WO2015199167A1 - PROCÉDÉ POUR PRÉPARER UN DÉRIVÉ SUBSTITUÉ DE SPIROPYRIDO[1,2-a]PYRAZINE ET INTERMÉDIAIRE - Google Patents

PROCÉDÉ POUR PRÉPARER UN DÉRIVÉ SUBSTITUÉ DE SPIROPYRIDO[1,2-a]PYRAZINE ET INTERMÉDIAIRE Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
salt
alkyl
reacting
Prior art date
Application number
PCT/JP2015/068295
Other languages
English (en)
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
Original Assignee
日本たばこ産業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 日本たばこ産業株式会社 filed Critical 日本たばこ産業株式会社
Publication of WO2015199167A1 publication Critical patent/WO2015199167A1/fr

Links

Classifications

    • 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

L'invention concerne un procédé de préparation d'un dérivé substitué de spiropyrido[1,2-a]pyrazine, ou d'un sel correspondant, utiles en tant qu'agents anti-VIH. L'invention concerne également un intermédiaire de préparation. Le composé [VIII] est obtenu par la réaction du composé [VII] (dans la formule, R1 représente benzyle qui est, soit non substitué, soit substitué par un halogène, alkyle en C1-4 ou alcoxy en C1-4) et d'hydroxyamine, ou d'un sel correspondant. Le composé (9) est obtenu par la soumission du composé [VIII] à une réaction de réduction catalytique. Le composé (18) est préparé à partir du composé (9).
PCT/JP2015/068295 2014-06-25 2015-06-25 PROCÉDÉ POUR PRÉPARER UN DÉRIVÉ SUBSTITUÉ DE SPIROPYRIDO[1,2-a]PYRAZINE ET INTERMÉDIAIRE WO2015199167A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014130328 2014-06-25
JP2014-130328 2014-06-25

Publications (1)

Publication Number Publication Date
WO2015199167A1 true WO2015199167A1 (fr) 2015-12-30

Family

ID=54938244

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2015/068295 WO2015199167A1 (fr) 2014-06-25 2015-06-25 PROCÉDÉ POUR PRÉPARER UN DÉRIVÉ SUBSTITUÉ DE SPIROPYRIDO[1,2-a]PYRAZINE ET INTERMÉDIAIRE

Country Status (1)

Country Link
WO (1) WO2015199167A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019070059A1 (fr) 2017-10-06 2019-04-11 塩野義製薬株式会社 Procédé pour la production stéréosélective d'un dérivé de pyridone polycyclique substitué
WO2019230858A1 (fr) 2018-05-31 2019-12-05 塩野義製薬株式会社 Dérivé de carbamoylpyridone polycyclique
CN112574155A (zh) * 2020-11-25 2021-03-30 南京杰运医药科技有限公司 一种3-(苄氧基)-4-氧代-4h-吡喃-2-羧酸的合成方法
WO2021107066A1 (fr) 2019-11-28 2021-06-03 塩野義製薬株式会社 Agent pharmaceutique prophylactique et thérapeutique pour maladies infectieuses à vih, caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'intégrase et d'un agent anti-vih
US11453669B2 (en) 2018-05-31 2022-09-27 Shionogi & Co., Ltd. Polycyclic pyridone derivative

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001524472A (ja) * 1997-11-24 2001-12-04 アベンティス・クロップサイエンス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング １−メチル−５−アルキルスルホニル−、１−メチル−５−アルキルスルフィニルおよび１−メチル−５−アルキルチオ−置換されたピラゾリルピラゾール、それらの製造法および除草剤としてのそれらの使用
JP2005519965A (ja) * 2002-03-13 2005-07-07 シェーリング　コーポレイション Ｎｋ１アンタゴニスト
WO2014104279A1 (fr) * 2012-12-27 2014-07-03 日本たばこ産業株式会社 DÉRIVÉ SUBSTITUÉ DE SPIROPYRIDO[1,2-a]PYRAZINE ET SON UTILISATION MÉDICALE EN TANT QU'INHIBITEUR D'INTÉGRASE DU VIH

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001524472A (ja) * 1997-11-24 2001-12-04 アベンティス・クロップサイエンス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング １−メチル−５−アルキルスルホニル−、１−メチル−５−アルキルスルフィニルおよび１−メチル−５−アルキルチオ−置換されたピラゾリルピラゾール、それらの製造法および除草剤としてのそれらの使用
JP2005519965A (ja) * 2002-03-13 2005-07-07 シェーリング　コーポレイション Ｎｋ１アンタゴニスト
WO2014104279A1 (fr) * 2012-12-27 2014-07-03 日本たばこ産業株式会社 DÉRIVÉ SUBSTITUÉ DE SPIROPYRIDO[1,2-a]PYRAZINE ET SON UTILISATION MÉDICALE EN TANT QU'INHIBITEUR D'INTÉGRASE DU VIH

