of the reaction, diisopropylethylamine (627 mg, 4.85 mmol) and water (2.0 mL) were added to the solution, and the mixture was stirred at room temperature for 30 minutes. To this solution was added methanol (8.0 mL) and 9 '-(benzyloxy) -N-[(3-chloro-2-fluorophenyl) methyl] -cis-3- (methoxymethyl) -2'-methyl-1', Added seed crystal of 8'-dioxo-1 ', 2', 3 ', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (17) Then, the mixture was stirred at room temperature for 1 hour. Water (8.0 mL) was added to the obtained suspension at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The suspension was further stirred for 1 hour and 30 minutes under ice cooling. The precipitated crystals were collected by filtration, and the crystals were washed with a mixed solution of methanol (16 mL) and water (8.0 mL). The obtained wet crystals were dried under reduced pressure to obtain Compound (17) (5.08 g, 9.17 mmol) in a yield of 94.5%.
The NMR and MS measurement results of the compound (17) synthesized according to the above method agreed with the measurement results of the compound (17) of Example 3.
MS: m / z = 554 [M + H] +
実施例５
N-[(3-クロロ-2-フルオロフェニル)メチル]-9'-ヒドロキシ-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１８）の製造 Example 5
N-[(3-Chloro-2-fluorophenyl) methyl] -9'-hydroxy-cis-3- (methoxymethyl) -2'-methyl-1 ', 8'-dioxo-1', 2 ', 3 Production of ', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (18)
工程１ Process 1
Figure JPOXMLDOC01-appb-C000246
Figure JPOXMLDOC01-appb-C000246
　窒素下、(E)-3-(ジメチルアミノ)アクリロニトリル（5.00 g、52.0 mmol）のアセトニトリル（40.0 mL）溶液にピリジン（4.53 g、57.2 mmol）を氷冷下で滴下した。この反応液に塩化2-(ベンジルオキシ)アセチル（10.1 g、54.6 mmol）を氷冷下、2.5時間かけて滴下した。この混合液を氷冷下、5時間撹拌した。反応終了を確認後、この反応液に0.8 mol/L塩酸（80 mL、64 mmol）を氷冷下で滴下し、氷冷下にて2時間撹拌した。析出した固体を濾取し、得られた固体をアセトニトリル(6.6 mL)と水（13.3 mL）の混合溶液で洗浄した。得られた湿固体を減圧下乾燥することで4-(ベンジルオキシ)-2-[(ジメチルアミノ)メチレン]-3-オキソブタンニトリル（２１）を（10.3 g, 42.3 mol）を収率81.3%で得た。
　上記の方法に準じて合成した化合物（２１）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.89 (s, 1H), 7.39-7.28 (m, 5H), 4.52 (s, 2H), 4.34 (s, 2H), 3.29 (s, 3H), 3.26 (s, 3H)
MS: m/z = 245 [M+H]+ Under nitrogen, pyridine (4.53 g, 57.2 mmol) was added dropwise to a solution of (E) -3- (dimethylamino) acrylonitrile (5.00 g, 52.0 mmol) in acetonitrile (40.0 mL) under ice cooling. To this reaction solution, 2- (benzyloxy) acetyl chloride (10.1 g, 54.6 mmol) was added dropwise over 2.5 hours under ice cooling. The mixture was stirred for 5 hours under ice cooling. After confirming the completion of the reaction, 0.8 mol / L hydrochloric acid (80 mL, 64 mmol) was added dropwise to the reaction solution under ice cooling, and the mixture was stirred for 2 hours under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was washed with a mixed solution of acetonitrile (6.6 mL) and water (13.3 mL). The obtained wet solid was dried under reduced pressure to give 4- (benzyloxy) -2-[(dimethylamino) methylene] -3-oxobutanenitrile (21) (10.3 g, 42.3 mol) in a yield of 81.3%. I got it.
NMR and MS were measured for the compound (21) synthesized according to the above method.
1 H-NMR (DMSO-d 6 ) δ: 7.89 (s, 1H), 7.39-7.28 (m, 5H), 4.52 (s, 2H), 4.34 (s, 2H), 3.29 (s, 3H), 3.26 (s, 3H)
MS: m / z = 245 [M + H] +
工程２ Process 2
Figure JPOXMLDOC01-appb-C000247
Figure JPOXMLDOC01-appb-C000247
　窒素下、4-(ベンジルオキシ)-2-[(ジメチルアミノ)メチレン]-３-オキソブタンニトリル（２１）（20.0 g、81.9 mmol）のアセトニトリル（120 mL）溶液にシュウ酸ジメチル（24.2 g、205 mmol）及び無水リチウムブロミド（10.7 g、123 mmol）を添加した。この反応液に1,8-ジアザビシクロ[5.4.0]-7-ウンデセン(22.4 g、147 mol)のアセトニトリル（20 mL）溶液を氷冷下で滴下し、使用した滴下ロートをアセトニトリル（20 mL）で洗浄した。この反応液を室温にて22時間撹拌した。反応終了を確認後、この反応液に0.5 mol/L塩酸（320 mL、160 mmol）を氷冷下で滴下し、室温にて22時間撹拌した。析出した固体を濾取し、得られた固体をアセトニトリル(20 mL)と水（40 mL）の混合溶液と水（60 mL）で順次洗浄した。得られた湿固体を減圧下乾燥することで3-(ベンジルオキシ)-5-シアノ-4-オキソ-4H-ピラン-2-カルボン酸メチル（２２）（19.4 g, 68.0 mol）を収率83.0%で得た。
　上記の方法に準じて合成した化合物（２２）について、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 9.18 (s, 1H), 7.47-7.34 (m, 5H), 5.17 (s, 2H), 3.83 (s, 3H).
MS: m/z = 286 [M+H]+ Under nitrogen, 4- (benzyloxy) -2-[(dimethylamino) methylene] -3-oxobutanenitrile (21) (20.0 g, 81.9 mmol) in acetonitrile (120 mL) was added to dimethyl oxalate (24.2 g, 205 mmol) and anhydrous lithium bromide (10.7 g, 123 mmol) were added. To this reaction solution, a solution of 1,8-diazabicyclo [5.4.0] -7-undecene (22.4 g, 147 mol) in acetonitrile (20 mL) was added dropwise under ice cooling, and the dropping funnel used was acetonitrile (20 mL). Washed with. The reaction was stirred at room temperature for 22 hours. After confirming the completion of the reaction, 0.5 mol / L hydrochloric acid (320 mL, 160 mmol) was added dropwise to the reaction solution under ice-cooling, followed by stirring at room temperature for 22 hours. The precipitated solid was collected by filtration, and the obtained solid was washed successively with a mixed solution of acetonitrile (20 mL) and water (40 mL) and water (60 mL). The obtained wet solid was dried under reduced pressure to obtain methyl 3- (benzyloxy) -5-cyano-4-oxo-4H-pyran-2-carboxylate (22) (19.4 g, 68.0 mol) in a yield of 83.0 Obtained in%.
NMR and MS were measured for the compound (22) synthesized according to the above method.
1 H-NMR (DMSO-d 6 ) δ: 9.18 (s, 1H), 7.47-7.34 (m, 5H), 5.17 (s, 2H), 3.83 (s, 3H).
MS: m / z = 286 [M + H] +
工程３ Process 3
Figure JPOXMLDOC01-appb-C000248
Figure JPOXMLDOC01-appb-C000248
　窒素下、シス-3-(メトキシメチル)-1-[(メチルアミノ)メチル]シクロブチルアミン（９）のメタノール溶液(48.4 mmol相当)にトリエチルアミン（22.1 g, 218 mmol）を氷冷下で滴下した。この反応液に3-(ベンジルオキシ)-5-シアノ-4-オキソ-4H-ピラン-2-カルボン酸メチル（２２）（14.5 g, 50.8 mmol）を氷冷下で添加した。この反応液を室温にて21時間撹拌した。反応終了を確認後、この反応液に2 mol/L塩酸(68 mL、136 mmol)を氷冷下で滴下した後、混合物を氷冷下で2時間撹拌した。析出した固体を濾取し、得られた固体をメタノール（45 mL）と水（23 mL）の混合溶液で洗浄した。得られた湿固体を減圧下乾燥することで9'-(ベンジルオキシ)-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボニトリル（２３）（16.1 g, 40.9 mol）を収率84.6%で得た。
　上記の方法に準じて合成した化合物（２３）について、NMRとMSを測定した。
1H-NMR (CDCl3) δ: 8.16 (s, 1H), 7.62-7.60(m, 2H), 7.37-7.27 (m, 3H), 5.31 (s, 2H), 3.56 (s, 2H), 3.43(s, 3H), 3.42(brs, 1H), 3.18 (s, 3H), 2.58-2.53 (m, 2H), 2.51-2.42(m, 1H), 2.29-2.24(m, 2H).
MS: m/z = 394 [M+H]+ Under nitrogen, triethylamine (22.1 g, 218 mmol) was added dropwise to a methanol solution of cis-3- (methoxymethyl) -1-[(methylamino) methyl] cyclobutylamine (9) (corresponding to 48.4 mmol) under ice cooling. . To this reaction solution, methyl 3- (benzyloxy) -5-cyano-4-oxo-4H-pyran-2-carboxylate (22) (14.5 g, 50.8 mmol) was added under ice cooling. The reaction was stirred at room temperature for 21 hours. After confirming the completion of the reaction, 2 mol / L hydrochloric acid (68 mL, 136 mmol) was added dropwise to the reaction solution under ice cooling, and the mixture was stirred for 2 hours under ice cooling. The precipitated solid was collected by filtration, and the obtained solid was washed with a mixed solution of methanol (45 mL) and water (23 mL). The obtained wet solid was dried under reduced pressure to give 9 '-(benzyloxy) -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ' , 8′-Tetrahydrospiro [cyclobutane-1,4′-pyrido [1,2-a] pyrazine] -7′-carbonitrile (23) (16.1 g, 40.9 mol) was obtained in a yield of 84.6%.
NMR and MS were measured for the compound (23) synthesized according to the above method.
1 H-NMR (CDCl 3 ) δ: 8.16 (s, 1H), 7.62-7.60 (m, 2H), 7.37-7.27 (m, 3H), 5.31 (s, 2H), 3.56 (s, 2H), 3.43 (s, 3H), 3.42 (brs, 1H), 3.18 (s, 3H), 2.58-2.53 (m, 2H), 2.51-2.42 (m, 1H), 2.29-2.24 (m, 2H).
MS: m / z = 394 [M + H] +
工程４ Process 4
Figure JPOXMLDOC01-appb-C000249
Figure JPOXMLDOC01-appb-C000249
　窒素下、9'-(ベンジルオキシ)-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボニトリル（２３）（5.00 g、12.7 mmol）のDMSO（10 mL）溶液に25%水酸化ナトリウム水溶液（25 mL、12.3 eq.）を添加した。この反応液を95℃にて5時間撹拌した。反応終了を確認後、この反応液に6 mol/L塩酸（30 mL、14.2 eq.）を氷冷下で滴下し、室温にて15時間撹拌した。析出した固体を濾取し、得られた固体を水（25 mL）で洗浄した。得られた
湿固体を減圧下乾燥することで9'-(ヒドロキシ)-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボン酸（２４）を（3.50 g, 10.9 mol）を収率85.5%で得た。
　上記の方法に準じて合成した化合物（２４）について、NMRとMSを測定した。
1H-NMR (CDCl3) δ: 14.9 (s, 1H), 12.8 (s, 1H), 8.71 (s, 1H), 3.74 (s, 2H), 3.41-3.40(m, 5H), 3.24(s, 3H), 2.65-2.60 (m, 2H), 2.56-2.50 (m, 1H), 2.37-2.32 (m, 2H).
MS: m/z = 323 [M+H]+ Under nitrogen, 9 '-(benzyloxy) -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ', 8'-tetrahydrospiro [cyclobutane- 1,4'-pyrido [1,2-a] pyrazine] -7'-carbonitrile (23) (5.00 g, 12.7 mmol) in DMSO (10 mL) was added to 25% aqueous sodium hydroxide (25 mL, 12.3 eq.) was added. The reaction was stirred at 95 ° C. for 5 hours. After confirming the completion of the reaction, 6 mol / L hydrochloric acid (30 mL, 14.2 eq.) Was added dropwise to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration, and the obtained solid was washed with water (25 mL). The obtained wet solid was dried under reduced pressure to obtain 9 ′-(hydroxy) -cis-3- (methoxymethyl) -2′-methyl-1 ′, 8′-dioxo-1 ′, 2 ′, 3 ′, 8′-tetrahydrospiro [cyclobutane-1,4′-pyrido [1,2-a] pyrazine] -7′-carboxylic acid (24) (3.50 g, 10.9 mol) was obtained in a yield of 85.5%.
NMR and MS were measured for the compound (24) synthesized according to the above method.
1 H-NMR (CDCl 3 ) δ: 14.9 (s, 1H), 12.8 (s, 1H), 8.71 (s, 1H), 3.74 (s, 2H), 3.41-3.40 (m, 5H), 3.24 (s , 3H), 2.65-2.60 (m, 2H), 2.56-2.50 (m, 1H), 2.37-2.32 (m, 2H).
MS: m / z = 323 [M + H] +
工程５ Process 5
Figure JPOXMLDOC01-appb-C000250
Figure JPOXMLDOC01-appb-C000250
　窒素下、9'-(ヒドロキシ)-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボン酸（２４）（1.00 g, 3.10 mmol）の1-メチル-2-ピロリドン（5.0 mL）溶液に氷冷下でジイソプロピルエチルアミン（921 mg, 7.13 mmol）及びクロロ炭酸イソブチル（889 mg, 6.51 mmol）を滴下した。この溶液を氷冷下で1時間30分撹拌した後、ここに3-クロロ-2-フルオロベンジルアミン（594 mg, 3.72 mmol）を同温で滴下した。この溶液を氷冷下で1時間30分撹拌した。反応終了後、この溶液に28%アンモニア水溶液（1.05 mL, 15.5 mmol）を添加し、室温で20時間撹拌した。得られた懸濁液にエタノール（2.5 mL）及び4 M塩酸（3.0 mL）を室温にて添加した後、同温で30分撹拌した。さらに氷冷下でこの懸濁液を3時間撹拌した。析出した結晶を濾取し、結晶をエタノール（3.0 mL）及び水（3.0 mL）の混合溶液で洗浄した。得られた湿結晶を減圧乾燥することでN-[(3-クロロ-2-フルオロフェニル)メチル]-9'-ヒドロキシ-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１８）（1.26 g, 2.72 mmol）を収率87.7%で得た。
　上記の方法に準じて合成した化合物（１８）のNMRとMSの測定結果は、実施例３の化合物（１８）の測定結果と一致した。
MS: m/z = 464 [M+H]+ 9 '-(hydroxy) -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ', 8'-tetrahydrospiro [cyclobutane-1 under nitrogen , 4'-pyrido [1,2-a] pyrazine] -7'-carboxylic acid (24) (1.00 g, 3.10 mmol) in 1-methyl-2-pyrrolidone (5.0 mL) solution under ice-cooling with diisopropylethylamine (921 mg, 7.13 mmol) and isobutyl chlorocarbonate (889 mg, 6.51 mmol) were added dropwise. This solution was stirred for 1 hour 30 minutes under ice cooling, and then 3-chloro-2-fluorobenzylamine (594 mg, 3.72 mmol) was added dropwise thereto at the same temperature. This solution was stirred for 1 hour 30 minutes under ice cooling. After completion of the reaction, 28% aqueous ammonia solution (1.05 mL, 15.5 mmol) was added to this solution and stirred at room temperature for 20 hours. Ethanol (2.5 mL) and 4 M hydrochloric acid (3.0 mL) were added to the obtained suspension at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The suspension was further stirred for 3 hours under ice cooling. The precipitated crystals were collected by filtration, and the crystals were washed with a mixed solution of ethanol (3.0 mL) and water (3.0 mL). The obtained wet crystals were dried under reduced pressure to give N-[(3-chloro-2-fluorophenyl) methyl] -9'-hydroxy-cis-3- (methoxymethyl) -2'-methyl-1 ', 8 '-Dioxo-1', 2 ', 3', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (18) (1.26 g, 2.72 mmol ) Was obtained in a yield of 87.7%.
The NMR and MS measurement results of the compound (18) synthesized according to the above method agreed with the measurement results of the compound (18) of Example 3.
MS: m / z = 464 [M + H] +
実施例６
7'-{[(3-クロロ-2-フルオロフェニル)メチル]カルバモイル}-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-9'-オレート 1ナトリウム（１９）の製造 Example 6
7 '-{[(3-Chloro-2-fluorophenyl) methyl] carbamoyl} -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ' Of 8,8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -9'-oleate monosodium (19)
工程１ Process 1
Figure JPOXMLDOC01-appb-C000251
Figure JPOXMLDOC01-appb-C000251
　9'-(ベンジルオキシ)-N-[(3-クロロ-2-フルオロフェニル)メチル]-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボキサミド（１７）（1.00 g、1.81 mmol）のDMSO（2.0 mL）溶液に4 mol/L水酸化ナトリウム水溶液（1.0 mL、397 mmol）を添加した。この混合液を100℃にて20時間撹拌した。反応終了を確認後、この反応液にエタノール（8.0 mL）と水（5.0 mL）の混合溶液を80℃で添加した。この懸濁液を80℃で1時間撹拌し、その後この懸濁液を50℃で1時間撹拌した。室温に冷却後、室温で1時間撹拌した。この懸濁液を氷冷下で2時間撹拌した。析出した結晶を濾取し、得られた結晶をエタノール（1.8 mL）と水（1.2 mL）の混合溶液で洗浄した。得られた結晶を減圧下乾燥することで、7'-{[(3-クロロ-2-フルオロフェニル)メチル]カルバモイル}-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-9'-オレート 1ナトリウム（１９）を（663 mg, 1.36 mmol）を収率75.6%で得た。
　上記の方法に準じて合成した化合物（１９）のNMRとMSの測定結果は、実施例３の化合物（１９）の測定結果と一致した。 9 '-(benzyloxy) -N-[(3-chloro-2-fluorophenyl) methyl] -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2 ', 3', 8'-Tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxamide (17) (1.00 g, 1.81 mmol) in DMSO (2.0 mL) 4 mol / L aqueous sodium hydroxide solution (1.0 mL, 397 mmol) was added. The mixture was stirred at 100 ° C. for 20 hours. After confirming the completion of the reaction, a mixed solution of ethanol (8.0 mL) and water (5.0 mL) was added to this reaction solution at 80 ° C. The suspension was stirred at 80 ° C. for 1 hour, after which the suspension was stirred at 50 ° C. for 1 hour. After cooling to room temperature, the mixture was stirred at room temperature for 1 hour. The suspension was stirred for 2 hours under ice cooling. The precipitated crystals were collected by filtration, and the obtained crystals were washed with a mixed solution of ethanol (1.8 mL) and water (1.2 mL). The obtained crystals were dried under reduced pressure to obtain 7 ′-{[(3-chloro-2-fluorophenyl) methyl] carbamoyl} -cis-3- (methoxymethyl) -2′-methyl-1 ′, 8 '-Dioxo-1', 2 ', 3', 8'-tetrahydrospiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -9'-oleate monosodium (19) (663 mg , 1.36 mmol) was obtained in a yield of 75.6%.
The NMR and MS measurement results of the compound (19) synthesized according to the above method agreed with the measurement results of the compound (19) of Example 3.
実施例７
工程１ Example 7
Process 1
Figure JPOXMLDOC01-appb-C000252
Figure JPOXMLDOC01-appb-C000252
　3-オキソシクロブタンカルボン酸（10.00 g, 87.6 mmol）のイソプロパノール（100 mL）溶液に濃硫酸（100 mg, 1.02 mmol）を加えた。この溶液を還流下で1.5時間撹拌した後、溶媒65 mLを還流下で留去した。この濃縮液にイソプロパノール（70 mL）を加え、還流下で3時間撹拌した。反応終了後、溶媒を減圧下留去した。得られた濃縮物に酢酸エチル（50 mL）と水（30 mL）を添加し抽出した。得られた有機層を5%重曹水（30 mL）で洗浄した後、無水硫酸マグネシウムで乾燥した。硫酸マグネシウムを除去した後、溶媒を減圧下留去した。得られた粗生成物を減圧蒸留（35 mmHg, 135℃）し、3-オキソシクロブタンカルボン酸イソプロピル（２５）（12.37 g, 79.2 mmol）を収率90.4%で得た。
　上記の方法に準じて合成した化合物（２５）のNMRを測定した。
1H-NMR (DMSO-d6) δ: 4.95 (septet, 1H, J = 6.0 Hz), 3.56-3.18 (m, 5H), 1.21 (d, 6H, J = 6.0 Hz). Concentrated sulfuric acid (100 mg, 1.02 mmol) was added to a solution of 3-oxocyclobutanecarboxylic acid (10.00 g, 87.6 mmol) in isopropanol (100 mL). After stirring this solution under reflux for 1.5 hours, 65 mL of the solvent was distilled off under reflux. To this concentrated solution was added isopropanol (70 mL), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Ethyl acetate (50 mL) and water (30 mL) were added to the resulting concentrate for extraction. The obtained organic layer was washed with 5% aqueous sodium bicarbonate (30 mL) and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was distilled under reduced pressure (35 mmHg, 135 ° C.) to obtain isopropyl 3-oxocyclobutanecarboxylate (25) (12.37 g, 79.2 mmol) in a yield of 90.4%.
NMR of the compound (25) synthesized according to the above method was measured.
1 H-NMR (DMSO-d 6 ) δ: 4.95 (septet, 1H, J = 6.0 Hz), 3.56-3.18 (m, 5H), 1.21 (d, 6H, J = 6.0 Hz).
工程２ Process 2
Figure JPOXMLDOC01-appb-C000253
Figure JPOXMLDOC01-appb-C000253
　3-オキソシクロブタンカルボン酸イソプロピル（２５）（3.00 g, 19.2 mmol）のトルエン（18 mL）溶液にベンジルアミン（2.16 g, 20.2 mmol）を添加した。この溶液を加熱還流下で1時間撹拌し、３-ベンジルイミノ-シクロブタンカルボン酸イソプロピル（２５’）とした。水の除去にはディーンスターク管を使用した。反応混合液を氷冷下まで冷却した。氷冷下でトリエチルアミン（2.91 g, 28.7 mmol）及びアセトンシアノヒドリン（2.45 g, 28.8 mmol）を添加し、同温で3時間撹拌した。反応終了後、この混合液に水（6.0 mL）を添加し抽出した。得られた有機層を5%重曹水（6.0 mL）で洗浄した。得られた溶液を無水硫酸マグネシウムで乾燥した。硫酸マグネシウムを除去した後、溶媒を減圧下留去し、3-ベンジルアミノ-3-シアノシクロブタンカルボン酸イソプロピル（２６）の粗生成物（6.55 g, 19.2 mmol相当）を得た。得られた化合物（２６）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（２６）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.37-7.23 (m, 5H), 4.93-4.86 (m, 1H), 3.68 (d, 0.15H, J = 7.6 Hz), 3.65 (d, 0.85H, J = 7.2 Hz), 3.46-3.44 (m, 1H), 3.28-3.11 (m, 1H), 2.68-2.63 (m, 0.85H), 2.58-2.53 (m, 0.15H), 2.41-2.36 (m, 0.15H), 2.32-2.27 (m, 0.85H), 1.22-2.16 (m, 6H).
MS: m/z = 273 [M+H]+ To a solution of isopropyl 3-oxocyclobutanecarboxylate (25) (3.00 g, 19.2 mmol) in toluene (18 mL) was added benzylamine (2.16 g, 20.2 mmol). This solution was stirred with heating under reflux for 1 hour to obtain isopropyl 3-benzylimino-cyclobutanecarboxylate (25 ′). A Dean Stark tube was used to remove the water. The reaction mixture was cooled to ice cooling. Triethylamine (2.91 g, 28.7 mmol) and acetone cyanohydrin (2.45 g, 28.8 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, water (6.0 mL) was added to the mixture and extracted. The obtained organic layer was washed with 5% aqueous sodium bicarbonate (6.0 mL). The resulting solution was dried over anhydrous magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product of isopropyl 3-benzylamino-3-cyanocyclobutanecarboxylate (26) (equivalent to 6.55 g, 19.2 mmol). The obtained crude product of compound (26) was used in the next step with a yield of 100%.
NMR and MS of the compound (26) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.37-7.23 (m, 5H), 4.93-4.86 (m, 1H), 3.68 (d, 0.15H, J = 7.6 Hz), 3.65 (d, 0.85H, J = 7.2 Hz), 3.46-3.44 (m, 1H), 3.28-3.11 (m, 1H), 2.68-2.63 (m, 0.85H), 2.58-2.53 (m, 0.15H), 2.41-2.36 (m, 0.15H), 2.32-2.27 (m, 0.85H), 1.22-2.16 (m, 6H).
MS: m / z = 273 [M + H] +
工程３ Process 3
Figure JPOXMLDOC01-appb-C000254
Figure JPOXMLDOC01-appb-C000254
　3-ベンジルアミノ-3-シアノシクロブタンカルボン酸イソプロピル（２６）の粗生成物（6.55 g, 19.2 mmol相当）の酢酸（12 mL）溶液に、シアン酸カリウム（1.76 g, 21.2 mmol）の水（4.5 mL）溶液を氷冷下で滴下した。この溶液を室温で1.5時間撹拌した後、8M塩酸水溶液（6.0 mL, 48.0 mmol）を添加した。この溶液を室温で1時間撹拌した。反応終了後、この混合液にトルエン（30 mL）を添加し抽出した。得られた有機層を水（12 mL）および10%リン酸カリウム水溶液（18 mL）で順次洗浄し、さらに10%食塩水（12 mL）で洗浄した。有機層を無水硫酸マグネシウムで乾燥した。硫酸マグネシウムを除去した後、溶媒を減圧下留去することで5-ベンジル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸イソプロピル（２７）の粗生成物（8.42 g, 19.2 mmol相当）を得た。得られた化合物（２７）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（２７）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 11.06 (s, 0.86H), 10.95 (s, 0.14H), 7.37-7.14 (m, 5H), 4.98-4.82 (m, 1H), 4.66 (s, 0.14H), 4.59 (s, 0.86H), 3.00 (quin, 1H, J = 8.4 Hz), 2.60-2.37 (m, 4H), 1.22-1.41 (m, 6H).
MS: m/z = 316 [M+H]+ To a solution of isopropyl 3-benzylamino-3-cyanocyclobutanecarboxylate (26) (6.55 g, equivalent to 19.2 mmol) in acetic acid (12 mL) was added potassium cyanate (1.76 g, 21.2 mmol) in water (4.5 mL) The solution was added dropwise under ice cooling. After stirring this solution at room temperature for 1.5 hours, 8M aqueous hydrochloric acid (6.0 mL, 48.0 mmol) was added. The solution was stirred at room temperature for 1 hour. After completion of the reaction, toluene (30 mL) was added to the mixture and extracted. The obtained organic layer was washed successively with water (12 mL) and 10% aqueous potassium phosphate solution (18 mL), and further washed with 10% brine (12 mL). The organic layer was dried over anhydrous magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off under reduced pressure to give a crude product of isopropyl 5-benzyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-2-carboxylate (27) (8.42). g, corresponding to 19.2 mmol). The obtained crude product of compound (27) was used in the next step with a yield of 100%.
NMR and MS of the compound (27) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 11.06 (s, 0.86H), 10.95 (s, 0.14H), 7.37-7.14 (m, 5H), 4.98-4.82 (m, 1H), 4.66 (s, 0.14H), 4.59 (s, 0.86H), 3.00 (quin, 1H, J = 8.4 Hz), 2.60-2.37 (m, 4H), 1.22-1.41 (m, 6H).
MS: m / z = 316 [M + H] +
工程４ Process 4
Figure JPOXMLDOC01-appb-C000255
Figure JPOXMLDOC01-appb-C000255
　5-ベンジル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸イソプロピル（２７）の粗生成物（8.42 g, 19.2 mmol相当）のDMF（12 mL）溶液に、炭酸カリウム（2.65 g, 19.2 mmol）及びヨウ化メチル（2.73 g, 19.2 mmol）を添加した。この溶液を室温で2時間撹拌した。反応終了後、この混合液にトルエン（30 mL）及び水（21 mL）を添加し抽出した。得られた有機層を5%食塩水（15 mL）で2回洗浄した後、溶媒を減圧下留去し、5-ベンジル-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸イソプロピル（２８）の粗生成物（19.2 mmol相当）を得た。得られた化合物（２８）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（２８）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.38-7.13 (m, 5H), 4.98-4.81 (m, 1H), 4.72 (s, 0.28H), 4.65 (s, 1.72H), 3.04 (quin, 1H, J = 8.8 Hz), 2.54-2.38 (m, 4H), 1.22-1.14 (m, 6H).
MS: m/z = 331 [M+H]+ To a solution of isopropyl 5-benzyl-6,8-dioxo-5,7-diazaspiro [3.4] isopropyl-2-carboxylate (27) (8.42 g, equivalent to 19.2 mmol) in DMF (12 mL) was added carbonic acid. Potassium (2.65 g, 19.2 mmol) and methyl iodide (2.73 g, 19.2 mmol) were added. The solution was stirred at room temperature for 2 hours. After completion of the reaction, toluene (30 mL) and water (21 mL) were added to the mixture and extracted. The obtained organic layer was washed twice with 5% brine (15 mL), and the solvent was evaporated under reduced pressure to give 5-benzyl-7-methyl-6,8-dioxo-5,7-diazaspiro [3.4 A crude product (equivalent to 19.2 mmol) of isopropyl octane-2-carboxylate (28) was obtained. The obtained crude product of compound (28) was used in the next step with a yield of 100%.
NMR and MS of the compound (28) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.38-7.13 (m, 5H), 4.98-4.81 (m, 1H), 4.72 (s, 0.28H), 4.65 (s, 1.72H), 3.04 (quin, 1H, J = 8.8 Hz), 2.54-2.38 (m, 4H), 1.22-1.14 (m, 6H).
MS: m / z = 331 [M + H] +
工程５ Process 5
Figure JPOXMLDOC01-appb-C000256
Figure JPOXMLDOC01-appb-C000256
　5-ベンジル-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸イソプロピル（２８）の粗生成物（19.2 mmol相当）のイソプロパノール（12 mL）溶液に、氷冷下で2M水酸化ナトリウム水溶液（9.6 mL, 19.2 mmol）を滴下した。この混合液を室温で4時間撹拌した。反応終了後、この混合液にトルエン（15 mL）を添加し、水層を分離した。得られた水層に氷冷下で2M塩酸（10.56 mL, 21.1 mmol）を加えた。水層に酢酸エチル（30 mL）を加え抽出した。得られた有機層を10%食塩水（15 mL）で2回洗浄した。有機層を無水硫酸ナトリウムで乾燥した。硫酸マグネシウムを除去した後、溶媒を減圧下留去し、5-ベンジル-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-2-カルボン酸（２９）の粗生成物を得た。化合物（２９）に酢酸エチルを添加し液量を24 mLに調整した。この溶液を60℃に加熱した。同温度でn-プロピルアミン（1.36 mL, 19.1 mmol）を溶液に加えた（溶液は懸濁する）。懸濁液を室温に冷却した後、1時間撹拌した。攪拌後、懸濁液に酢酸イソプロピル（24 mL）を加え室温で6時間撹拌した。析出した結晶を濾取し、酢酸イソプロピル（9.0 mL）で洗浄した。得られた湿結晶を減圧乾燥することで4-ベンジル-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸　n-プロピルアミン塩（２９a-nPrNH2）の粗結晶（3.49 g, 10.05 mmol）を収率52.3%で得た。
　得られた化合物（２９a-nPrNH2）の粗結晶（2.00 g, 5.76 mmol）の酢酸イソプロピル（16 mL）懸濁液を室温で4時間撹拌した。析出した結晶を濾取し、酢酸イソプロピル（4.0 mL）で洗浄した。得られた湿結晶を減圧下乾燥し、化合物（２９a-nPrNH2）（1.90 g, 5.47 mmol）を収率95.0%で得た。
　上記の方法に準じて合成した化合物（２９a-nPrNH2）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.86 (brs, 1H), 7.35-7.23 (m, 5H), 4.63 (s, 2H), 2.90 (s, 3H), 2.74 (quin, 1H, J = 8.8 Hz), 3.64-2.61 (m, 2H), 2.51-2.44 (m, 2H), 2.31-2.26 (m, 2H), 1.48 (sextet, 2H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz).
MS: m/z = 289 [M-C3H7N+H]+
　得られた化合物（29a-nPrNH2）は以下の分析条件でcis体：trans体＝99：1であった。
HPLC分析条件
カラム：Atlantis(登録商標) T3 : 3 μm、4.6 mm×150 mm (Waters)
カラム温度：40℃付近の一定温度
移動相：移動相A：10 mMリン酸緩衝液（pH=2.6）
　　　　移動相B：MeCN
グラジエント条件：
時間（分）   0  25  35  36  40
A(%)　　　  80  20  20  80  80
B(%)　　　  20  80  80  20  20
流速：1.0 mL/分
検出方法：UV 220 nm
参考；保持時間：cis体（約8.3分）、trans体（約8.5分） To a solution of a crude product of isopropyl 5-benzyl-7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-2-carboxylate (28) (corresponding to 19.2 mmol) in isopropanol (12 mL), 2M aqueous sodium hydroxide solution (9.6 mL, 19.2 mmol) was added dropwise under ice cooling. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, toluene (15 mL) was added to the mixture and the aqueous layer was separated. 2M hydrochloric acid (10.56 mL, 21.1 mmol) was added to the obtained aqueous layer under ice-cooling. The aqueous layer was extracted with ethyl acetate (30 mL). The obtained organic layer was washed twice with 10% brine (15 mL). The organic layer was dried over anhydrous sodium sulfate. After removing magnesium sulfate, the solvent was distilled off under reduced pressure to give a crude product of 5-benzyl-7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-2-carboxylic acid (29) Got. Ethyl acetate was added to the compound (29) to adjust the liquid volume to 24 mL. The solution was heated to 60 ° C. N-Propylamine (1.36 mL, 19.1 mmol) was added to the solution at the same temperature (the solution was suspended). The suspension was cooled to room temperature and then stirred for 1 hour. After stirring, isopropyl acetate (24 mL) was added to the suspension, and the mixture was stirred at room temperature for 6 hours. The precipitated crystals were collected by filtration and washed with isopropyl acetate (9.0 mL). The obtained wet crystals were dried under reduced pressure to give 4-benzyl-7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylic acid n-propylamine salt (29a-nPrNH 2 ) crude crystals (3.49 g, 10.05 mmol) were obtained in a yield of 52.3%.
A suspension of the obtained compound (29a-nPrNH 2 ) in crude crystals (2.00 g, 5.76 mmol) in isopropyl acetate (16 mL) was stirred at room temperature for 4 hours. The precipitated crystals were collected by filtration and washed with isopropyl acetate (4.0 mL). The obtained wet crystals were dried under reduced pressure to obtain the compound (29a-nPrNH 2 ) (1.90 g, 5.47 mmol) in a yield of 95.0%.
NMR and MS of the compound (29a-nPrNH 2 ) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.86 (brs, 1H), 7.35-7.23 (m, 5H), 4.63 (s, 2H), 2.90 (s, 3H), 2.74 (quin, 1H, J = 8.8 Hz), 3.64-2.61 (m, 2H), 2.51-2.44 (m, 2H), 2.31-2.26 (m, 2H), 1.48 (sextet, 2H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz).
MS: m / z = 289 [M-C3H7N + H] +
The obtained compound (29a-nPrNH 2 ) was cis form: trans form = 99: 1 under the following analysis conditions.
HPLC analysis condition column: Atlantis (registered trademark) T3: 3 μm, 4.6 mm × 150 mm (Waters)
Column temperature: Constant temperature around 40 ° C. Mobile phase: Mobile phase A: 10 mM phosphate buffer (pH = 2.6)
Mobile phase B: MeCN
Gradient condition:
Time (minutes) 0 25 35 36 40
A (%) 80 20 20 80 80
B (%) 20 80 80 20 20
Flow rate: 1.0 mL / min Detection method: UV 220 nm
Reference; Retention time: cis form (approximately 8.3 minutes), trans form (approximately 8.5 minutes)
工程６ Step 6
Figure JPOXMLDOC01-appb-C000257
Figure JPOXMLDOC01-appb-C000257
　4-ベンジル-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸　n-プロピルアミン塩（２９a-nPrNH2）（2.00 g, 5.76 mmol）の酢酸エチル（10 mL）懸濁液に2 mol/L塩酸（3.15 mL, 6.30 mmol）を室温で加え抽出した。得られた有機層を10%食塩水（4.0 mL）で洗浄し、無水硫酸ナトリウムで乾燥した。硫酸ナトリウムを除去した後、溶媒を減圧下留去し、4-ベンジル-7-メチル-6,8-ジオキソ-5,7-ジアザスピロ[3.4]オクタン-シス-2-カルボン酸（２９a）の粗生成物を得た。化合物（２９a）の粗生成物にテトラヒドロフランを加え再度溶媒を減圧下留去した。得られた濃縮物のテトラヒドロフラン（3.0 ml）溶液を、氷冷下、水素化ホウ素ナトリウム（240 mg, 6.34 mmol）のテトラヒドロフラン（4.0 mL）懸濁液に加えた。この混合物を氷冷下で1時間撹拌した後、三フッ化ホウ素－ジエチルエーテル錯体（0.72 mL, 5.73 mmol）を同温で加えた。この混合物を氷冷下で3時間撹拌した。反応終了後、この溶液を5%重曹水（4.0 mL）と10%食塩水（4.0 mL）の混合溶液に氷冷下で滴下した。反応容器をテトラヒドロフラン（1.0 mL）で洗浄した。この混合液にトルエン（8.0 mL）と酢酸エチル（8.0 mL）の混合溶液を加え抽出した。得られた有機層を5%重曹水（6.0 mL）で2回、10%食塩水（6.0 mL）で1回洗浄した。有機層を無水硫酸マグネシウムで乾燥した。硫酸マグネシウムを除去した後、溶媒を減圧下留去することでシス-5-ベンジル-2-(ヒドロキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（３０a）の粗生成物（2.26 g, 5.76 mmol相当）を得た。得られた化合物（３０a）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（３０a）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.36-7.24 (m, 5H), 4.63 (s, 2H), 4.60 (t, 1H, J = 5.6 Hz), 3.32-3.28 (m, 2H), 3.30 (s, 3H), 2.90 (s, 3H), 2.47-2.38 (m, 1H), 2.23-2.11 (m, 4H).
MS: m/z = 275 [M+H]+ Acetic acid of 4-benzyl-7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylic acid n-propylamine salt (29a-nPrNH 2 ) (2.00 g, 5.76 mmol) The ethyl (10 mL) suspension was extracted with 2 mol / L hydrochloric acid (3.15 mL, 6.30 mmol) at room temperature. The obtained organic layer was washed with 10% brine (4.0 mL) and dried over anhydrous sodium sulfate. After removing the sodium sulfate, the solvent was distilled off under reduced pressure to give crude 4-benzyl-7-methyl-6,8-dioxo-5,7-diazaspiro [3.4] octane-cis-2-carboxylic acid (29a). The product was obtained. Tetrahydrofuran was added to the crude product of compound (29a), and the solvent was evaporated again under reduced pressure. A solution of the obtained concentrate in tetrahydrofuran (3.0 ml) was added to a suspension of sodium borohydride (240 mg, 6.34 mmol) in tetrahydrofuran (4.0 mL) under ice cooling. The mixture was stirred for 1 hour under ice cooling, and then boron trifluoride-diethyl ether complex (0.72 mL, 5.73 mmol) was added at the same temperature. The mixture was stirred for 3 hours under ice cooling. After completion of the reaction, this solution was added dropwise to a mixed solution of 5% aqueous sodium bicarbonate (4.0 mL) and 10% brine (4.0 mL) under ice cooling. The reaction vessel was washed with tetrahydrofuran (1.0 mL). To this mixture was added a mixed solution of toluene (8.0 mL) and ethyl acetate (8.0 mL), and extracted. The obtained organic layer was washed twice with 5% aqueous sodium bicarbonate (6.0 mL) and once with 10% brine (6.0 mL). The organic layer was dried over anhydrous magnesium sulfate. After removing magnesium sulfate, the solvent was distilled off under reduced pressure to obtain cis-5-benzyl-2- (hydroxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane-6,8-dione (30a ) Crude product (2.26 g, corresponding to 5.76 mmol). The obtained crude product of compound (30a) was used in the next step with a yield of 100%.
NMR and MS of the compound (30a) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.36-7.24 (m, 5H), 4.63 (s, 2H), 4.60 (t, 1H, J = 5.6 Hz), 3.32-3.28 (m, 2H), 3.30 (s, 3H), 2.90 (s, 3H), 2.47-2.38 (m, 1H), 2.23-2.11 (m, 4H).
MS: m / z = 275 [M + H] +
工程７ Step 7
Figure JPOXMLDOC01-appb-C000258
Figure JPOXMLDOC01-appb-C000258
　シス-5-ベンジル-2-(ヒドロキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（３０a）の粗生成物（5.76 mmol相当）とヨウ化メチル（2.04 g, 14.4 mmol）のテトラヒドロフラン（10 mL）溶液に、氷冷下、カリウムtert-ブトキシド（1.62 g, 14.4 mmol）のDMF（4.0 mL）溶液を加えた。この混合液を同温で1時間撹拌した。反応終了後、反応液に水（10 mL）を加えた。この溶液にトルエン（10 mL）を加え抽出した。得られた有機層を10%食塩水（6.0 mL）で2回洗浄した。有機層の溶媒を減圧下留去し、得られた濃縮液にトルエンを加え、再度減圧下、溶媒を留去することで5-ベンジル-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（３１a）の粗生成物（5.76 mmol相当）を得た。得られた化合物（３１a）の粗生成物を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（３１a）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.36-7.14 (m, 5H), 4.64 (s, 2H), 3.23 (d, 2H, J = 5.6 Hz), 3.21 (s, 3H), 2.90 (s, 3H), 2.57-2.46 (m, 1H), 2.22-2.13 (m, 4H).
MS: m/z = 289 [M+H]+ Crude product of cis-5-benzyl-2- (hydroxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane-6,8-dione (30a) (corresponding to 5.76 mmol) and methyl iodide (2.04 g, 14.4 mmol) in tetrahydrofuran (10 mL) was added a solution of potassium tert-butoxide (1.62 g, 14.4 mmol) in DMF (4.0 mL) under ice cooling. The mixture was stirred at the same temperature for 1 hour. After completion of the reaction, water (10 mL) was added to the reaction solution. Toluene (10 mL) was added to this solution for extraction. The obtained organic layer was washed twice with 10% brine (6.0 mL). The solvent of the organic layer was distilled off under reduced pressure, toluene was added to the resulting concentrated solution, and the solvent was distilled off again under reduced pressure to give 5-benzyl-cis-2- (methoxymethyl) -7-methyl-5. , 7-Diazaspiro [3.4] octane-6,8-dione (31a) crude product (corresponding to 5.76 mmol) was obtained. The obtained crude product of compound (31a) was used in the next step with a yield of 100%.
NMR and MS of the compound (31a) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.36-7.14 (m, 5H), 4.64 (s, 2H), 3.23 (d, 2H, J = 5.6 Hz), 3.21 (s, 3H), 2.90 (s , 3H), 2.57-2.46 (m, 1H), 2.22-2.13 (m, 4H).
MS: m / z = 289 [M + H] +
工程８ Process 8
Figure JPOXMLDOC01-appb-C000259
Figure JPOXMLDOC01-appb-C000259
　70%水素化ビス(2-メトキシエトキシ)アルミニウムナトリウム（3.33 g, 11.5 mmol）のトルエン（1.5 mL）溶液を70℃に加温した。この溶液に5-ベンジル-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン-6,8-ジオン（３１a）の粗生成物（2.88 mmol相当）のトルエン（5.0 mL）溶液を同温で加えた。この混合物を同温で4.5時間撹拌した。反応終了後、この溶液を室温に冷却した。この溶液を（＋）－酒石酸ナトリウムカリウム四水和物（3.66 g, 13.0 mmol）の水（8.0 mL）溶液に氷冷下で滴下した。反応容器をトルエン(1.0 mL)で洗浄した。この混合溶液を室温で1時間撹拌した。この溶液を有機層と水層に分液した。有機層を10%食塩水（2.0 mL）で洗浄し、5-ベンジル-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン（３２a）のトルエン溶液（2.88 mmol相当）を得た。得られた化合物（３２a）のトルエン溶液を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（３２a）のトルエン溶液を濃縮乾固し、NMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 7.35-7.19 (m, 5H), 3.70 (s, 2H), 3.25 (d, 2H, J = 6.4 Hz), 3.22 (s, 2H), 3.21 (s, 3H), 2.82 (s, 2H), 2.26-2.09 (m, 1H), 2.21 (s, 3H), 2.02-1.97 (m, 2H), 1.91-1.36 (m, 2H).
MS: m/z = 261 [M+H]+ A solution of 70% sodium bis (2-methoxyethoxy) aluminum hydride (3.33 g, 11.5 mmol) in toluene (1.5 mL) was heated to 70 ° C. To this solution was added 5-benzyl-cis-2- (methoxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane-6,8-dione (31a) crude product (equivalent to 2.88 mmol) in toluene (equivalent to 2.88 mmol). 5.0 mL) solution was added at the same temperature. The mixture was stirred at the same temperature for 4.5 hours. After completion of the reaction, the solution was cooled to room temperature. This solution was added dropwise to a solution of (+)-potassium sodium tartrate tetrahydrate (3.66 g, 13.0 mmol) in water (8.0 mL) under ice cooling. The reaction vessel was washed with toluene (1.0 mL). The mixed solution was stirred at room temperature for 1 hour. This solution was separated into an organic layer and an aqueous layer. The organic layer was washed with 10% brine (2.0 mL), and 5-benzyl-cis-2- (methoxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane (32a) in toluene (2.88 mmol). Equivalent). The toluene solution of the obtained compound (32a) was used in the next step with a yield of 100%.
A toluene solution of the compound (32a) synthesized according to the above method was concentrated to dryness, and NMR and MS were measured.
1 H-NMR (DMSO-d 6 ) δ: 7.35-7.19 (m, 5H), 3.70 (s, 2H), 3.25 (d, 2H, J = 6.4 Hz), 3.22 (s, 2H), 3.21 (s , 3H), 2.82 (s, 2H), 2.26-2.09 (m, 1H), 2.21 (s, 3H), 2.02-1.97 (m, 2H), 1.91-1.36 (m, 2H).
MS: m / z = 261 [M + H] +
工程９ Step 9
Figure JPOXMLDOC01-appb-C000260
Figure JPOXMLDOC01-appb-C000260
　5-ベンジル-シス-2-(メトキシメチル)-7-メチル-5,7-ジアザスピロ[3.4]オクタン(３２a）のトルエン溶液（2.88 mmol相当）に2 mol/L塩酸（4.0 mL）を室温で加えて水層を分離した。得られた水層に塩化ヒドロキシルアンモニウム（400 mg, 5.76 mmol）を室温で添加した。この反応液を室温で2時間撹拌した。反応終了後、この溶液に4 mol/L水酸化ナトリウム水溶液（3.8 mL）を室温で滴下した。この混合溶液に酢酸エチル（5.0 mL）を加え抽出した。得られた有機層を10%食塩水（3.0 mL）で洗浄した。有機層の溶媒を減圧下留去しN-ベンジル-シス-2-(メトキシメチル)-1-((メチルアミノ)メチル)シクロブチルアミン（３３a）の粗生成物を得た。化合物（３３a）の粗生成物に酢酸エチルを加え液量8.0 mLに調整した。この溶液にエタノール（3.0 mL）を加えた。この溶液に4 mol/L HCl/酢酸エチル溶液（0.79 mL, 3.16 mmol）を室温で加えた。得られた懸濁液を30分間室温で撹拌し、ここに4 mol/L HCl/酢酸エチル溶液（0.65 mL, 2.60 mmol）を加えた。この懸濁液を室温で2時間撹拌した。析出した結晶を濾取し、この濾取した固体を酢酸エチル（4.5 mL）とエタノール（1.5 mL）の混合溶液で洗浄した。得られた湿結晶を減圧乾燥することでN-ベンジル-シス-2-(メトキシメチル)-1-((メチルアミノ)メチル)シクロブチルアミン　２塩酸塩（３３a-2HCl）（461 mg, 1.43 mmol）を収率49.7%で得た。
　上記の方法に準じて合成した化合物（３３a）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 9.92 (brs, 2H), 9.34 (brs, 2H), 7.68-7.66 (m, 2H), 7.46-7.43 (m, 3H), 4.19 (brs, 2H), 3.60 (brs, 2H), 3.45-3.37 (m, 2H), 3.23 (s, 3H), 2.69 (brs, 3H), 2.55-2.47 (m, 1H), 2.42-2.37 (m, 2H), 2.26-2.21 (m, 2H).
MS: m/z = 249 [M-H-2Cl]+
　Cl含量を、イオンクロマトグラフィーを用いて測定した。
Cl含量: 22.2% 2-Benzyl-cis-2- (methoxymethyl) -7-methyl-5,7-diazaspiro [3.4] octane (32a) in toluene solution (equivalent to 2.88 mmol) was added 2 mol / L hydrochloric acid (4.0 mL) at room temperature. In addition, the aqueous layer was separated. To the obtained aqueous layer, hydroxylammonium chloride (400 mg, 5.76 mmol) was added at room temperature. The reaction was stirred at room temperature for 2 hours. After completion of the reaction, 4 mol / L aqueous sodium hydroxide solution (3.8 mL) was added dropwise to this solution at room temperature. The mixed solution was extracted with ethyl acetate (5.0 mL). The obtained organic layer was washed with 10% brine (3.0 mL). The solvent of the organic layer was distilled off under reduced pressure to obtain a crude product of N-benzyl-cis-2- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine (33a). Ethyl acetate was added to the crude product of the compound (33a) to adjust the liquid volume to 8.0 mL. Ethanol (3.0 mL) was added to this solution. To this solution was added 4 mol / L HCl / ethyl acetate solution (0.79 mL, 3.16 mmol) at room temperature. The resulting suspension was stirred for 30 minutes at room temperature, and 4 mol / L HCl / ethyl acetate solution (0.65 mL, 2.60 mmol) was added thereto. The suspension was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, and the collected solid was washed with a mixed solution of ethyl acetate (4.5 mL) and ethanol (1.5 mL). The obtained wet crystals were dried under reduced pressure to give N-benzyl-cis-2- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine dihydrochloride (33a-2HCl) (461 mg, 1.43 mmol) Was obtained in a yield of 49.7%.
NMR and MS of the compound (33a) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 9.92 (brs, 2H), 9.34 (brs, 2H), 7.68-7.66 (m, 2H), 7.46-7.43 (m, 3H), 4.19 (brs, 2H) , 3.60 (brs, 2H), 3.45-3.37 (m, 2H), 3.23 (s, 3H), 2.69 (brs, 3H), 2.55-2.47 (m, 1H), 2.42-2.37 (m, 2H), 2.26 -2.21 (m, 2H).
MS: m / z = 249 [MH-2Cl] +
The Cl content was measured using ion chromatography.
Cl content: 22.2%
工程１０ Step 10
Figure JPOXMLDOC01-appb-C000261
Figure JPOXMLDOC01-appb-C000261
　N-ベンジル-シス-2-(メトキシメチル)-1-((メチルアミノ)メチル)シクロブチルアミン　２塩酸塩（３３a-2HCl）（200 mg, 0.622 mmol）のメタノール（1.4 mL）溶液に酢酸ナトリウム（102 mg, 1.24 mmol）、酢酸（74 mg, 1.23 mmol）及び10%パラジウム炭素（N.E. CHEMCAT社製PEタイプ, 50%含水, 20 mg）を室温で添加した。反応容器を水素で置換し、水素ガス圧0.4 MPaで室温で6.5時間撹拌した。反応終了後、反応容器を窒素で置換し、不溶物を濾過で除去した。反応容器と不溶物をメタノール(1.0 mL)で洗浄し、シス-3-(メトキシメチル)-1-((メチルアミノ)メチル)シクロブチルアミン（９）のメタノール溶液(0.622 mmol相当)を得た。得られた化合物（９）のメタノール溶液を収率100%として次工程に用いた。
　上記の方法に準じて合成した化合物（９）のメタノール溶液にナトリウムメトキシド（メタノール溶液）を適量添加し、その濃縮乾固物のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 3.28 (d, 2H, J = 6.0 Hz), 3.20 (s, 3H), 2.42 (s, 2H), 2.31 (s, 3H), 2.10-1.98 (m, 3H), 1.59 (brs, 2H), 1.46-1.41 (m, 2H).
MS: m/z = 171 [M+Na]+ To a solution of N-benzyl-cis-2- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine dihydrochloride (33a-2HCl) (200 mg, 0.622 mmol) in methanol (1.4 mL) was added sodium acetate ( 102 mg, 1.24 mmol), acetic acid (74 mg, 1.23 mmol) and 10% palladium carbon (PE type manufactured by NE CHEMCAT, 50% water content, 20 mg) were added at room temperature. The reaction vessel was replaced with hydrogen, and the mixture was stirred at a hydrogen gas pressure of 0.4 MPa at room temperature for 6.5 hours. After completion of the reaction, the reaction vessel was replaced with nitrogen, and insoluble matters were removed by filtration. The reaction vessel and insoluble material were washed with methanol (1.0 mL) to obtain a methanol solution (corresponding to 0.622 mmol) of cis-3- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine (9). The methanol solution of the obtained compound (9) was used in the next step with a yield of 100%.
An appropriate amount of sodium methoxide (methanol solution) was added to a methanol solution of the compound (9) synthesized according to the above method, and NMR and MS of the concentrated dry solid were measured.
1 H-NMR (DMSO-d 6 ) δ: 3.28 (d, 2H, J = 6.0 Hz), 3.20 (s, 3H), 2.42 (s, 2H), 2.31 (s, 3H), 2.10-1.98 (m , 3H), 1.59 (brs, 2H), 1.46-1.41 (m, 2H).
MS: m / z = 171 [M + Na] +
工程１１ Step 11
Figure JPOXMLDOC01-appb-C000262
Figure JPOXMLDOC01-appb-C000262
　シス-3-(メトキシメチル)-1-((メチルアミノ)メチル)シクロブチルアミン（９）のメタノール溶液（1.30 g, 0.622 mmol相当）にトリエチルアミン（283 mg, 2.80 mmol）を加えた後、室温で3-(ベンジルオキシ)-2-(エトキシカルボニル)-4-オキソ-4H-ピラン-5-カルボン酸（１５）（218 mg, 0.685 mmol）を1時間かけて少しずつ添加した。この混合液を室温で1.5時間撹拌した。反応終了後、この溶液に9'-(ベンジルオキシ)-シス-3-(メトキシメチル)-2'-メチル-1',8'-ジオキソ-1',2',3',8'-テトラヒドロスピロ[シクロブタン-1,4'-ピリド[1,2-a]ピラジン]-7'-カルボン酸（２０）の種晶（1.0 mg）を添加し、氷冷下で30分間撹拌した。得られた懸濁液に2 mol/L塩酸（0.6 mL, 0.12 mmol）を氷冷下で30分間かけて滴下した後、同温で1.5時間撹拌した。析出した結晶を濾取し、結晶を冷却したメタノール（0.33 mL）と水（0.17 mL）の混合溶液で洗浄した。得られた湿結晶を減圧乾燥することで化合物（２０）（164 mg, 0.398 mmol）を収率64.0%で得た。
　上記の方法に準じて合成した化合物（２０）のNMRとMSを測定した。
1H-NMR (DMSO-d6) δ: 15.59 (s, 1H), 8.70 (s, 1H), 7.45-7.52 (m, 2H), 7.40-7.31 (m, 3H), 5.15 (s, 2H), 3.84 (s, 2H), 3.44 (d, 2H, J = 5.2 Hz), 3.31 (s, 3H), 3.12 (s, 3H), 2.64-2.45 (m, 3H), 2.28-2.23 (m, 2H).
MS: m/z = 413 [M+H]+ Triethylamine (283 mg, 2.80 mmol) was added to a methanol solution of cis-3- (methoxymethyl) -1-((methylamino) methyl) cyclobutylamine (9) (equivalent to 1.30 g, 0.622 mmol), and then at room temperature. 3- (Benzyloxy) -2- (ethoxycarbonyl) -4-oxo-4H-pyran-5-carboxylic acid (15) (218 mg, 0.685 mmol) was added in portions over 1 hour. The mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, 9 '-(benzyloxy) -cis-3- (methoxymethyl) -2'-methyl-1', 8'-dioxo-1 ', 2', 3 ', 8'-tetrahydro Spiro [cyclobutane-1,4'-pyrido [1,2-a] pyrazine] -7'-carboxylic acid (20) seed crystals (1.0 mg) were added, and the mixture was stirred for 30 minutes under ice cooling. To the obtained suspension, 2 mol / L hydrochloric acid (0.6 mL, 0.12 mmol) was added dropwise over 30 minutes under ice cooling, followed by stirring at the same temperature for 1.5 hours. The precipitated crystals were collected by filtration and washed with a cooled mixed solution of methanol (0.33 mL) and water (0.17 mL). The obtained wet crystals were dried under reduced pressure to obtain Compound (20) (164 mg, 0.398 mmol) in a yield of 64.0%.
NMR and MS of the compound (20) synthesized according to the above method were measured.
1 H-NMR (DMSO-d 6 ) δ: 15.59 (s, 1H), 8.70 (s, 1H), 7.45-7.52 (m, 2H), 7.40-7.31 (m, 3H), 5.15 (s, 2H) , 3.84 (s, 2H), 3.44 (d, 2H, J = 5.2 Hz), 3.31 (s, 3H), 3.12 (s, 3H), 2.64-2.45 (m, 3H), 2.28-2.23 (m, 2H ).
MS: m / z = 413 [M + H] +
実施例８
　化合物（２９）の塩の検討は、以下の方法で行った。
　化合物（２９）に溶媒を加え溶液とし、室温で有機塩基を加えた（溶液は懸濁する）。得られた懸濁液を同温で1時間から16時間撹拌した。析出した結晶を濾取し、得られた湿結晶を減圧乾燥することで化合物（２９）の各アミン塩を取得した。
　なお、原料として、その異性体比がcis体：trans体＝８６：１４から８９：１１の化合物（２９）を用いた。
　異性体比は、下記分析条件において液体クロマトグラフィーを用いて測定した。
結果： Example 8
The salt of compound (29) was examined by the following method.
A solvent was added to compound (29) to form a solution, and an organic base was added at room temperature (the solution was suspended). The resulting suspension was stirred at the same temperature for 1 to 16 hours. The precipitated crystals were collected by filtration, and the resulting wet crystals were dried under reduced pressure to obtain each amine salt of compound (29).
As a raw material, compound (29) having an isomer ratio of cis form: trans form = 86: 14 to 89:11 was used.
The isomer ratio was measured using liquid chromatography under the following analysis conditions.
result:
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000263
分析条件
カラム：Atlantis(登録商標) T3 : 3 μm、4.6 mm×150 mm (Waters)
カラム温度：40℃付近の一定温度
移動相：移動相A：10 mMリン酸緩衝液（pH=2.6）
　　　　移動相B：MeCN
グラジエント条件：
時間（分）   0  25  35  36  40
A(%)　　　  80  20  20  80  80 
B(%)　　　  20  80  80  20  20
流速：1.0 mL/分
検出方法：UV 220 nm
参考；保持時間：cis体（約8.3分）、trans体（約8.5分） Analysis condition column: Atlantis (registered trademark) T3: 3 μm, 4.6 mm × 150 mm (Waters)
Column temperature: Constant temperature around 40 ° C. Mobile phase: Mobile phase A: 10 mM phosphate buffer (pH = 2.6)
Mobile phase B: MeCN
Gradient condition:
Time (minutes) 0 25 35 36 40
A (%) 80 20 20 80 80
B (%) 20 80 80 20 20
Flow rate: 1.0 mL / min Detection method: UV 220 nm
Reference; Retention time: cis form (approximately 8.3 minutes), trans form (approximately 8.5 minutes)
　本発明によれば、ＨＩＶインテグラーゼ阻害活性を有し、抗ＨＩＶ剤として有用な式（１８）の化合物又はその塩を製造するための中間体及びその中間体の製造方法が提供される。また、本発明によれば、式（１８）の化合物又はその塩の製造方法が提供される。 According to the present invention, there are provided an intermediate for producing a compound of formula (18) or a salt thereof having HIV integrase inhibitory activity and useful as an anti-HIV agent, and a method for producing the intermediate. Moreover, according to this invention, the manufacturing method of the compound or its salt of Formula (18) is provided.

Claims (63)

  1. 　式（９）
    Figure JPOXMLDOC01-appb-C000001
    の化合物又はその塩を製造する方法であって、式[VIII]
    Figure JPOXMLDOC01-appb-C000002
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
    の化合物又はその塩を接触水素還元反応に付し、式（９）の化合物又はその塩を得る工程を含む方法。     Formula (9)
    Figure JPOXMLDOC01-appb-C000001
    Or a salt thereof, comprising the formula [VIII]
    Figure JPOXMLDOC01-appb-C000002
    Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
    A method comprising a step of subjecting a compound of the formula or a salt thereof to a catalytic hydrogen reduction reaction to obtain a compound of the formula (9) or a salt thereof.
  2. 　式[VII]
    Figure JPOXMLDOC01-appb-C000003
    （式中、Ｒ１は請求項１に記載の通りである。）
    の化合物又はその塩と、ヒドロキシアミン又はその塩とを反応させ、式[VIII]の化合物又はその塩を得る工程をさらに含む請求項１記載の方法。     Formula [VII]
    Figure JPOXMLDOC01-appb-C000003
    (Wherein R 1 is as defined in claim 1)
    The method according to claim 1, further comprising the step of reacting a compound of the formula (I) or a salt thereof with a hydroxyamine or a salt thereof to obtain a compound of the formula [VIII] or a salt thereof.
  3. 　式[VI]
    Figure JPOXMLDOC01-appb-C000004
    （式中、Ｒ１は請求項１に記載の通りである。）
    の化合物と、アルミニウム系還元剤とを反応させ、式[VII]の化合物又はその塩を得る工程をさらに含む請求項２記載の方法。     Formula [VI]
    Figure JPOXMLDOC01-appb-C000004
    (Wherein R 1 is as defined in claim 1)
    The method of Claim 2 which further includes the process of making the compound of this, and an aluminum type reducing agent react, and obtaining the compound or its salt of Formula [VII].
  4. 　式[V]
    Figure JPOXMLDOC01-appb-C000005
    （式中、Ｒ１は請求項１に記載の通りである。）
    の化合物と、メチル化剤を反応させ、式[VI]の化合物を得る工程をさらに含む請求項３記載の方法。     Formula [V]
    Figure JPOXMLDOC01-appb-C000005
    (Wherein R 1 is as defined in claim 1)
    The method of Claim 3 which further includes the process of making the compound of this, and a methylating agent react, and obtaining the compound of Formula [VI].
  5. 　式[IV-a]
    Figure JPOXMLDOC01-appb-C000006
    （式中、Ｒ１は請求項１に記載の通りである。）
    の化合物又はその塩と、ボラン系還元剤とを反応させ、式[V]の化合物を得る工程をさらに含む請求項４記載の方法。     Formula [IV-a]
    Figure JPOXMLDOC01-appb-C000006
    (Wherein R 1 is as defined in claim 1)
    The method of Claim 4 which further includes the process of reacting the compound of this, or its salt, and a borane-type reducing agent, and obtaining the compound of Formula [V].
  6. 　式[III]
    Figure JPOXMLDOC01-appb-C000007
    （式中、Ｒ１は請求項１に記載の通りである。）
    の化合物を、アルカリ加水分解に付し、式[IV-a]の化合物又はその塩を得る工程をさらに含む請求項５記載の方法。     Formula [III]
    Figure JPOXMLDOC01-appb-C000007
    (Wherein R 1 is as defined in claim 1)
    6. The method according to claim 5, further comprising the step of subjecting the compound of the above to alkali hydrolysis to obtain a compound of the formula [IV-a] or a salt thereof.
  7. 　式（２）
    Figure JPOXMLDOC01-appb-C000008
    の化合物と、ベンジル化剤とを反応させ、式[III]の化合物を得る工程をさらに含む請求項６記載の方法。     Formula (2)
    Figure JPOXMLDOC01-appb-C000008
    The method of Claim 6 which further includes the process of making the compound of this, and a benzylating agent react, and obtaining the compound of Formula [III].
  8. 　式（１）
    Figure JPOXMLDOC01-appb-C000009
    の化合物又はその塩と、メチル化剤とを反応させ、再結晶により式（２）の化合物を得る工程をさらに含む請求項７記載の方法。     Formula (1)
    Figure JPOXMLDOC01-appb-C000009
    The method of Claim 7 which further includes the process of making the compound or its salt, and a methylating agent react, and obtaining the compound of Formula (2) by recrystallization.
  9. 　式[IV]
    Figure JPOXMLDOC01-appb-C000010
    （式中、Ｒ１は請求項１に記載の通りである。）
    の化合物又はその塩から式[IV-a]の化合物又はその塩を得る工程をさらに含む請求項５記載の方法。     Formula [IV]
    Figure JPOXMLDOC01-appb-C000010
    (Wherein R 1 is as defined in claim 1)
    The method according to claim 5, further comprising the step of obtaining a compound of the formula [IV-a] or a salt thereof from the compound of
  10. 　式[XXVIII]
    Figure JPOXMLDOC01-appb-C000011
    （式中、Ｒ５は、Ｃ１－６アルキルであり、Ｒ１は請求項１に記載の通りである。）
    の化合物を、アルカリ加水分解に付し、式[IV]の化合物又はその塩を得る工程をさらに含む請求項９記載の方法。     Formula [XXVIII]
    Figure JPOXMLDOC01-appb-C000011
    (Wherein R 5 is C 1-6 alkyl and R 1 is as defined in claim 1)
    The method according to claim 9, further comprising the step of subjecting the compound of formula (IV) to alkaline hydrolysis to obtain a compound of formula [IV] or a salt thereof.
  11. 　式[XXVII]
    Figure JPOXMLDOC01-appb-C000012
    （式中、Ｒ５は、Ｃ１－６アルキルであり、Ｒ１は請求項１に記載の通りである。）
    の化合物又はその塩と、メチル化剤を反応させ、式[XXVIII]の化合物を得る工程をさらに含む請求項１０記載の方法。     Formula [XXVII]
    Figure JPOXMLDOC01-appb-C000012
    (Wherein R 5 is C 1-6 alkyl and R 1 is as defined in claim 1)
    The method according to claim 10, further comprising a step of reacting a compound of the above or a salt thereof with a methylating agent to obtain a compound of the formula [XXVIII].
  12. 　式[XXVI]
    Figure JPOXMLDOC01-appb-C000013
    （式中、Ｒ５は、Ｃ１－６アルキルであり、Ｒ１は請求項１に記載の通りである。）
    の化合物又はその塩とシアン酸カリウム又はシアン酸ナトリウムを反応させ、式[XXVII]の化合物又はその塩を得る工程をさらに含む請求項１１記載の方法。     Formula [XXVI]
    Figure JPOXMLDOC01-appb-C000013
    (Wherein R 5 is C 1-6 alkyl and R 1 is as defined in claim 1)
    The method according to claim 11, further comprising a step of reacting a compound of the above or a salt thereof with potassium cyanate or sodium cyanate to obtain a compound of the formula [XXVII] or a salt thereof.
  13. 　式[XXV]
    Figure JPOXMLDOC01-appb-C000014
    （式中、Ｒ５は、Ｃ１－６アルキルである。）
    の化合物と式Ｒ１－ＮＨ２（式中、Ｒ１は請求項１に記載の通りである。）の化合物又はその塩を反応させた後、続いてシアノ化剤を反応させ、式[XXVI]の化合物又はその塩を得る工程をさらに含む請求項１２記載の方法。     Formula [XXV]
    Figure JPOXMLDOC01-appb-C000014
    Wherein R 5 is C 1-6 alkyl.
    And a compound of the formula R 1 —NH 2 (wherein R 1 is as defined in claim 1) or a salt thereof, followed by a reaction with a cyanating agent to produce a compound of the formula [XXVI The method of Claim 12 which further includes the process of obtaining the compound or its salt.
  14. 　式（９）
    Figure JPOXMLDOC01-appb-C000015
    の化合物又はその塩。     Formula (9)
    Figure JPOXMLDOC01-appb-C000015
    Or a salt thereof.
  15. 　式[VIII]
    Figure JPOXMLDOC01-appb-C000016
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
    の化合物又はその塩。     Formula [VIII]
    Figure JPOXMLDOC01-appb-C000016
    Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
    Or a salt thereof.
  16. 　式[VII]
    Figure JPOXMLDOC01-appb-C000017
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
    の化合物又はその塩。     Formula [VII]
    Figure JPOXMLDOC01-appb-C000017
    Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
    Or a salt thereof.
  17. 　式[VI]
    Figure JPOXMLDOC01-appb-C000018
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
    の化合物。     Formula [VI]
    Figure JPOXMLDOC01-appb-C000018
    Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
    Compound.
  18. 　式[V]
    Figure JPOXMLDOC01-appb-C000019
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
    の化合物。     Formula [V]
    Figure JPOXMLDOC01-appb-C000019
    Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
    Compound.
  19. 　式[IV]
    Figure JPOXMLDOC01-appb-C000020
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルである。）
    の化合物又はその塩。     Formula [IV]
    Figure JPOXMLDOC01-appb-C000020
    Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy.
    Or a salt thereof.
  20. 　式[XXVIII]
    Figure JPOXMLDOC01-appb-C000021
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、Ｒ５は、Ｃ１－６アルキルである。）
    の化合物。     Formula [XXVIII]
    Figure JPOXMLDOC01-appb-C000021
    (Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, and R 5 is C 1-6 alkyl.)
    Compound.
  21. 　式（２）
    Figure JPOXMLDOC01-appb-C000022
    の化合物。     Formula (2)
    Figure JPOXMLDOC01-appb-C000022
    Compound.
  22. 　式[XXVII]
    Figure JPOXMLDOC01-appb-C000023
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、Ｒ５は、Ｃ１－６アルキルである。）
    の化合物又はその塩。     Formula [XXVII]
    Figure JPOXMLDOC01-appb-C000023
    (Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, and R 5 is C 1-6 alkyl.)
    Or a salt thereof.
  23. 　式[XXVI]
    Figure JPOXMLDOC01-appb-C000024
    （式中、Ｒ１は、無置換又はハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジルであり、Ｒ５は、Ｃ１－６アルキルである。）
    の化合物又はその塩。     Formula [XXVI]
    Figure JPOXMLDOC01-appb-C000024
    (Wherein R 1 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, and R 5 is C 1-6 alkyl.)
    Or a salt thereof.
  24. 　式（１８）
    Figure JPOXMLDOC01-appb-C000025
    の化合物又はその塩を製造する方法であって、
    式[XX]
    Figure JPOXMLDOC01-appb-C000026
    （式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVII]
    Figure JPOXMLDOC01-appb-C000027
    （式中、Ｒ２は前記の通りである。）
    の化合物又はその塩を得る工程；及び
    式[XVII]の化合物又はその塩と、酸とを反応させ、式（１８）の化合物又はその塩を得る工程を含む方法。     Formula (18)
    Figure JPOXMLDOC01-appb-C000025
    A method for producing a compound or a salt thereof, comprising:
    Formula [XX]
    Figure JPOXMLDOC01-appb-C000026
    (Wherein R 2 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, or C 1-4 alkyl.)
    Or a salt thereof with 3-chloro-2-fluorobenzylamine to give a compound of the formula [XVII]
    Figure JPOXMLDOC01-appb-C000027
    (Wherein R 2 is as described above.)
    And a step of obtaining a compound of the formula (18) or a salt thereof by reacting a compound of the formula [XVII] or a salt thereof with an acid.
  25. 　式（９）
    Figure JPOXMLDOC01-appb-C000028
    の化合物又はその塩と、式[XV]
    Figure JPOXMLDOC01-appb-C000029
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項２４に記載の通りである。）
    の化合物又はその塩とを、有機塩基の存在下で反応させ、式[XX]の化合物又はその塩を得る工程をさらに含む請求項２４記載の方法。     Formula (9)
    Figure JPOXMLDOC01-appb-C000028
    Or a salt thereof and the formula [XV]
    Figure JPOXMLDOC01-appb-C000029
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 24.
    The method according to claim 24, further comprising a step of reacting the compound of the formula (I) or a salt thereof in the presence of an organic base to obtain a compound of the formula [XX] or a salt thereof.
  26. 　式（１８）
    Figure JPOXMLDOC01-appb-C000030
    の化合物又はその塩を製造する方法であって、
    式（９）
    Figure JPOXMLDOC01-appb-C000031
    の化合物又はその塩と、式[XVI]
    Figure JPOXMLDOC01-appb-C000032
    （式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルであり、Ｒ３はＣ１－４アルキルである。）
    の化合物を有機塩基の存在下で反応させ、式[XVII]
    Figure JPOXMLDOC01-appb-C000033
    （式中、Ｒ２は前記の通りである。）
    の化合物又はその塩を得る工程；及び
    式[XVII]の化合物又はその塩と、酸とを反応させ、式（１８）の化合物又はその塩を得る工程を含む方法。     Formula (18)
    Figure JPOXMLDOC01-appb-C000030
    A method for producing a compound or a salt thereof, comprising:
    Formula (9)
    Figure JPOXMLDOC01-appb-C000031
    Or a salt thereof and the formula [XVI]
    Figure JPOXMLDOC01-appb-C000032
    Wherein R 2 is unsubstituted or halogen, C 1-4 alkyl or benzyl substituted with C 1-4 alkoxy, or C 1-4 alkyl, and R 3 is C 1-4 alkyl. )
    Is reacted in the presence of an organic base to produce a compound of formula [XVII]
    Figure JPOXMLDOC01-appb-C000033
    (Wherein R 2 is as described above.)
    And a step of obtaining a compound of the formula (18) or a salt thereof by reacting a compound of the formula [XVII] or a salt thereof with an acid.
  27. 　式[XV]
    Figure JPOXMLDOC01-appb-C000034
    （式中、Ｒ２及びＲ３は請求項２６に記載の通りである。）
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVI]の化合物を得る工程をさらに含む請求項２６記載の方法。     Formula [XV]
    Figure JPOXMLDOC01-appb-C000034
    (Wherein R 2 and R 3 are as defined in claim 26).
    27. The method according to claim 26, further comprising the step of reacting the compound of the above or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula [XVI].
  28. 　式[XIV]
    Figure JPOXMLDOC01-appb-C000035
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項２６に記載の通りである。）
    の化合物と、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸とを反応させ、式[XV]の化合物又はその塩を得る工程をさらに含む請求項２５又は２７記載の方法。     Formula [XIV]
    Figure JPOXMLDOC01-appb-C000035
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 26.
    28. The method according to claim 25 or 27, further comprising a step of reacting the compound of the above with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of the formula [XV] or a salt thereof.
  29. 　式[XII]
    Figure JPOXMLDOC01-appb-C000036
    （式中、Ｒ２は請求項２６に記載の通りである。）
    の化合物又はその塩と、式[XIII]
    Figure JPOXMLDOC01-appb-C000037
    （式中、Ｒ３は請求項２６に記載の通りである。）
    の化合物とを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XIV]の化合物を得る工程をさらに含む請求項２８記載の方法。     Formula [XII]
    Figure JPOXMLDOC01-appb-C000036
    (Wherein R 2 is as defined in claim 26).
    Or a salt thereof and the formula [XIII]
    Figure JPOXMLDOC01-appb-C000037
    (Wherein R 3 is as defined in claim 26).
    29. The method of claim 28, further comprising reacting the compound of formula (XIV) in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide to obtain a compound of formula [XIV]. .
  30. 　式（１０）
    Figure JPOXMLDOC01-appb-C000038
    の化合物又はその塩と式[XI]
    Figure JPOXMLDOC01-appb-C000039
    （式中、Ｒ２は請求項２６に記載の通りである。）
    の化合物を有機塩基の存在下で反応させ、式[XII]の化合物又はその塩を得る工程をさらに含む請求項２９記載の方法。     Formula (10)
    Figure JPOXMLDOC01-appb-C000038
    Or a salt thereof and the formula [XI]
    Figure JPOXMLDOC01-appb-C000039
    (Wherein R 2 is as defined in claim 26).
    30. The method according to claim 29, further comprising the step of reacting the compound of formula (XII) in the presence of an organic base to obtain a compound of formula [XII] or a salt thereof.
  31. 　プロピオル酸tert-ブチルと、ジエチルアミンとを反応させ、式（１０）の化合物又はその塩を得る工程をさらに含む請求項３０記載の方法。 The method according to claim 30, further comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of formula (10) or a salt thereof.
  32. 　式[XX]
    Figure JPOXMLDOC01-appb-C000040
    （式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩。     Formula [XX]
    Figure JPOXMLDOC01-appb-C000040
    Wherein R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy. Benzyl, or C 1-4 alkyl).
    Or a salt thereof.
  33. 　式（１８）
    Figure JPOXMLDOC01-appb-C000041
    の化合物又はその塩を製造する方法であって、式（２４）
    Figure JPOXMLDOC01-appb-C000042
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式（１８）の化合物又はその塩を得る工程を含む方法。     Formula (18)
    Figure JPOXMLDOC01-appb-C000041
    Or a salt thereof, comprising the formula (24)
    Figure JPOXMLDOC01-appb-C000042
    A method comprising a step of reacting a compound of the formula (I) or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula (18) or a salt thereof.
  34. 　式[XXIII]
    Figure JPOXMLDOC01-appb-C000043
    （式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩と、水酸化ナトリウム水溶液とを反応させ、式（２４）の化合物又はその塩を得る工程をさらに含む請求項３３記載の方法。     Formula [XXIII]
    Figure JPOXMLDOC01-appb-C000043
    Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
    34. The method according to claim 33, further comprising the step of reacting the compound or a salt thereof with an aqueous sodium hydroxide solution to obtain a compound of the formula (24) or a salt thereof.
  35. 　式（９）
    Figure JPOXMLDOC01-appb-C000044
    の化合物又はその塩と、式[XXII]
    Figure JPOXMLDOC01-appb-C000045
    （式中、Ｒ４は請求項３４に記載の通りである。）
    の化合物を、有機塩基の存在下で反応させ、式[XXIII]の化合物又はその塩を得る工程をさらに含む請求項３４記載の方法。     Formula (9)
    Figure JPOXMLDOC01-appb-C000044
    Or a salt thereof and the formula [XXII]
    Figure JPOXMLDOC01-appb-C000045
    (Wherein R 4 is as defined in claim 34).
    35. The method according to claim 34, further comprising the step of reacting the compound of formula (XXIII) to obtain a compound of the formula [XXIII] or a salt thereof.
  36. 　式[XXI]
    Figure JPOXMLDOC01-appb-C000046
    （式中、Ｒ４は請求項３４に記載の通りである。）
    の化合物又はその塩と、シュウ酸ジメチルとを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XXII]の化合物を得る工程をさらに含む請求項３５記載の方法。     Formula [XXI]
    Figure JPOXMLDOC01-appb-C000046
    (Wherein R 4 is as defined in claim 34).
    Or a salt thereof and dimethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide to obtain a compound of formula [XXII]. 36. The method of claim 35, further comprising:
  37. 　３－（ジメチルアミノ）アクリロニトリルと式[XI']
    Figure JPOXMLDOC01-appb-C000047
    （式中、Ｒ４は請求項３４に記載の通りである。）
    の化合物を有機塩基の存在下で反応させ、式[XXI]の化合物又はその塩を得る工程をさらに含む請求項３６記載の方法。     3- (Dimethylamino) acrylonitrile and the formula [XI ']
    Figure JPOXMLDOC01-appb-C000047
    (Wherein R 4 is as defined in claim 34).
    37. The method according to claim 36, further comprising the step of reacting the compound of formula (XXI) in the presence of an organic base to obtain a compound of formula [XXI] or a salt thereof.
  38. 　式（２４）
    Figure JPOXMLDOC01-appb-C000048
    の化合物又はその塩。     Formula (24)
    Figure JPOXMLDOC01-appb-C000048
    Or a salt thereof.
  39. 　式[XXIII]
    Figure JPOXMLDOC01-appb-C000049
    （式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩。     Formula [XXIII]
    Figure JPOXMLDOC01-appb-C000049
    Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
    Or a salt thereof.
  40. 　式（１９）
    Figure JPOXMLDOC01-appb-C000050
    の化合物を製造する方法であって、
    式[XX]
    Figure JPOXMLDOC01-appb-C000051
    （式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVII]
    Figure JPOXMLDOC01-appb-C000052
    （式中、Ｒ２は前記の通りである。）
    の化合物を得る工程；
    式[XVII]の化合物と、酸とを反応させ、式（１８）
    Figure JPOXMLDOC01-appb-C000053
    の化合物を得る工程；及び
    式（１８）の化合物と、水酸化ナトリウムとを反応させ、式（１９）の化合物を得る工程を含む方法。     Formula (19)
    Figure JPOXMLDOC01-appb-C000050
    A process for producing a compound of
    Formula [XX]
    Figure JPOXMLDOC01-appb-C000051
    (Wherein R 2 is unsubstituted or benzyl substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy, or C 1-4 alkyl.)
    Or a salt thereof with 3-chloro-2-fluorobenzylamine to give a compound of the formula [XVII]
    Figure JPOXMLDOC01-appb-C000052
    (Wherein R 2 is as described above.)
    Obtaining a compound of:
    A compound of formula [XVII] is reacted with an acid to give a compound of formula (18)
    Figure JPOXMLDOC01-appb-C000053
    And a step of reacting a compound of formula (18) with sodium hydroxide to obtain a compound of formula (19).
  41. 　式（９）
    Figure JPOXMLDOC01-appb-C000054
    の化合物又はその塩と、式[XV]
    Figure JPOXMLDOC01-appb-C000055
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項４０に記載の通りである。）
    の化合物又はその塩とを、有機塩基の存在下で反応させ、式[XX]の化合物又はその塩を得る工程をさらに含む請求項４０記載の方法。     Formula (9)
    Figure JPOXMLDOC01-appb-C000054
    Or a salt thereof and the formula [XV]
    Figure JPOXMLDOC01-appb-C000055
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 40.
    41. The method according to claim 40, further comprising the step of reacting the compound of the formula (I) or a salt thereof in the presence of an organic base to obtain the compound of the formula [XX] or a salt thereof.
  42. 　式（１９）
    Figure JPOXMLDOC01-appb-C000056
    の化合物を製造する方法であって、
    式（９）
    Figure JPOXMLDOC01-appb-C000057
    の化合物又はその塩と、式[XVI]
    Figure JPOXMLDOC01-appb-C000058
    （式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルであり、Ｒ３はＣ１－４アルキルである。）
    の化合物を有機塩基の存在下で反応させ、式[XVII]
    Figure JPOXMLDOC01-appb-C000059
    （式中、Ｒ２は前記の通りである。）
    の化合物又はその塩を得る工程；
    式[XVII]の化合物又はその塩と、酸とを反応させ、式（１８）
    Figure JPOXMLDOC01-appb-C000060
    の化合物を得る工程；及び
    式（１８）の化合物と、水酸化ナトリウム水溶液とを反応させ、式（１９）の化合物を得る工程を含む方法。     Formula (19)
    Figure JPOXMLDOC01-appb-C000056
    A process for producing a compound of
    Formula (9)
    Figure JPOXMLDOC01-appb-C000057
    Or a salt thereof and the formula [XVI]
    Figure JPOXMLDOC01-appb-C000058
    Wherein R 2 is unsubstituted or halogen, C 1-4 alkyl or benzyl substituted with C 1-4 alkoxy, or C 1-4 alkyl, and R 3 is C 1-4 alkyl. )
    Is reacted in the presence of an organic base to produce a compound of formula [XVII]
    Figure JPOXMLDOC01-appb-C000059
    (Wherein R 2 is as described above.)
    Obtaining a compound of or a salt thereof;
    A compound of formula [XVII] or a salt thereof is reacted with an acid to give a compound of formula (18)
    Figure JPOXMLDOC01-appb-C000060
    And a step of reacting a compound of formula (18) with an aqueous sodium hydroxide solution to obtain a compound of formula (19).
  43. 　式[XV]
    Figure JPOXMLDOC01-appb-C000061
    （式中、Ｒ２及びＲ３は請求項４２に記載の通りである。）
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVI]の化合物を得る工程をさらに含む請求項４２記載の方法。     Formula [XV]
    Figure JPOXMLDOC01-appb-C000061
    (Wherein R 2 and R 3 are as defined in claim 42).
    43. The method according to claim 42, further comprising a step of reacting the compound of the above or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula [XVI].
  44. 　式[XIV]
    Figure JPOXMLDOC01-appb-C000062
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項４０に記載の通りである。）
    の化合物と、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸とを反応させ、式[XV]の化合物又はその塩を得る工程をさらに含む請求項４１又は４３記載の方法。     Formula [XIV]
    Figure JPOXMLDOC01-appb-C000062
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 40.
    44. The method according to claim 41 or 43, further comprising a step of reacting a compound of the above with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of the formula [XV] or a salt thereof.
  45. 　式[XII]
    Figure JPOXMLDOC01-appb-C000063
    （式中、Ｒ２は請求項４０に記載の通りである。）
    の化合物又はその塩と、式[XIII]
    Figure JPOXMLDOC01-appb-C000064
    （式中、Ｒ３はＣ１－４アルキルである。）
    の化合物とを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XIV]の化合物を得る工程をさらに含む請求項４４記載の方法。     Formula [XII]
    Figure JPOXMLDOC01-appb-C000063
    (Wherein R 2 is as defined in claim 40).
    Or a salt thereof and the formula [XIII]
    Figure JPOXMLDOC01-appb-C000064
    Wherein R 3 is C 1-4 alkyl.
    45. The method of claim 44, further comprising reacting the compound of formula (XIV) with a compound of formula [XIV] in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide. .
  46. 　式（１０）
    Figure JPOXMLDOC01-appb-C000065
    の化合物又はその塩と式[XI]
    Figure JPOXMLDOC01-appb-C000066
    （式中、Ｒ２は請求項４０に記載の通りである。）
    の化合物を有機塩基の存在下で反応させ、式[XII]の化合物又はその塩を得る工程をさらに含む請求項４５記載の方法。     Formula (10)
    Figure JPOXMLDOC01-appb-C000065
    Or a salt thereof and the formula [XI]
    Figure JPOXMLDOC01-appb-C000066
    (Wherein R 2 is as defined in claim 40).
    46. The method according to claim 45, further comprising the step of reacting the compound of formula (XII) in the presence of an organic base to obtain a compound of formula [XII] or a salt thereof.
  47. 　プロピオル酸tert-ブチルと、ジエチルアミンとを反応させ、式（１０）の化合物又はその塩を得る工程をさらに含む請求項４６記載の方法。 The method according to claim 46, further comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of formula (10) or a salt thereof.
  48. 　式（１９）
    Figure JPOXMLDOC01-appb-C000067
    の化合物を製造する方法であって、
    式（２４）
    Figure JPOXMLDOC01-appb-C000068
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式（１８）
    Figure JPOXMLDOC01-appb-C000069
    の化合物を得る工程；及び
    式（１８）の化合物と、水酸化ナトリウム水溶液とを反応させ、式（１９）の化合物を得る工程を含む方法。     Formula (19)
    Figure JPOXMLDOC01-appb-C000067
    A process for producing a compound of
    Formula (24)
    Figure JPOXMLDOC01-appb-C000068
    Or a salt thereof with 3-chloro-2-fluorobenzylamine to give a compound of formula (18)
    Figure JPOXMLDOC01-appb-C000069
    And a step of reacting a compound of formula (18) with an aqueous sodium hydroxide solution to obtain a compound of formula (19).
  49. 　式[XXIII]
    Figure JPOXMLDOC01-appb-C000070
    （式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩と、水酸化ナトリウム水溶液とを反応させ、式（２４）の化合物又はその塩を得る工程をさらに含む請求項４８記載の方法。     Formula [XXIII]
    Figure JPOXMLDOC01-appb-C000070
    Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
    49. The method according to claim 48, further comprising a step of reacting the compound or a salt thereof with an aqueous sodium hydroxide solution to obtain a compound of the formula (24) or a salt thereof.
  50. 　式（９）
    Figure JPOXMLDOC01-appb-C000071
    の化合物又はその塩と、式[XXII]
    Figure JPOXMLDOC01-appb-C000072
    （式中、Ｒ４は請求項４９に記載の通りである。）
    の化合物とを、有機塩基の存在下で反応させ、式[XXIII]の化合物又はその塩を得る工程をさらに含む請求項４９記載の方法。     Formula (9)
    Figure JPOXMLDOC01-appb-C000071
    Or a salt thereof and the formula [XXII]
    Figure JPOXMLDOC01-appb-C000072
    (Wherein R 4 is as defined in claim 49).
    The method according to claim 49, further comprising the step of reacting the compound of formula (XXIII) in the presence of an organic base to obtain a compound of formula [XXIII] or a salt thereof.
  51. 　式[XXI]
    Figure JPOXMLDOC01-appb-C000073
    （式中、Ｒ４は請求項４９に記載の通りである。）
    の化合物又はその塩と、シュウ酸ジメチルとを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XXII]の化合物を得る工程をさらに含む請求項５０記載の方法。     Formula [XXI]
    Figure JPOXMLDOC01-appb-C000073
    (Wherein R 4 is as defined in claim 49).
    Or a salt thereof and dimethyl oxalate are reacted in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide to obtain a compound of formula [XXII]. 51. The method of claim 50 further comprising:
  52. 　３－（ジメチルアミノ）アクリロニトリルと式[XI']
    Figure JPOXMLDOC01-appb-C000074
    （式中、Ｒ４は請求項４９に記載の通りである。）
    の化合物を有機塩基の存在下で反応させ、式[XXI]の化合物又はその塩を得る工程をさらに含む請求項５１記載の方法。     3- (Dimethylamino) acrylonitrile and the formula [XI ']
    Figure JPOXMLDOC01-appb-C000074
    (Wherein R 4 is as defined in claim 49).
    52. The method according to claim 51, further comprising the step of reacting the compound of formula (XXI) to obtain a compound of the formula [XXI] or a salt thereof.
  53. 　式（１９）
    Figure JPOXMLDOC01-appb-C000075
    の化合物を製造する方法であって、式[XVII]
    Figure JPOXMLDOC01-appb-C000076
    （式中、Ｒ２は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩と、水酸化ナトリウムとを反応させ、式（１９）の化合物を得る工程を含む方法。     Formula (19)
    Figure JPOXMLDOC01-appb-C000075
    Wherein the compound of formula [XVII]
    Figure JPOXMLDOC01-appb-C000076
    Wherein R 2 is unsubstituted or substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy or nitro substituted phenyl, unsubstituted or halogen, C 1-4 alkyl or C 1-4 alkoxy. Benzyl, or C 1-4 alkyl).
    A method comprising a step of reacting a compound of the formula (I) or a salt thereof with sodium hydroxide to obtain a compound of the formula (19).
  54. 　式[XX]
    Figure JPOXMLDOC01-appb-C000077
    （式中、Ｒ２は請求項５３に記載の通りである。）
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVII]の化合物又はその塩を得る工程をさらに含む請求項５３記載の方法。     Formula [XX]
    Figure JPOXMLDOC01-appb-C000077
    Wherein R 2 is as described in claim 53.
    54. The method according to claim 53, further comprising the step of reacting the compound of the above or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula [XVII] or a salt thereof.
  55. 　式（９）
    Figure JPOXMLDOC01-appb-C000078
    の化合物又はその塩と、式[XV]
    Figure JPOXMLDOC01-appb-C000079
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項５３に記載の通りである。）
    の化合物又はその塩とを、有機塩基の存在下で反応させ、式[XX]の化合物又はその塩を得る工程をさらに含む請求項５４記載の方法。     Formula (9)
    Figure JPOXMLDOC01-appb-C000078
    Or a salt thereof and the formula [XV]
    Figure JPOXMLDOC01-appb-C000079
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 53.
    55. The method according to claim 54, further comprising the step of reacting the compound of the formula (I) or a salt thereof in the presence of an organic base to obtain a compound of the formula [XX] or a salt thereof.
  56. 　式（９）
    Figure JPOXMLDOC01-appb-C000080
    の化合物又はその塩と、式[XVI]
    Figure JPOXMLDOC01-appb-C000081
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項５３に記載の通りである。）
    の化合物を有機塩基の存在下で反応させ、式[XVII]の化合物又はその塩を得る工程をさらに含む請求項５３記載の方法。     Formula (9)
    Figure JPOXMLDOC01-appb-C000080
    Or a salt thereof and the formula [XVI]
    Figure JPOXMLDOC01-appb-C000081
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 53.
    54. The method according to claim 53, further comprising the step of reacting the compound of formula (XVII) to obtain a compound of the formula [XVII] or a salt thereof.
  57. 　式[XV]
    Figure JPOXMLDOC01-appb-C000082
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項５３に記載の通りである。）
    の化合物又はその塩と、３－クロロ－２－フルオロベンジルアミンとを反応させ、式[XVI]の化合物又はその塩を得る工程をさらに含む請求項５６記載の方法。     Formula [XV]
    Figure JPOXMLDOC01-appb-C000082
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 53.
    57. The method according to claim 56, further comprising a step of reacting the compound of the above or a salt thereof with 3-chloro-2-fluorobenzylamine to obtain a compound of the formula [XVI] or a salt thereof.
  58. 　式[XIV]
    Figure JPOXMLDOC01-appb-C000083
    （式中、Ｒ３はＣ１－４アルキルであり、Ｒ２は請求項５３に記載の通りである。）
    の化合物と、塩化水素の酢酸エチル溶液又はトリフルオロ酢酸とを反応させ、式[XV]の化合物又はその塩を得る工程をさらに含む請求項５５又は５７記載の方法。     Formula [XIV]
    Figure JPOXMLDOC01-appb-C000083
    Wherein R 3 is C 1-4 alkyl and R 2 is as defined in claim 53.
    58. The method according to claim 55 or 57, further comprising a step of reacting a compound of the above with an ethyl acetate solution of hydrogen chloride or trifluoroacetic acid to obtain a compound of the formula [XV] or a salt thereof.
  59. 　式[XII]
    Figure JPOXMLDOC01-appb-C000084
    （式中、Ｒ２は請求項５３に記載の通りである。）
    の化合物又はその塩と、式[XIII]
    Figure JPOXMLDOC01-appb-C000085
    （式中、Ｒ３はＣ１－４アルキルである。）
    の化合物とを、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン及び無水リチウムブロミドの存在下で反応させ、式[XIV]の化合物を得る工程をさらに含む請求項５８記載の方法。     Formula [XII]
    Figure JPOXMLDOC01-appb-C000084
    Wherein R 2 is as described in claim 53.
    Or a salt thereof and the formula [XIII]
    Figure JPOXMLDOC01-appb-C000085
    Wherein R 3 is C 1-4 alkyl.
    59. The method of claim 58, further comprising reacting the compound of formula (XIV) with a compound of formula [XIV] in the presence of 1,8-diazabicyclo [5.4.0] -7-undecene and anhydrous lithium bromide. .
  60. 　式（１０）
    Figure JPOXMLDOC01-appb-C000086
    の化合物又はその塩と式[XI]
    Figure JPOXMLDOC01-appb-C000087
    （式中、Ｒ２は請求項５３に記載の通りである。）
    の化合物を有機塩基の存在下で反応させ、式[XII]の化合物又はその塩を得る工程をさらに含む請求項５９記載の方法。     Formula (10)
    Figure JPOXMLDOC01-appb-C000086
    Or a salt thereof and the formula [XI]
    Figure JPOXMLDOC01-appb-C000087
    Wherein R 2 is as described in claim 53.
    60. The method according to claim 59, further comprising a step of reacting the compound of formula (XII) in the presence of an organic base to obtain a compound of formula [XII] or a salt thereof.
  61. 　プロピオル酸tert-ブチルと、ジエチルアミンとを反応させ、式（１０）の化合物又はその塩を得る工程をさらに含む請求項６０記載の方法。 61. The method according to claim 60, further comprising a step of reacting tert-butyl propiolate with diethylamine to obtain a compound of formula (10) or a salt thereof.
  62. 　式[XXII]
    Figure JPOXMLDOC01-appb-C000088
    （式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物。     Formula [XXII]
    Figure JPOXMLDOC01-appb-C000088
    Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
    Compound.
  63. 　式[XXI]
    Figure JPOXMLDOC01-appb-C000089
    （式中、Ｒ４は、無置換若しくはハロゲン、Ｃ１－４アルキル、Ｃ１－４アルコキシ若しくはニトロで置換されたフェニル、無置換若しくはハロゲン、Ｃ１－４アルキル若しくはＣ１－４アルコキシで置換されたベンジル、又はＣ１－４アルキルである。）
    の化合物又はその塩。     Formula [XXI]
    Figure JPOXMLDOC01-appb-C000089
    Wherein R 4 is unsubstituted or substituted with halogen, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy or nitro, unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 alkoxy Benzyl, or C 1-4 alkyl).
    Or a salt thereof.
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