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GAONI,Y.: "Synthesis of aminocyclobutane mono- and dicarboxylic acids and derivatives thereof from (phenylsulfonyl)bicyclobutanes", ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, vol. 27, no. 2, 1995, pages 185 - 212, XP008159261 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019070059A1 (fr) 2017-10-06 2019-04-11 塩野義製薬株式会社 Procédé pour la production stéréosélective d'un dérivé de pyridone polycyclique substitué
KR20200066644A (ko) 2017-10-06 2020-06-10 시오노기세야쿠 가부시키가이샤 치환된 다환성 피리돈 유도체의 입체 선택적인 제조 방법
US11286262B2 (en) 2017-10-06 2022-03-29 Shionogi & Co., Ltd. Stereoselective process for preparing substituted polycyclic pyridone derivatives
WO2019230858A1 (fr) 2018-05-31 2019-12-05 塩野義製薬株式会社 Dérivé de carbamoylpyridone polycyclique
KR20210015922A (ko) 2018-05-31 2021-02-10 시오노기 앤드 컴파니, 리미티드 다환성 카바모일피리돈 유도체
US11453669B2 (en) 2018-05-31 2022-09-27 Shionogi & Co., Ltd. Polycyclic pyridone derivative
US11649236B2 (en) 2018-05-31 2023-05-16 Shionogi & Co., Ltd. Polycyclic carbamoylpyridone derivative
EP4257137A2 (fr) 2018-05-31 2023-10-11 Shionogi & Co., Ltd Dérivés de carbamoylpyridone polycycliques pour le traitement du vih
WO2021107066A1 (fr) 2019-11-28 2021-06-03 塩野義製薬株式会社 Agent pharmaceutique prophylactique et thérapeutique pour maladies infectieuses à vih, caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'intégrase et d'un agent anti-vih
CN112574155A (zh) * 2020-11-25 2021-03-30 南京杰运医药科技有限公司 一种3-(苄氧基)-4-氧代-4h-吡喃-2-羧酸的合成方法

Similar Documents

Publication Publication Date Title
JP6340391B2 (ja) 置換された５−フルオロ−１ｈ−ピラゾロピリジン類を製造するための方法
JP5765965B2 (ja) １，３，４，８−テトラヒドロ−２Ｈ−ピリド［１，２−ａ］ピラジン誘導体及びそのＨＩＶインテグラーゼ阻害剤としての利用
WO2015199167A1 (fr) PROCÉDÉ POUR PRÉPARER UN DÉRIVÉ SUBSTITUÉ DE SPIROPYRIDO[1,2-a]PYRAZINE ET INTERMÉDIAIRE
JP6240164B2 (ja) ピロール誘導体の結晶及びその製造方法
KR20230098690A (ko) 테트라하이드로피라닐 아미노-피롤로피리미디논 및 이의 사용 방법
KR20090106633A (ko) ＰＤＥ5 억제제로서 유용한 6-벤질-2,3,4,7-테트라히드로-인돌로[2,3-ｃ]퀴놀린 화합물
JP6580218B2 (ja) エナンチオマー濃縮された３−アミノピペリジンの調製のためのプロセス
US20060128700A1 (en) Morpoline-bridged indazole derivatives
WO2018001332A1 (fr) Composé ayant une activité inhibitrice contre l'isocitrate déshydrogénase mutante, son procédé de préparation et son utilisation
JPWO2018021508A1 (ja) ピラゾール−アミド化合物の製造方法
WO2016042441A1 (fr) Nouveau procédé de préparation de silodosine largement pure
US10377710B2 (en) Process for the preparation of considerably pure Silodosin
US20100174073A1 (en) Process for the preparation of alfuzosin and salts thereof
US20120259116A1 (en) Novel Process for the Preparation of Paliperidone
US9556204B2 (en) Methods and intermediates for the preparation of (4bS,5aR)-12-cyclohexyl-N-(N,N-dimethylsulfamoyl)-3-methoxy-5a-((1R,5S)-3-methyl-3,8-diazabicyclo [3.2.1]octane-8-carbonyl)-4b,5,5a,6-tetrahydrobenzo [3,4]cyclopropa[5,6]azepino[1,2-A]indole-9-carboxamide
WO2010082111A1 (fr) Synthèse de la 3-(2-hydroxyéthyl)-9-hydroxy-2-méthyl-4h-pyrido-[1,2-a]-pyrimidin-4-one ou de son sel d'addition acide

Legal Events

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

Ref document number: 15812100

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15812100

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP