WO2006129781A1 - Process for production of dibenzoxepin derivative - Google Patents

Process for production of dibenzoxepin derivative Download PDF

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WO2006129781A1
WO2006129781A1 PCT/JP2006/311060 JP2006311060W WO2006129781A1 WO 2006129781 A1 WO2006129781 A1 WO 2006129781A1 JP 2006311060 W JP2006311060 W JP 2006311060W WO 2006129781 A1 WO2006129781 A1 WO 2006129781A1
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general formula
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formula
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PCT/JP2006/311060
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Koichiro Nishimura
Masahiko Kinugawa
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to CN2006800106989A priority Critical patent/CN101151256B/en
Priority to JP2007519078A priority patent/JP5099830B2/en
Publication of WO2006129781A1 publication Critical patent/WO2006129781A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/75—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of acids with a six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/753—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of polycyclic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed

Definitions

  • the present invention relates to a method for producing 11 alkylidene dibenz [b, e] oxepin derivatives useful as pharmaceuticals or pharmaceutical intermediates.
  • Patent Documents 1, 2, 3 and non-patent documents Patent Documents 1 and 2
  • a method of producing compound (VII) force using Grignard reaction and the like see Patent Documents 1 and 2 and Non-Patent Document 1
  • it is not easy to control the configuration of the double bond site and it is known that the target product is obtained as a mixture of geometric isomers.
  • Patent Document 1 Japanese Patent Laid-Open No. 63-10784
  • Patent Document 2 JP-A 62-45557
  • Patent Document 3 Japanese Patent Laid-Open No. 2-250
  • Non-Patent Document 1 "Journal of Medicina 1 Chemistry", 1992, 35th, p. 2074
  • Non-Patent Document 2 “Pharmacia”, 2002, No. 38, p. 224
  • Non-Patent Document 3 "Tetrahedron Letters J, 1993, 34th, p. 8353
  • An object of the present invention is to provide a method for producing a desired geometric isomer in a high yield in the production of 11 alkylidene dibenz [b, e] oxepin derivatives useful as pharmaceuticals or pharmaceutical intermediates. is there.
  • the present invention relates to the following (1) to (18).
  • R 1 represents a hydrogen atom, lower alkyl, cycloalkyl, aralkyl or aryl
  • X 1 represents a chlorine atom, a bromine atom, an iodine atom or trifluoromethanesulfonyloxy
  • n is 0. Represents an integer of ⁇ 4)
  • R 2 is selected from the group consisting of hydroxy, lower alkoxy, amino-containing lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbole, cycloalkyl, aryl, aromatic heterocyclic group and aliphatic heterocyclic group.
  • substituents! / May be lower alkyl, or hydroxy, lower alkoxy, amino-substituted lower alkylamino, di-low And may have a substituent selected from the group consisting of carboxy, alkenyl carbo, lower alkoxy carbo, oxo, aryl, aromatic heterocyclic group and aliphatic heterocyclic group).
  • Phosphines whose intramolecular cyclization reaction is also selected from the group force consisting of triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine and tricyclohexylphosphine.
  • X 1 is a bromine atom
  • X 2 is an iodine atom, according to any one of (1) to (8) Method.
  • R 2 is lower alkyl, hydroxy-substituted lower alkyl, amino-substituted lower alkyl, lower alkylamino-substituted lower alkyl or di-lower alkylamino-substituted lower alkyl (1) and (3) to (11) The method described in 1.
  • Examples of the lower alkyl of lower alkyl and lower alkoxy, dialkyl lower alkylamino and lower alkoxy carboyl include linear or branched alkyl having 1 to 10 carbon atoms, more specifically methyl. , Ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, noel, decyl and the like.
  • the two lower alkyl moieties of the di-lower alkylamino may be the same or different.
  • cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, and more specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • aryls examples include aryls having 6 to 14 carbon atoms.
  • aralkyl examples include aralkyl having 7 to 16 carbon atoms, and more specifically, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, naphthylmethyl, Naphthyltil.
  • aliphatic heterocyclic group examples include a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 3- to 8-membered ring.
  • Condensed bicyclic or tricyclic nitrogen, oxygen and sulfur nuclear power And, more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, perhydroazepinyl, imidazolidinyl, virazolidinyl, piperazinyl, homopiperazinyl, oxylanyl, and the like.
  • aromatic heterocyclic group examples include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 3 to 8 members.
  • a condensed ring aromatic heterocyclic group containing at least one atom selected from the group consisting of a bicyclic or tricyclic condensed nitrogen ring, an oxygen atom and a sulfur nuclear power, and more specifically furyl, Chael, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazil, pyrimidinyl, pyrazyl, triazyl, benzofuranyl, benzothiol Benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazo Ril, benzotriazolyl, oxazolopyrimidyl, thiazolopyrimidyl,
  • X 1 is preferably a chlorine atom, a bromine atom, or trifluoromethanesulfonyloxy, more preferably a chlorine atom or a bromine atom, and even more preferably a bromine atom.
  • X 1 is a chlorine atom and X 2 is a bromine or iodine atom or X 1 is a chlorine atom Child, a bromine atom or triflate Ruo b methanesulfonyl O carboxymethyl
  • X 2 is an iodine atom in Ah Rukoto is preferably fixture
  • X 1 is a bromine atom or triflate Ruo Russia methanesulfonyl - a Ruokishi
  • X 2 force s iodine atom
  • R 1 is more preferably methyl, ethyl or the like, preferably lower alkyl.
  • X 1 is preferably a chlorine atom, a bromine atom, or trifluoromethanesulfonyloxy, more preferably a chlorine atom or a bromine atom, and even more preferably a bromine atom.
  • R 1 is more preferably methyl, ethyl or the like, preferably lower alkyl.
  • R 2 is preferably hydroxyethyl, dimethylaminoethyl, etc., preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl and the like.
  • Salts of compounds (IV), (IV), (V) and (VI) include, for example, acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • acid addition salts of compounds (11), (IV), (V) and (VI) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, and acetates.
  • Organic salts such as oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate, and metal salts include, for example, alkali metals such as sodium salt and potassium salt Examples thereof include alkaline earth metal salts such as salts, magnesium salts and calcium salts, aluminum salts, and zinc salts.
  • alkali metals such as sodium salt and potassium salt
  • alkaline earth metal salts such as salts, magnesium salts and calcium salts, aluminum salts, and zinc salts.
  • ammonium salts include salts such as ammonium and tetramethyl ammonium.
  • organic amine addition salts include addition salts such as morpholine and piperidine, and examples of amino acid addition salts include addition of lysine, glycine, ferrolanine, aspartic acid, dartamic acid and the like. Salt, and the like.
  • Halogenation in the present invention is a reaction for introducing a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom into a benzene ring, and more specifically, for example, the reaction shown in Step 1 of the following production method.
  • the coupling reaction in the present invention is a reaction for coupling a halogen aryl and an alkyne compound, such as a Sono gashim reaction, and more specifically, for example, shown in Step 2 of the following production method.
  • a reaction process is mentioned.
  • Examples of the intramolecular cyclization reaction in the present invention include a reaction for forming an oxepin ring in the presence of a palladium catalyst, and more specifically, for example, the reaction step shown in Step 3 of the production method below.
  • 11 alkylidene dibenz [b, e] oxepin derivative (V) can be produced from benzyl phenyl ether derivative (I) through the following three steps.
  • This process is carried out by a known method for halogenating a benzene ring (for example, Organic 'Synthesis (Organic Synthesis), 1963, 4 ⁇ , p. 872; Organic' Synthesis (Organic Synthesis), 1973, 5 ⁇ , p. 117; Organic Synt hesis, 1963, 4 ⁇ , p. 547; Tetrahedron Letters, 1993, 34 ⁇ , p. 6223; Angevante 'Cemi' International 'Edition (A ngew. Chem. Int. Ed.), 2001, 40 ⁇ , p. 1967).
  • Compound ( ⁇ ) can be produced by treating compound (I) without solvent or in a suitable solvent with a suitable halogenating agent for 5 minutes to 72 hours, preferably 1 to: L0 hours. it can.
  • Compound (I) can be obtained, for example, by the method described in WO2005Z009104 or in conformity thereto. Togashi.
  • halogenating agent examples include chlorine agents such as chlorine and sulfuryl chloride, bromine agents such as bromine and N-bromosuccinimide, iodine, salt iodine and bis (pyridine iodine).
  • bromine agents such as bromine and N-bromosuccinimide
  • iodine, salt iodine and bis pyridine iodine
  • examples include iodine fluorides such as tetrafluoroborate (F-TEDA) and bis (pyridine iodine) boron tetrafluoride, and these can also be used in combination. Examples of combinations include a combination of iodine and F-TEDA.
  • halogenating agents are preferably used in an amount of 1 to 30 equivalents, more preferably 1 to 5 equivalents, more preferably 1 to 2 equivalents, and even more preferably 1 to 1.5 equivalents, relative to compound (I). .
  • These halogenating agents can also be used in combination with various additives.
  • the power combinations that can use various additives depending on the type of halogenating agent used include, for example, a combination of chlorine and hydrogen chloride, Combinations of bromine and Lewis acids such as aluminum chloride, combinations of odor and iron, combinations of iodine and silver sulfate, combinations of iodine and potassium iodide, combinations of iodine and silver trifluoroacetate, etc. Can be given.
  • the combination of iodine and silver sulfate is preferred.
  • the amount of additive used varies depending on the halogenating agent used and the type of additive. For example, when using a combination of odor and salt-aluminum, Preferably 2 to 5 equivalents, more preferably 1 to 1.5 equivalents are used.
  • silver sulfate is preferably 0.5 to 3 equivalents, more preferably, relative to iodine. 0.8 to 2 equivalents, more preferably 1 equivalent is used.
  • potassium iodide is preferably 0.5 to 3 equivalents, more preferably 0.8 to 2 equivalents, more preferably 1 equivalent is used.
  • the solvent examples include alcohol solvents such as methanol, ethanol, and propanol, hydrophilic solvents such as acetone, acetonitrile, N, N-dimethylformamide (DMF), and N-methylpyrrolidone (NMP), hexane, and the like.
  • alcohol solvents such as methanol, ethanol, and propanol
  • hydrophilic solvents such as acetone, acetonitrile, N, N-dimethylformamide (DMF), and N-methylpyrrolidone (NMP), hexane, and the like.
  • Hydrocarbon solvents such as ethyl acetate, ether solvents such as jetyl ether, tetrahydrofuran (THF), 1,4-dioxane and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, pyridine
  • ester solvents such as ethyl acetate
  • ether solvents such as jetyl ether
  • THF tetrahydrofuran
  • 1,4-dioxane and dimethoxyethane 1,4-dioxane and dimethoxyethane
  • halogen solvents such as dichloromethane and chloroform
  • pyridine examples thereof include basic solvents such as acetic acid, acidic solvents such as acetic acid, water and the like, and these can be used alone or in combination.
  • Iodine and sulfuric acid as halogenating agents
  • an iodine additive such as silver or salt or iodine is used
  • the treatment in this step is usually at a temperature between 78 ° C and 150 ° C, preferably at a temperature between 0 ° C and 100 ° C, more preferably between 10 ° C and 70 ° C. At a temperature of
  • This step is carried out by a known method (for example, Tetrahedron Letters, 1975, 16 ⁇ , p. 4467; Tetrahedron Letters, 1 993, 34 ⁇ , p Can be performed according to 8353).
  • Compound (IV) is compound (IV) in an appropriate solvent, for example, in the presence of a copper compound, a palladium catalyst having a phosphine ligand and optionally a base, 1 to 20 equivalents, preferably 1 to 10 equivalents. More preferably, it can be produced by reacting with 1 to 3 equivalents of compound (III) for 5 minutes to 72 hours, preferably 1 to 24 hours.
  • Compound ( ⁇ ) can be obtained in a commercially available or known manner (for example, Journal of Organic Chemistry, Org. Chem.), 1999, 64 ⁇ , p. 1798) or to them. It can be obtained similarly.
  • Examples of the copper compound include copper iodide.
  • the copper compound is preferably used in an amount of 0.001 to L equivalents, more preferably 0.01-0.2 equivalents relative to compound (II).
  • Examples of the palladium catalyst having a phosphine ligand include compounds in which a phosphine ligand is coordinated to palladium.
  • Examples of the phosphine ligand include triphenylphosphine and tri (o-tolyl).
  • Phosphine tri (m-tolyl) phosphine, tri ( ⁇ tolyl) phosphine, tris (2,4 dimethoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (dimethylamino) phosphine, tri (tert —Butyl) phosphine, tricyclohexenolephosphine, ethylenebis (diphenylenophosphine), 1,3bis (diphenylenophosphino) propane, 1,1, monobis (diphenylphosphino) phenol, 2, 2, One-bis (diphenyl phosphino)-1, 1,-binaphthyl.
  • the noradium catalyst having these phosphine ligands for example, the one produced in the reaction solution by adding the phosphine ligand and the palladium compound mentioned above into the reaction solution can be used. In this case, it is preferable to use 1 to 4 equivalents of the phosphine ligand with respect to the palladium compound.
  • the Examples of the radium compound include palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon, and the like.
  • the palladium catalyst having a phosphine coordination is usually used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalent, relative to the compound ( ⁇ ).
  • the palladium catalyst having a phosphine ligand for example, commercially available dichroic bis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium acetate, tetrakis (triphenylphosphine) palladium and the like are used. Dichlorobis (triphenylphosphine) palladium is preferred.
  • Examples of the base include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert butoxide, sodium methoxide, and other inorganic bases such as pyridine, triethylamine, diisopropyl ether. And organic bases such as 1,8 diazabicyclo [5.4.0] undeque 7 (DBU), piperidine and N-methylmorpholine, and preferably triethylamine.
  • the base is preferably used in an amount of 0.5 to 20 equivalents, more preferably 1 to 10 equivalents, and even more preferably 1 to 5 equivalents relative to compound ( ⁇ ).
  • Examples of the solvent include alcohol solvents such as methanol, ethanol and propanol, hydrophilic solvents such as acetone, acetonitrile, DMF and NMP, hydrocarbon solvents such as toluene, xylene and hexane, and ethyl acetate.
  • examples include ester solvents, ether solvents such as jetyl ether, THF, 1,4 dioxane, and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. Or it can be used in a mixture, preferably DMF etc.
  • the reaction in this step is usually performed at a temperature between 78 ° C and the boiling point of the solvent used, preferably at a temperature between 0 ° C and 100 ° C, more preferably between 10 ° C and 70 ° C. Between temperatures.
  • Compound (V) is compound (IV) in a suitable solvent in the presence of a suitable base and a hydrogen source. It can be produced by treating with a noradium catalyst, preferably a palladium catalyst having a phosphine ligand, for 5 minutes to 72 hours, preferably 1 to 10 hours.
  • a noradium catalyst preferably a palladium catalyst having a phosphine ligand
  • Examples of the noradium catalyst include a palladium catalyst having a phosphine ligand, and examples of the palladium catalyst having the phosphine ligand include a compound in which the phosphine ligand is coordinated to noradium.
  • Examples of the phosphine ligand include triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri ( ⁇ -tolyl) phosphine, tris (2,4-dimethoxyphenol).
  • Phosphine tris (4-methoxyphenol) phosphine, tris (dimethylamino) phosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, ethylenebis (diphenylenophosphine), 1,3-bis (diphenyl-) Ruphosphino) propane, 1,1,1bis (diphenylphosphino) phenol, 2,2,1bis (diphosphosphino) 1,1,1, binaphthyl, etc., preferably triphenylphosphine, triphenyl (O-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, tricyclohexylphosphine
  • tri (o-tolyl) phosphine emission and the like tri (o-tolyl) phosphine emission and the like.
  • the palladium catalyst having these phosphine ligands for example, those produced in the reaction solution by adding the phosphine ligand and palladium compound mentioned above to the reaction solution can be used.
  • preferred examples of the phosphine ligand include triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (P-tolyl) phosphine, and tricyclohexylphosphine. (O-Tolyl) phosphine and the like are more preferable. These are preferably used in an amount of 1 to 4 equivalents with respect to the palladium compound.
  • the palladium compound examples include palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon and the like, preferably palladium acetate, palladium chloride, palladium carbon and the like, and more preferably acetate acetate.
  • radium As the palladium catalyst having a phosphine ligand, for example, commercially available dichroic bis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium and the like can be used.
  • the radium catalyst is usually used in an amount of 0.001 to L equivalents, preferably 0.01 to 0.2 equivalents, relative to the compound (IV).
  • bases include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide,
  • organic bases such as methylamine, dimethylamine, pyridine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, triethylamine, diisopropylethylamine, DBU, and preferably piperidine.
  • the base is preferably used in an amount of 0.5 to 30 equivalents, more preferably 1 to 20 equivalents, still more preferably 1 to 10 equivalents, relative to compound (IV).
  • Examples of the hydrogen source include organic acids such as acetic acid and formic acid, and organic acids such as ammonia, methylamine, dimethylamine, triethylamine, pyrrolidine, piperidine, morpholine, and N-methylmorpholine.
  • Ammonium salts, metal salts of the organic acids such as sodium, potassium, strength, and the like, preferably ammonium formate, ammonium acetate, pyrrolidinium formate, piperidium formate, etc. More preferably, for example, pyridium formate.
  • organic acid ammonium salts and organic acid metal salts include, for example, organic acids such as acetic acid and formic acid and ammonia, the organic amines mentioned above, sodium hydroxide, potassium hydroxide, and hydroxide. ⁇ Calcium, potassium carbonate, etc. added to the reaction solution can be used in the reaction solution. Formic acid and piperidine can be added to the reaction solution. It is preferable to use it.
  • organic acids, ammonium salts of organic acids and metal salts of organic acids are preferably used in an amount equivalent to 1 to LO for compound (IV). Hydrogen gas can also be used as the hydrogen source.
  • Examples of the solvent include alcohol solvents such as methanol, ethanol, and propanol, hydrophilic solvents such as acetone, acetonitrile, DMF, and NMP, hydrocarbon solvents such as toluene, xylene, and hexane, and ethyl acetate.
  • examples include ester solvents, ether solvents such as jetyl ether, THF, 1,4 dioxane, and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. Alternatively, they can be used as a mixture, and preferred examples include DMF and acetonitrile.
  • the treatment in this step is usually performed at a temperature between 78 ° C and the boiling point of the solvent used, preferably at a temperature between 0 ° C and 120 ° C, more preferably between 10 ° C and 100 ° C. Between temperatures.
  • the conversion of the functional group contained in R 2 in the compounds (IV), (V) and (VI) can be carried out by a known method [for example, Complicative 'Organic' Transformations 2nd Edition (Compr ehensive Organic Transformations 2nd edition), RC Larock, Vch Verlagsgesellschaft Mbh (1999), etc.] or similar methods.
  • R 1 is a hydrogen atom and R 2 is dimethylaminoethyl.
  • Compound (Vc) known as an antiallergic agent is a compound obtained by the above production method From (Va), for example, it can also be produced by a known method shown below.
  • Compound (Vb) is obtained by converting Compound (Va) obtained in Step 3 above into (1) 1 to 10 equivalents of methanesulfonyl chloride in an appropriate solvent, if necessary in the presence of 1 to 20 equivalents of an appropriate base. 5 to 72 minutes at a temperature between 20 ° C and the boiling point of the solvent used, and a sulfonating agent such as trifluoromethanesulfuric anhydride, benzenesulfuric chloride, and p-toluenesulfuric chloride (2)
  • the obtained compound is then reacted in the absence of solvent or in a suitable solvent, optionally in the presence of 1 to 20 equivalents of a suitable base, preferably 1 equivalent to a large excess, preferably Can be produced by reacting with 1 to 20 equivalents of dimethylamine at a temperature between -20 ° C and 100 ° C for 5 minutes to 72 hours.
  • Examples of the solvent used in (1) include hydrophilic solvents such as acetone, acetonitrile, DMF, and NMP, hydrocarbon solvents such as toluene, xylene, and hexane, and ethyl acetate.
  • hydrophilic solvents such as acetone, acetonitrile, DMF, and NMP
  • hydrocarbon solvents such as toluene, xylene, and hexane
  • ethyl acetate examples include ester solvents, ether solvents such as jetyl ether, THF, 1,4 dioxane and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. Or mixed.
  • Examples of the base used in (1) include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, and other inorganic bases, pyridine, and triethylamine. And organic bases such as diisopropylethylamine and DBU.
  • Examples of the solvent used in (2) include alcohol solvents such as methanol, ethanol and propanol, hydrophilic solvents such as acetone, acetonitrile, DMF and NMP, hydrocarbon solvents such as toluene, xylene and hexane, and ethyl acetate.
  • alcohol solvents such as methanol, ethanol and propanol
  • hydrophilic solvents such as acetone, acetonitrile, DMF and NMP
  • hydrocarbon solvents such as toluene, xylene and hexane
  • ethyl acetate such as ester solvents such as diethyl ether, THF, 1,4 dioxane and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, basic solvents such as pyridine, water, etc. These may be used alone or in combination.
  • Examples of the base used in (2) include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert butoxide, sodium methoxide, and other inorganic bases, pyridine, triethylamine, Organic bases such as diisopropylethylamine and DBU.
  • Compound (Vc) is produced by treating compound (Vb) in an aqueous solvent with 1 to 20 equivalents, preferably 1 to 3 equivalents of a suitable base for 5 minutes to 72 hours, preferably 10 minutes to 6 hours. It can be done.
  • Examples of the hydrous solvent include mixed solvents of various organic solvents and water.
  • Examples of the organic solvent include alcohol solvents such as methanol, ethanol, and propanol, acetone, acetonitrile, DMF, and NMP.
  • Hydrophilic solvents hydrocarbon solvents such as toluene, xylene, hexane, ester solvents such as ethyl acetate, ether solvents such as jetyl ether, THF, 1,4 dioxane, dimethoxyethane, dichloromethane, black mouth
  • Examples thereof include halogen solvents such as form, basic solvents such as pyridine, and the like. These can be used alone or as a mixture, preferably methanol, ethanol, etc. can give.
  • Examples of the base include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert butoxide, sodium methoxide, and other inorganic bases such as pyridine, triethylamine, diisopropyl ether. And organic bases such as min and DBU.
  • the treatment in this step is usually at a temperature between 0 ° C and the boiling point of the solvent used, preferably 10 ° C to
  • the intermediates and target compounds in each of the above production methods are simply separated and purified commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. It can be separated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.
  • the compounds ( ⁇ ), (IV), (V) and (VI) and their salts may exist in the form of adducts with water or various solvents, and these adducts are also present in the present invention. Is included in
  • (VI) can be purified as it is in the form of a salt, and when it is obtained in a free form, the compound ( ⁇ ), (IV), (V) or (VI) can be appropriately converted. It can be isolated or purified by dissolving or suspending in a solvent and adding an acid or base to form a salt.

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Abstract

A process for producing a 11-alkylidene dibenz[b,e]oxepin derivative represented by the general formula (V) or a salt thereof, the process comprising the steps of: (i) haloganating a compound represented by the general formula (I) to yield a compound represented by the general formula (II); (ii) subjecting the compound represented by the general formula (II) to coupling reaction with an alkyne compound represented by the general formula (III) to yield a compound represented by the general formula (IV); and (iii) subjecting the compound represented by the general formula (IV) to intramolecular cyclization: Step 1 Step 2 (I) (II) Step 3 (IV) (V) wherein R1 represents a hydrogen atom or the like; R2 represents a lower alkyl or the like; X1 represents a chlorine atom or the like; X2 represents a chlorine atom or the like; and n represents an integer of 0 to 4.

Description

ジベンズォキセピン誘導体の製造方法  Method for producing dibenzoxepin derivative
技術分野  Technical field
[0001] 本発明は、医薬品または医薬品の中間体として有用な 11 アルキリデンジベンズ[ b, e]ォキセピン誘導体を製造する方法に関する。  [0001] The present invention relates to a method for producing 11 alkylidene dibenz [b, e] oxepin derivatives useful as pharmaceuticals or pharmaceutical intermediates.
背景技術  Background art
[0002] 多くのジベンズ [b, e]ォキセピン誘導体が医薬品、医薬品の中間体などとして知ら れている。中でも 11位にビュル基を有する化合物、例えば式 (Via)に示すような 11 アルキリデンジベンズ [b, e]ォキセピン誘導体などが優れた抗アレルギー作用を 有することが知られている (特許文献 1、 2参照)。  [0002] Many dibenz [b, e] oxepin derivatives are known as pharmaceuticals and pharmaceutical intermediates. Among them, a compound having a bur group at the 11-position, for example, an 11 alkylidene benz [b, e] oxepin derivative represented by the formula (Via) is known to have an excellent antiallergic action (Patent Document 1, 2).
[0003] [化 1]  [0003] [Chemical 1]
Figure imgf000003_0001
Figure imgf000003_0001
( Via )  (Via)
[0004] これら 11 アルキリデンジベンズ [b, e]ォキセピン誘導体の製造方法としては、例 えば公知の方法 (例えば、特開昭 48— 36983、ジャーナル'ォブ 'メディシナル 'ケミ ストリー (J. Med. Chem. )、 1976年、 19卷、 p. 941など）で製造した化合物（VII) [0004] As a method for producing these 11 alkylidene dibenz [b, e] oxepin derivatives, for example, a known method (for example, JP-A-48-36983, Journal of Ob Medicinal Chemistry (J. Med. Chem.), 1976, 19 卷, p. 941, etc.) (VII)
[0005] [化 2] [0005] [Chemical 2]
Figure imgf000003_0002
Figure imgf000003_0002
(式中、 Rは水素原子または低級アルキルを表し、 mは 0〜4の整数を表す） と対応するホスホ-ゥム塩とのゥイツティッヒ反応により製造する方法 (特許文献 1、 2、 3および非特許文献 1、 2参照）、化合物 (VII)力もグリニャール反応などを用いて製 造する方法 (特許文献 1、 2および非特許文献 1参照)などが知られている。しかしな がら、これらの製造方法では二重結合部位の立体配置を制御することが容易ではな く、目的物が幾何異性体の混合物として得られることが知られている。また、この混合 物を精製して望む異性体を単離することも容易ではなぐ更に収率も満足のいくもの ではない。 (Wherein, R represents a hydrogen atom or lower alkyl, m represents an integer of 0 to 4) and a corresponding phospho-um salt (Whichtich reaction) (Patent Documents 1, 2, 3 and non-patent documents) Patent Documents 1 and 2), a method of producing compound (VII) force using Grignard reaction and the like (see Patent Documents 1 and 2 and Non-Patent Document 1) are known. But However, in these production methods, it is not easy to control the configuration of the double bond site, and it is known that the target product is obtained as a mixture of geometric isomers. Also, it is not easy to purify this mixture to isolate the desired isomer, and the yield is not satisfactory.
[0007] 一方、アルキン化合物（VIII)をグリック環化（Grigg— cyclisation)することで三環 系化合物 (IX)を製造する方法が知られて!/ヽる (非特許文献 3参照)。  [0007] On the other hand, a method for producing a tricyclic compound (IX) by Glygg cyclisation of an alkyne compound (VIII) is known!
[0008] [化 3] [0008] [Chemical 3]
Figure imgf000004_0001
Figure imgf000004_0001
( VIII )  (VIII)
特許文献 1：特開昭 63— 10784号公報  Patent Document 1: Japanese Patent Laid-Open No. 63-10784
特許文献 2 :特開昭 62— 45557号公報  Patent Document 2: JP-A 62-45557
特許文献 3：特開平 2— 250号公報  Patent Document 3: Japanese Patent Laid-Open No. 2-250
非特許文献 1 :「ジャーナル'ォブ 'メディシナル 'ケミストリー（Journal of Medicina 1 Chemistry)」、 1992年、第 35卷、 p. 2074  Non-Patent Document 1: "Journal of Medicina 1 Chemistry", 1992, 35th, p. 2074
非特許文献 2 :「フアルマシア（Pharmacia)」、 2002年、第 38卷、 p. 224  Non-Patent Document 2: “Pharmacia”, 2002, No. 38, p. 224
非特許文献 3 :「テトラへドロン'レターズ (Tetrahedron Letters) J , 1993年、第 34 卷、 p. 8353  Non-Patent Document 3: "Tetrahedron Letters J, 1993, 34th, p. 8353
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0009] 本発明の目的は、医薬品または医薬品の中間体として有用な 11 アルキリデンジ ベンズ [b, e]ォキセピン誘導体の製造において、望む幾何異性体を収率よく製造す る方法を提供することにある。 An object of the present invention is to provide a method for producing a desired geometric isomer in a high yield in the production of 11 alkylidene dibenz [b, e] oxepin derivatives useful as pharmaceuticals or pharmaceutical intermediates. is there.
課題を解決するための手段  Means for solving the problem
[0010] 本発明は、以下の（1)〜（18)に関する。 (i)一般式 (I) [0010] The present invention relates to the following (1) to (18). (i) General formula (I)
[0011] [化 4]  [0011] [Chemical 4]
Figure imgf000005_0001
Figure imgf000005_0001
( I )  (I)
[0012] (式中、 R1は水素原子、低級アルキル、シクロアルキル、ァラルキルまたはァリールを 表し、 X1は塩素原子、臭素原子、ヨウ素原子またはトリフルォロメタンスルホ二ルォキ シを表し、 nは 0〜4の整数を表す） [In the formula, R 1 represents a hydrogen atom, lower alkyl, cycloalkyl, aralkyl or aryl, X 1 represents a chlorine atom, a bromine atom, an iodine atom or trifluoromethanesulfonyloxy, and n is 0. Represents an integer of ~ 4)
で表される化合物を、ハロゲンィ匕して、一般式 (II)  A compound represented by general formula (II)
[0013] [化 5]  [0013] [Chemical 5]
Figure imgf000005_0002
Figure imgf000005_0002
[0014] (式中、 R\ X1および nはそれぞれ前記と同義であり、 X2は塩素原子、臭素原子また はヨウ素原子を表す） [0014] (wherein R \ X 1 and n are as defined above, and X 2 represents a chlorine atom, a bromine atom or an iodine atom)
で表される化合物を得る工程、 (ii)一般式 (Π)で表される化合物を一般式 (III) [0015] [化 6]  (Ii) converting the compound represented by the general formula (Π) into the general formula (III) [0015]
(式中、 R2はヒドロキシ、低級アルコキシ、アミ入低級アルキルァミノ、ジ低級アルキ ルァミノ、カルボキシ、低級アルコキシカルボ-ル、シクロアルキル、ァリール、芳香族 複素環基および脂肪族複素環基からなる群から選ばれる置換基を有して!/、てもよ 、 低級アルキル、またはヒドロキシ、低級アルコキシ、アミ入低級アルキルァミノ、ジ低 級アルキルアミ入カルボキシ、低級アルコキシカルボ-ル、ォキソ、ァリール、芳香 族複素環基および脂肪族複素環基からなる群から選ばれる置換基を有していてもよ Vヽシクロアルキルを表す） (Wherein R 2 is selected from the group consisting of hydroxy, lower alkoxy, amino-containing lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbole, cycloalkyl, aryl, aromatic heterocyclic group and aliphatic heterocyclic group. With selected substituents! /, May be lower alkyl, or hydroxy, lower alkoxy, amino-substituted lower alkylamino, di-low And may have a substituent selected from the group consisting of carboxy, alkenyl carbo, lower alkoxy carbo, oxo, aryl, aromatic heterocyclic group and aliphatic heterocyclic group).
で表されるアルキンィ匕合物とのカップリング反応に付して、一般式 (IV)  Is subjected to a coupling reaction with an alkyne compound represented by the general formula (IV)
[0017] [化 7]  [0017] [Chemical 7]
Figure imgf000006_0001
Figure imgf000006_0001
[0018] (式中、
Figure imgf000006_0002
R2、 X1および nはそれぞれ前記と同義である） [0018] (where
Figure imgf000006_0002
R 2 , X 1 and n are as defined above)
で表される化合物を得る工程、および (iii)一般式 (IV)で表される化合物を分子内環 化反応に付す工程、を含む一般式 (V)  And (iii) subjecting the compound represented by the general formula (IV) to an intramolecular cyclization reaction.
[0019] [化 8] [0019] [Chemical 8]
Figure imgf000006_0003
Figure imgf000006_0003
( V )  (V)
[0020] (式中、
Figure imgf000006_0004
R2および nはそれぞれ前記と同義である） [0020] (where
Figure imgf000006_0004
R 2 and n are as defined above)
で表される 11—アルキリデンジベンズ [b, e]ォキセピン誘導体またはその塩の製造 方法。  A process for producing 11-alkylidene dibenz [b, e] oxepin derivatives represented by the formula:
(2) 一般式 (I)  (2) General formula (I)
[0021] [化 9]
Figure imgf000007_0001
[0021] [Chemical 9]
Figure imgf000007_0001
( I )  (I)
[0022] (式中、
Figure imgf000007_0002
X1および nはそれぞれ前記と同義である） で表される化合物をハロゲンィ匕する工程を含む一般式 (II) [0023] [化 10] [0022] (wherein
Figure imgf000007_0002
Wherein X 1 and n are as defined above, respectively), which comprises a step of halogenating a compound represented by the general formula (II) [0023] [Chemical Formula 10]
Figure imgf000007_0003
Figure imgf000007_0003
[0024] (式中、 R X1、 X2および nはそれぞれ前記と同義である) で表される化合物またはその塩の製造方法。 [0024] (wherein RX 1 , X 2 and n are as defined above) or a salt thereof.
(3) 一般式 (II)  (3) General formula (II)
[0025] [化 11]  [0025] [Chemical 11]
Figure imgf000007_0004
( II )
Figure imgf000007_0004
(II)
[0026] (式中、 R X1、 X2および nはそれぞれ前記と同義である) で表される化合物を一般式 (III) [0026] (wherein, RX 1 , X 2 and n are as defined above), a compound represented by the general formula (III)
[0027] [化 12] ( III ) [0027] [Chemical 12] (III)
[0028] (式中、 R2は前記と同義である） [Wherein, R 2 is as defined above]
で表されるアルキンィ匕合物とのカップリング反応に付す工程を含む一般式 (IV) Including the step of subjecting to a coupling reaction with an alkyne compound represented by formula (IV)
[0029] [化 13] [0029] [Chemical 13]
Figure imgf000008_0001
Figure imgf000008_0001
[0030] (式中、 R R2、 X1および nはそれぞれ前記と同義である) [0030] (wherein, RR 2 , X 1 and n are as defined above)
で表される化合物またはその塩の製造方法。  Or a salt thereof.
(4) 一般式 (IV)  (4) General formula (IV)
[0031] [化 14]  [0031] [Chemical 14]
Figure imgf000008_0002
Figure imgf000008_0002
[0032] (式中、
Figure imgf000008_0003
R2、 X1および nはそれぞれ前記と同義である） [0032] (where
Figure imgf000008_0003
R 2 , X 1 and n are as defined above)
で表される化合物を分子内環化反応に付す工程を含む一般式 (V)  Including the step of subjecting the compound represented by the formula to an intramolecular cyclization reaction (V)
[0033] [化 15]  [0033] [Chemical 15]
Figure imgf000008_0004
Figure imgf000008_0004
( V ) [0034] (式中、 R R2および nはそれぞれ前記と同義である） (V) [0034] (wherein, RR 2 and n are as defined above)
で表される 11—アルキリデンジベンズ [b, e]ォキセピン誘導体またはその塩の製造 方法。  A process for producing 11-alkylidene dibenz [b, e] oxepin derivatives represented by the formula:
(5) ノ、ロゲン化が、ヨウ素と硫酸銀を用いるヨウ素化であり、 X2がヨウ素原子である（ 1)または（2)記載の方法。 (5) The method according to (1) or (2), wherein the norogenation is iodination using iodine and silver sulfate, and X 2 is an iodine atom.
(6) カップリング反応力 ジクロロビス（トリフエ-ルホスフィン)パラジウムおよびヨウ ィ匕銅の存在下で行う反応である（1)または（3)記載の方法。  (6) Coupling reaction force The method according to (1) or (3), which is a reaction carried out in the presence of dichlorobis (triphenylphosphine) palladium and copper iodide.
(7) 分子内環化反応が、トリフエニルホスフィン、トリ（o—トリル)ホスフィン、トリ（m— トリル）ホスフィン、トリ（p -トリル）ホスフィンおよびトリシクロへキシルホスフィンからな る群力も選ばれるホスフィンィ匕合物ならびに酢酸パラジウム、塩化パラジウムおよび パラジウム炭素力もなる群力も選ばれるパラジウム化合物の存在下で行う反応である (1)または (4)記載の方法。  (7) Phosphines whose intramolecular cyclization reaction is also selected from the group force consisting of triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine and tricyclohexylphosphine. The method according to (1) or (4), wherein the reaction is carried out in the presence of a compound and a palladium compound in which palladium acetate, palladium chloride and palladium carbon power are also selected.
(8) (1)〜（7)のいずれかに記載の方法 (但し、 R1は水素原子ではない）を含む一 般式 (VI) (8) General formula (VI) including the method according to any one of (1) to (7) (where R 1 is not a hydrogen atom)
[0035] [化 16]  [0035] [Chemical 16]
Figure imgf000009_0001
Figure imgf000009_0001
( VI )  (VI)
[0036] (式中、 R2および nはそれぞれ前記と同義である） [0036] (wherein R 2 and n are as defined above)
で表される 11—アルキリデンジベンズ [b, e]ォキセピン誘導体またはその塩の製造 方法。  A process for producing 11-alkylidene dibenz [b, e] oxepin derivatives represented by the formula:
(9) X1が塩素原子、臭素原子またはトリフルォロメタンスルホニルォキシであり、 X2 力 Sヨウ素原子である（1)〜（8)の 、ずれかに記載の方法。 (9) The method according to any one of (1) to (8), wherein X 1 is a chlorine atom, a bromine atom or trifluoromethanesulfonyloxy, and is an X 2 force S iodine atom.
(10) X1が塩素原子であり、 X2が臭素原子またはヨウ素原子である（1)〜（8)のい ずれかに記載の方法。 (10) The method according to any one of (1) to (8), wherein X 1 is a chlorine atom and X 2 is a bromine atom or an iodine atom.
(11) X1が臭素原子であり、 X2がヨウ素原子である（1)〜（8)のいずれかに記載の 方法。 (11) X 1 is a bromine atom, and X 2 is an iodine atom, according to any one of (1) to (8) Method.
(12) R2が低級アルキル、ヒドロキシ置換低級アルキル、ァミノ置換低級アルキル、 低級アルキルアミノ置換低級アルキルまたはジ低級アルキルアミノ置換低級アルキル である（1)および（3)〜（11)の 、ずれかに記載の方法。 (12) R 2 is lower alkyl, hydroxy-substituted lower alkyl, amino-substituted lower alkyl, lower alkylamino-substituted lower alkyl or di-lower alkylamino-substituted lower alkyl (1) and (3) to (11) The method described in 1.
(13) R2がヒドロキシ置換低級アルキルまたはジ低級アルキルアミノ置換低級アルキ ルである（1)および（3)〜（11)の 、ずれかに記載の方法。 (13) The method according to any one of (1) and (3) to (11), wherein R 2 is hydroxy-substituted lower alkyl or di-lower alkylamino-substituted lower alkyl.
(14) nが 0または 1である（1)〜（13)のいずれかに記載の方法。  (14) The method according to any one of (1) to (13), wherein n is 0 or 1.
(15) R1が低級アルキルである（1)〜（14)のいずれかに記載の方法。 (15) The method according to any one of (1) to (14), wherein R 1 is lower alkyl.
(16) 一般式 (II)  (16) General formula (II)
[0037] [化 17]  [0037] [Chemical 17]
Figure imgf000010_0001
Figure imgf000010_0001
[0038] (式中、
Figure imgf000010_0002
X1、 X2および nはそれぞれ前記と同義である） [0038] (where
Figure imgf000010_0002
X 1 , X 2 and n are as defined above)
で表される化合物またはその塩。  Or a salt thereof.
(17) X1が臭素原子であり、 X2がヨウ素原子である（16)記載の化合物またはその 塩。 (17) The compound or a salt thereof according to (16), wherein X 1 is a bromine atom and X 2 is an iodine atom.
(18) 一般式 (IV)  (18) General formula (IV)
[0039] [化 18] [0039] [Chemical 18]
Figure imgf000010_0003
[0040] (式中、 R R2、 X1および nはそれぞれ前記と同義である）
Figure imgf000010_0003
[Wherein, RR 2 , X 1 and n are as defined above]
で表される化合物またはその塩。  Or a salt thereof.
発明の効果  The invention's effect
[0041] 本発明により、医薬品または医薬品の中間体として有用な 11 アルキリデンジベン ズ [b, e]ォキセピン誘導体の製造において、望む幾何異性体を収率よく製造する方 法を提供することができる。  [0041] According to the present invention, it is possible to provide a method for producing a desired geometric isomer with high yield in the production of 11 alkylidene dibenz [b, e] oxepin derivatives useful as pharmaceuticals or pharmaceutical intermediates. .
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0042] 以下、一般式 (I)で表される化合物を化合物 (I) t 、う。その他の式番号の化合物 についても同様である。 [0042] Hereinafter, the compound represented by the general formula (I) will be referred to as compound (I) t. The same applies to the compounds of other formula numbers.
一般式 (I)〜 (VI)の各基の定義にお!、て、  In the definition of each group of the general formulas (I) to (VI)!
低級アルキルならびに低級アルコキシ、低級アルキルアミ入ジ低級アルキルアミノ および低級アルコキシカルボ-ルの低級アルキル部分としては、例えば直鎖または 分岐状の炭素数 1〜10のアルキルがあげられ、より具体的にはメチル、ェチル、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、ィ ソペンチル、ネオペンチル、へキシル、ヘプチル、ォクチル、ノエル、デシルなどがあ げられる。ジ低級アルキルァミノの 2つの低級アルキル部分は、同一でも異なってい てもよい。  Examples of the lower alkyl of lower alkyl and lower alkoxy, dialkyl lower alkylamino and lower alkoxy carboyl include linear or branched alkyl having 1 to 10 carbon atoms, more specifically methyl. , Ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, noel, decyl and the like. The two lower alkyl moieties of the di-lower alkylamino may be the same or different.
[0043] シクロアルキルとしては、例えば炭素数 3〜8のシクロアルキルがあげられ、より具体 的にはシクロプロピル、シクロブチル、シクロペンチル、シクロへキシル、シクロへプチ ル、シクロォクチルなどがあげられる。  [0043] Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and more specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
ァリールとしては、例えば炭素数 6〜14のァリールがあげられ、より具体的にはフエ Examples of aryls include aryls having 6 to 14 carbon atoms.
-ル、ナフチル、アントリルなどがあげられる。 -Le, naphthyl, anthryl, etc.
[0044] ァラルキルとしては、例えば炭素数 7〜16のァラルキルがあげられ、より具体的には ベンジル、フエネチル、 3—フエ-ルプロピル、 4—フエ-ルブチル、 5—フエ-ルペン チル、ナフチルメチル、ナフチルェチルなどがあげられる。 [0044] Examples of aralkyl include aralkyl having 7 to 16 carbon atoms, and more specifically, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, naphthylmethyl, Naphthyltil.
脂肪族複素環基としては、例えば窒素原子、酸素原子および硫黄原子から選ばれ る少なくとも 1個の原子を含む 5員または 6員の単環性脂肪族複素環基、 3〜8員の 環が縮合した二環または三環性で窒素原子、酸素原子および硫黄原子力 選ばれ る少なくとも 1個の原子を含む縮環性脂肪族複素環基などがあげられ、より具体的に はアジリジニル、ァゼチジニル、ピロリジニル、ピペリジノ、ピベリジニル、パーヒドロア ゼピニル、イミダゾリジニル、ビラゾリジニル、ピペラジニル、ホモピペラジニル、ォキシ ラニル、テトラヒドロフラニル、テトラヒドロー 2H—ビラニル、ォキサゾリジニル、モルホ リ入モルホリニル、チォキサゾリジニル、チオモルホリニル、ジヒドロインドリル、ジヒド 口イソインドリル、ジヒドロベンゾフラ -ル、ベンゾイミダゾリジ-ル、ジヒドロベンゾォキ サゾリル、ジヒドロベンゾチォキサゾリル、ベンゾジォキソリニル、テトラヒドロキノリル、 テトラヒドロイソキノリル、ジヒドロー 2H—クロマニル、ジヒドロー 1H—クロマニル、ジヒ ドロー 2H—チォクロマニル、ジヒドロー 1H—チォクロマニル、テトラヒドロキノキサリニ ル、テトラヒドロキナゾリニル、ジヒドロべンゾジォキサニルなどがあげられる。 Examples of the aliphatic heterocyclic group include a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and a 3- to 8-membered ring. Condensed bicyclic or tricyclic nitrogen, oxygen and sulfur nuclear power And, more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, perhydroazepinyl, imidazolidinyl, virazolidinyl, piperazinyl, homopiperazinyl, oxylanyl, and the like. Tetrahydrofuranyl, tetrahydro-2H-biranyl, oxazolidinyl, morpholinylated morpholinyl, thixazolidinyl, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuryl, benzimidazolidyl, dihydrobenzoxazolyl, dihydro Benzothixazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro 2H- Examples include thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl and the like.
[0045] 芳香族複素環基としては、例えば窒素原子、酸素原子および硫黄原子から選ばれ る少なくとも 1個の原子を含む 5員または 6員の単環性芳香族複素環基、 3〜8員の 環が縮合した二環または三環性で窒素原子、酸素原子および硫黄原子力 選ばれ る少なくとも 1個の原子を含む縮環性芳香族複素環基などがあげられ、より具体的に はフリル、チェ-ル、ピロリル、イミダゾリル、ピラゾリル、ォキサゾリル、イソォキサゾリ ル、ォキサジァゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、トリァゾリル、テト ラゾリル、ピリジル、ピリダジ -ル、ピリミジニル、ピラジ -ル、トリアジ-ル、ベンゾフラ ニル、ベンゾチォフ ニル、ベンゾォキサゾリル、ベンゾチアゾリル、イソインドリル、ィ ンドリル、インダゾリル、ベンゾイミダゾリル、ベンゾトリアゾリル、ォキサゾロピリミジ -ル 、チアゾロピリミジ -ル、ピロ口ピリジ -ル、ピロ口ピリミジ -ル、イミダゾピリジ -ル、プリ ニル、キノリニル、イソキノリニル、シンノリニル、フタラジュル、キナゾリニル、キノキサ リニル、ナフチリジ-ルなどがあげられる。  [0045] Examples of the aromatic heterocyclic group include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 3 to 8 members. And a condensed ring aromatic heterocyclic group containing at least one atom selected from the group consisting of a bicyclic or tricyclic condensed nitrogen ring, an oxygen atom and a sulfur nuclear power, and more specifically furyl, Chael, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazil, pyrimidinyl, pyrazyl, triazyl, benzofuranyl, benzothiol Benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazo Ril, benzotriazolyl, oxazolopyrimidyl, thiazolopyrimidyl, pyropyridyl, pyropyrimidyl, imidazopyridyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthaladyl, quinazolinyl, quinoxalinyl And naphthyldiol.
[0046] 化合物（I)の各基において、  [0046] In each group of the compound (I),
X1が塩素原子、臭素原子またはトリフルォロメタンスルホニルォキシであることが好ま しぐ塩素原子または臭素原子であることがより好ましぐ臭素原子であることが更に 好ましい。 X 1 is preferably a chlorine atom, a bromine atom, or trifluoromethanesulfonyloxy, more preferably a chlorine atom or a bromine atom, and even more preferably a bromine atom.
化合物 (Π)の各基において、  In each group of compounds (Π)
X1が塩素原子であり、 X2が臭素原子もしくはヨウ素原子である力 または X1が塩素原 子、臭素原子もしくはトリフルォロメタンスルホニルォキシであり、 X2がヨウ素原子であ ることが好ましぐ X1が臭素原子もしくはトリフルォロメタンスルホ-ルォキシであり、 X2 力 sヨウ素原子であることがより好ましぐ X1が臭素原子であり、 X2がヨウ素原子であるこ とがさらに好ましい。 R1としては、低級アルキルが好ましぐメチル、ェチルなどがより 好ましい。 Force where X 1 is a chlorine atom and X 2 is a bromine or iodine atom or X 1 is a chlorine atom Child, a bromine atom or triflate Ruo b methanesulfonyl O carboxymethyl, X 2 is an iodine atom in Ah Rukoto is preferably fixture X 1 is a bromine atom or triflate Ruo Russia methanesulfonyl - a Ruokishi, is X 2 force s iodine atom It is even more preferable that X 1 is a bromine atom and X 2 is an iodine atom. R 1 is more preferably methyl, ethyl or the like, preferably lower alkyl.
[0047] 化合物（IV)の各基にぉ 、て、  [0047] For each group of the compound (IV),
X1が塩素原子、臭素原子またはトリフルォロメタンスルホニルォキシであることが好ま しぐ塩素原子または臭素原子であることがより好ましぐ臭素原子であることが更に 好ましい。 R1としては、低級アルキルが好ましぐメチル、ェチルなどがより好ましい。 R2としては、ヒドロキシメチル、ヒドロキシェチル、ヒドロキシプロピル、ジメチルアミノメ チル、ジメチルアミノエチル、ジメチルァミノプロピルなどが好ましぐヒドロキシェチル 、ジメチルアミノエチルなどがより好ましい。 X 1 is preferably a chlorine atom, a bromine atom, or trifluoromethanesulfonyloxy, more preferably a chlorine atom or a bromine atom, and even more preferably a bromine atom. R 1 is more preferably methyl, ethyl or the like, preferably lower alkyl. R 2 is preferably hydroxyethyl, dimethylaminoethyl, etc., preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl and the like.
[0048] 化合物（Π)、 (IV)、 (V)および (VI)の塩は、例えば酸付加塩、金属塩、アンモニゥ ム塩、有機アミン付加塩、アミノ酸付加塩などを包含する。化合物 (11)、（IV)、（V)お よび (VI)の酸付加塩としては、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン 酸塩などの無機酸塩、酢酸塩、シユウ酸塩、マレイン酸塩、フマル酸塩、クェン酸塩、 安息香酸塩、メタンスルホン酸塩などの有機酸塩などがあげられ、金属塩としては、 例えばナトリウム塩、カリウム塩などのアルカリ金属塩、マグネシウム塩、カルシウム塩 などのアルカリ土類金属塩、アルミニウム塩、亜鉛塩などがあげられ、アンモ-ゥム塩 としては、例えばアンモ-ゥム、テトラメチルアンモ -ゥムなどの塩があげられ、有機ァ ミン付加塩としては、例えばモルホリン、ピぺリジンなどの付加塩があげられ、アミノ酸 付加塩としては、例えばリジン、グリシン、フエ-ルァラニン、ァスパラギン酸、ダルタミ ン酸などの付加塩があげられる。  [0048] Salts of compounds (IV), (IV), (V) and (VI) include, for example, acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of acid addition salts of compounds (11), (IV), (V) and (VI) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, and acetates. Organic salts such as oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate, and metal salts include, for example, alkali metals such as sodium salt and potassium salt Examples thereof include alkaline earth metal salts such as salts, magnesium salts and calcium salts, aluminum salts, and zinc salts. Examples of ammonium salts include salts such as ammonium and tetramethyl ammonium. Examples of organic amine addition salts include addition salts such as morpholine and piperidine, and examples of amino acid addition salts include addition of lysine, glycine, ferrolanine, aspartic acid, dartamic acid and the like. Salt, and the like.
[0049] 本発明におけるハロゲン化とは、ベンゼン環に塩素原子、臭素原子、ヨウ素原子な どのハロゲン原子を導入する反応のことであり、より具体的には例えば下記製造方法 の工程 1に示す反応工程があげられる。本発明におけるカップリング反応とは、ハロ ゲンィ匕ァリールとアルキン化合物とをカップリングする反応のことであり、例えば Sono gashim反応などがあげられ、より具体的には例えば下記製造方法の工程 2に示す 反応工程があげられる。本発明における分子内環化反応としては、例えばパラジウム 触媒の存在下、ォキセピン環を形成させる反応があげられ、より具体的には例えば下 記製造方法の工程 3に示す反応工程があげられる。 [0049] Halogenation in the present invention is a reaction for introducing a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom into a benzene ring, and more specifically, for example, the reaction shown in Step 1 of the following production method. Process. The coupling reaction in the present invention is a reaction for coupling a halogen aryl and an alkyne compound, such as a Sono gashim reaction, and more specifically, for example, shown in Step 2 of the following production method. A reaction process is mentioned. Examples of the intramolecular cyclization reaction in the present invention include a reaction for forming an oxepin ring in the presence of a palladium catalyst, and more specifically, for example, the reaction step shown in Step 3 of the production method below.
[0050] 以下、本発明の製造方法をより詳細に説明する。本発明により、 11 アルキリデン ジベンズ [b, e]ォキセピン誘導体 (V)は、ベンジルフ ニルエーテル誘導体 (I)より 以下の 3工程を経て製造することができる。 [0050] Hereinafter, the production method of the present invention will be described in more detail. According to the present invention, 11 alkylidene dibenz [b, e] oxepin derivative (V) can be produced from benzyl phenyl ether derivative (I) through the following three steps.
[0051] [化 19] [0051] [Chemical 19]
Figure imgf000014_0001
Figure imgf000014_0001
( IV ) ( V )  (IV) (V)
(式中、
Figure imgf000014_0002
R2、 X1、 X2および nはそれぞれ前記と同義である） (Where
Figure imgf000014_0002
R 2 , X 1 , X 2 and n are as defined above)
工程 1  Process 1
本工程は、公知のベンゼン環のハロゲン化方法（例えば、オーガニック 'シンセシス (Organic Synthesis)、 1963年、 4卷、 p. 872 ;オーガニック 'シンセシス（Organi c Synthesis)、 1973年、 5卷、 p. 117 ;オーガニック 'シンセシス（Organic Synt hesis)、 1963年、 4卷、 p. 547 ;テトラへドロン'レターズ（Tetrahedron Letters) 、 1993年、 34卷、 p. 6223 ;アンゲバンテ'ケミ'インターナショナル'エディション (A ngew. Chem. Int. Ed. )、 2001年、 40卷、 p. 1967)に準じて行うこと力 Sできる。  This process is carried out by a known method for halogenating a benzene ring (for example, Organic 'Synthesis (Organic Synthesis), 1963, 4 卷, p. 872; Organic' Synthesis (Organic Synthesis), 1973, 5 卷, p. 117; Organic Synt hesis, 1963, 4 卷, p. 547; Tetrahedron Letters, 1993, 34 卷, p. 6223; Angevante 'Cemi' International 'Edition (A ngew. Chem. Int. Ed.), 2001, 40 卷, p. 1967).
[0053] 化合物 (Π)は、化合物 (I)を無溶媒でまたは適当な溶媒中、適当なハロゲン化剤で 5分間〜 72時間、好ましくは 1〜： L0時間処理することにより製造することができる。 化合物（I)は例えば WO2005Z009104記載の方法でまたはそれに準じて得るこ とがでさる。 [0053] Compound (Π) can be produced by treating compound (I) without solvent or in a suitable solvent with a suitable halogenating agent for 5 minutes to 72 hours, preferably 1 to: L0 hours. it can. Compound (I) can be obtained, for example, by the method described in WO2005Z009104 or in conformity thereto. Togashi.
[0054] ハロゲンィ匕剤としては、例えば塩素、スルフリルクロリドなどの塩素ィ匕剤、臭素、 N— ブロモスクシンイミドなどの臭素ィ匕剤、ヨウ素、塩ィ匕ヨウ素、ビス（ピリジンョードニゥム） テトラフルォロボレート（F—TEDA)、ビス（ピリジンョードニゥム）四フッ化ホウ素など のヨウ素ィ匕剤などがあげられ、これらを組み合わせて用いることもできる。組み合わせ としては、例えばヨウ素と F— TEDAとの組み合わせなどがあげられる。これらハロゲ ン化剤は、化合物 (I)に対して、好ましくは 1〜30当量、より好ましくは 1〜5当量、更 に好ましくは 1〜2当量、更に好ましくは 1〜1. 5当量用いられる。また、これらハロゲ ン化剤は、各種添加物と組み合わせて用いることもでき、用いるハロゲン化剤の種類 によって各種添加物を用いることができる力 組み合わせとしては、例えば塩素と塩 化水素との組み合わせ、臭素と塩ィ匕アルミニウムなどのルイス酸との組み合わせ、臭 素と鉄との組み合わせ、ヨウ素と硫酸銀との組み合わせ、ヨウ素とヨウ化カリウムとの組 み合わせ、ヨウ素とトリフルォロ酢酸銀との組み合わせなどがあげられる。中でも、ヨウ 素と硫酸銀との組み合わせが好まし 、。これら組み合わせて用いる場合の添加物の 使用量は、用いるハロゲン化剤と添加物の種類などによって変動する力 例えば臭 素と塩ィ匕アルミニウムを組み合わせて用いる場合、塩ィ匕アルミニウムは臭素に対して 好ましくは 2〜5当量、より好ましくは 1〜1. 5当量用いられ、ヨウ素と硫酸銀を組み合 わせて用いる場合、硫酸銀はヨウ素に対して好ましくは 0. 5〜3当量、より好ましくは 0. 8〜2当量、更に好ましくは 1当量用いられ、ヨウ素とヨウ化カリウムを組み合わせて 用いる場合、ヨウ化カリウムはヨウ素に対して好ましくは 0. 5〜3当量、より好ましくは 0 . 8〜2当量、更に好ましくは 1当量用いられる。  [0054] Examples of the halogenating agent include chlorine agents such as chlorine and sulfuryl chloride, bromine agents such as bromine and N-bromosuccinimide, iodine, salt iodine and bis (pyridine iodine). Examples include iodine fluorides such as tetrafluoroborate (F-TEDA) and bis (pyridine iodine) boron tetrafluoride, and these can also be used in combination. Examples of combinations include a combination of iodine and F-TEDA. These halogenating agents are preferably used in an amount of 1 to 30 equivalents, more preferably 1 to 5 equivalents, more preferably 1 to 2 equivalents, and even more preferably 1 to 1.5 equivalents, relative to compound (I). . These halogenating agents can also be used in combination with various additives. Examples of the power combinations that can use various additives depending on the type of halogenating agent used include, for example, a combination of chlorine and hydrogen chloride, Combinations of bromine and Lewis acids such as aluminum chloride, combinations of odor and iron, combinations of iodine and silver sulfate, combinations of iodine and potassium iodide, combinations of iodine and silver trifluoroacetate, etc. Can be given. Of these, the combination of iodine and silver sulfate is preferred. When used in combination, the amount of additive used varies depending on the halogenating agent used and the type of additive. For example, when using a combination of odor and salt-aluminum, Preferably 2 to 5 equivalents, more preferably 1 to 1.5 equivalents are used. When iodine and silver sulfate are used in combination, silver sulfate is preferably 0.5 to 3 equivalents, more preferably, relative to iodine. 0.8 to 2 equivalents, more preferably 1 equivalent is used. When iodine and potassium iodide are used in combination, potassium iodide is preferably 0.5 to 3 equivalents, more preferably 0.8 to 2 equivalents, more preferably 1 equivalent is used.
[0055] 溶媒としては、例えばメタノール、エタノール、プロパノールなどのアルコール系溶 媒、アセトン、ァセトニトリル、 N, N—ジメチルホルムアミド（DMF)、 N—メチルピロリ ドン (NMP)などの親水性溶媒、へキサンなどの炭化水素系溶媒、酢酸ェチルなど のエステル系溶媒、ジェチルエーテル、テトラヒドロフラン (THF)、 1, 4—ジォキサン 、ジメトキシェタンなどのエーテル系溶媒、ジクロロメタン、クロ口ホルムなどのハロゲン 系溶媒、ピリジンなどの塩基性溶媒、酢酸などの酸性溶媒、水などがあげられ、これ らを単独でまたは混合して用いることができる。ハロゲン化剤としてヨウ素および硫酸 銀、塩ィ匕ヨウ素などのヨウ素ィ匕剤を用いる場合は、メタノールなどのアルコール系溶 媒が好ましい。 [0055] Examples of the solvent include alcohol solvents such as methanol, ethanol, and propanol, hydrophilic solvents such as acetone, acetonitrile, N, N-dimethylformamide (DMF), and N-methylpyrrolidone (NMP), hexane, and the like. Hydrocarbon solvents, ester solvents such as ethyl acetate, ether solvents such as jetyl ether, tetrahydrofuran (THF), 1,4-dioxane and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, pyridine Examples thereof include basic solvents such as acetic acid, acidic solvents such as acetic acid, water and the like, and these can be used alone or in combination. Iodine and sulfuric acid as halogenating agents When an iodine additive such as silver or salt or iodine is used, an alcohol solvent such as methanol is preferred.
[0056] 本工程の処理は、通常 78°C〜150°Cの間の温度で、好ましくは 0°C〜100°Cの 間の温度で、より好ましくは 10°C〜 70°Cの間の温度で行われる。  [0056] The treatment in this step is usually at a temperature between 78 ° C and 150 ° C, preferably at a temperature between 0 ° C and 100 ° C, more preferably between 10 ° C and 70 ° C. At a temperature of
工程 2  Process 2
本工程は、公知の方法（例えば、テトラへドロン'レターズ（Tetrahedron Letters )、 1975年、 16卷、 p. 4467 ;テ卜ラへドロン ·レターズ（Tetrahedron Letters) , 1 993年、 34卷、 p. 8353)に準じて行うこと力できる。  This step is carried out by a known method (for example, Tetrahedron Letters, 1975, 16 卷, p. 4467; Tetrahedron Letters, 1 993, 34 卷, p Can be performed according to 8353).
[0057] 化合物 (IV)は、化合物 (Π)を適当な溶媒中、例えば銅化合物、ホスフィン配位子 を有するパラジウム触媒および必要により塩基の存在下、 1〜20当量、好ましくは 1 〜10当量、より好ましくは 1〜3当量の化合物（III)と、 5分間〜 72時間、好ましくは 1 〜24時間反応させること〖こより製造することができる。 [0057] Compound (IV) is compound (IV) in an appropriate solvent, for example, in the presence of a copper compound, a palladium catalyst having a phosphine ligand and optionally a base, 1 to 20 equivalents, preferably 1 to 10 equivalents. More preferably, it can be produced by reacting with 1 to 3 equivalents of compound (III) for 5 minutes to 72 hours, preferably 1 to 24 hours.
化合物 (ΠΙ)は、市販品として得られる力または公知の方法で (例えば、ジャーナル •ォブ'オーガニック 'ケミストリーお. Org. Chem. ) , 1999年、 64卷、 p. 1798)また はそれらに準じて得ることができる。  Compound (ΠΙ) can be obtained in a commercially available or known manner (for example, Journal of Organic Chemistry, Org. Chem.), 1999, 64 卷, p. 1798) or to them. It can be obtained similarly.
[0058] 銅化合物としては、例えばヨウ化銅などがあげられる。該銅化合物は、化合物 (II) に対して好ましくは 0. 001〜： L当量、より好ましくは 0. 01-0. 2当量用いられる。 ホスフィン配位子を有するパラジウム触媒としては、例えばホスフィン配位子がパラ ジゥムに配位したィ匕合物があげられ、該ホスフィン配位子としては、例えばトリフエ- ルホスフィン、トリ（o トリル）ホスフィン、トリ（m—トリル）ホスフィン、トリ（ρ トリル）ホ スフイン、トリス（2, 4 ジメトキシフエ-ル）ホスフィン、トリス（4—メトキシフエ-ル）ホス フィン、トリス（ジメチルァミノ）ホスフィン、トリ（tert—ブチル）ホスフィン、トリシクロへキ シノレホスフィン、エチレンビス（ジフエ二ノレホスフィン）、 1, 3 ビス（ジフエ二ノレホスフィ ノ）プロパン、 1, 1， 一ビス（ジフエ-ルホスフイノ）フエ口セン、 2, 2， 一ビス（ジフエ-ル ホスフイノ）— 1, 1，—ビナフチルなどがあげられる。これらホスフィン配位子を有する ノ ラジウム触媒は、例えば上記であげたホスフィン配位子とパラジウム化合物とを反 応溶液中に添加することで反応溶液中に生成したものを用いることができる。このとき 、ホスフィン配位子は、パラジウム化合物に対して 1〜4当量用いるのが好ましい。該 ノ《ラジウム化合物としては、例えば酢酸パラジウム、塩化パラジウム、トリス (ジベンジリ デンアセトン)ジパラジウム、パラジウム炭素などがあげられる。また、ホスフィン配位 子を有するパラジウム触媒は、化合物 (Π)に対して通常 0. 001〜1当量、好ましくは 0. 01〜0. 2当量用いられる。また、ホスフィン配位子を有するパラジウム触媒として は、例えば市販のジクロ口ビス（トリフエ-ルホスフィン)パラジウム、酢酸ビス（トリフエ -ルホスフィン）パラジウム、テトラキス（トリフエ-ルホスフィン）パラジウムなどを利用 することもでき、ジクロロビス（トリフエ-ルホスフィン)パラジウムなどが好まし 、。 [0058] Examples of the copper compound include copper iodide. The copper compound is preferably used in an amount of 0.001 to L equivalents, more preferably 0.01-0.2 equivalents relative to compound (II). Examples of the palladium catalyst having a phosphine ligand include compounds in which a phosphine ligand is coordinated to palladium. Examples of the phosphine ligand include triphenylphosphine and tri (o-tolyl). Phosphine, tri (m-tolyl) phosphine, tri (ρ tolyl) phosphine, tris (2,4 dimethoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (dimethylamino) phosphine, tri (tert —Butyl) phosphine, tricyclohexenolephosphine, ethylenebis (diphenylenophosphine), 1,3bis (diphenylenophosphino) propane, 1,1, monobis (diphenylphosphino) phenol, 2, 2, One-bis (diphenyl phosphino)-1, 1,-binaphthyl. As the noradium catalyst having these phosphine ligands, for example, the one produced in the reaction solution by adding the phosphine ligand and the palladium compound mentioned above into the reaction solution can be used. In this case, it is preferable to use 1 to 4 equivalents of the phosphine ligand with respect to the palladium compound. The Examples of the radium compound include palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon, and the like. Further, the palladium catalyst having a phosphine coordination is usually used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalent, relative to the compound (Π). In addition, as the palladium catalyst having a phosphine ligand, for example, commercially available dichroic bis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium acetate, tetrakis (triphenylphosphine) palladium and the like are used. Dichlorobis (triphenylphosphine) palladium is preferred.
[0059] 塩基としては、例えば水酸化リチウム、水酸ィ匕カリウム、水酸化ナトリウム、炭酸ナトリ ゥム、炭酸カリウム、カリウム tert ブトキシド、ナトリウムメトキシドなどの無機塩基、 ピリジン、トリェチルァミン、ジイソプロピルェチルァミン、 1, 8 ジァザビシクロ [5. 4. 0]ゥンデクー 7 ェン（DBU)、ピペリジン、 N—メチルモルホリンなどの有機塩基な どがあげられ、好ましくはトリエチルァミンなどがあげられる。該塩基は、化合物 (Π)に 対して、好ましくは 0. 5〜20当量、より好ましくは 1〜10当量、更に好ましくは 1〜5当 量用いられる。 [0059] Examples of the base include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert butoxide, sodium methoxide, and other inorganic bases such as pyridine, triethylamine, diisopropyl ether. And organic bases such as 1,8 diazabicyclo [5.4.0] undeque 7 (DBU), piperidine and N-methylmorpholine, and preferably triethylamine. The base is preferably used in an amount of 0.5 to 20 equivalents, more preferably 1 to 10 equivalents, and even more preferably 1 to 5 equivalents relative to compound (Π).
[0060] 溶媒としては、例えばメタノール、エタノール、プロパノールなどのアルコール系溶 媒、アセトン、ァセトニトリル、 DMF、 NMPなどの親水性溶媒、トルエン、キシレン、 へキサンなどの炭化水素系溶媒、酢酸ェチルなどのエステル系溶媒、ジェチルエー テル、 THF、 1, 4 ジォキサン、ジメトキシェタンなどのエーテル系溶媒、ジクロロメ タン、クロ口ホルムなどのハロゲン系溶媒、ピリジンなどの塩基性溶媒などがあげられ 、これらを単独でまたは混合して用いることができ、好ましくは DMFなどがあげられる  [0060] Examples of the solvent include alcohol solvents such as methanol, ethanol and propanol, hydrophilic solvents such as acetone, acetonitrile, DMF and NMP, hydrocarbon solvents such as toluene, xylene and hexane, and ethyl acetate. Examples include ester solvents, ether solvents such as jetyl ether, THF, 1,4 dioxane, and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. Or it can be used in a mixture, preferably DMF etc.
[0061] 本工程の反応は、通常 78°C〜用いる溶媒の沸点の間の温度で、好ましくは 0°C 〜100°Cの間の温度で、より好ましくは 10°C〜70°Cの間の温度で行われる。 [0061] The reaction in this step is usually performed at a temperature between 78 ° C and the boiling point of the solvent used, preferably at a temperature between 0 ° C and 100 ° C, more preferably between 10 ° C and 70 ° C. Between temperatures.
工程 3  Process 3
本工程は、公知の方法（例えば、テトラへドロン'レターズ（Tetrahedron Letters ) , 1993年、 34卷、 p. 8353 ;テトラへドロン'レターズ (Tetrahedron Letters)ゝ 1 988年、 29卷、 p. 4325)に準じて行うこと力できる。  This process is carried out by a known method (for example, Tetrahedron Letters, 1993, 34 卷, p. 8353; Tetrahedron Letters ゝ 1 988, 29 卷, p. 4325). ) Can be done according to.
[0062] 化合物 (V)は、化合物 (IV)を適当な溶媒中、適当な塩基および水素源の存在下、 ノ ラジウム触媒、好ましくはホスフィン配位子を有するパラジウム触媒で 5分間〜 72 時間、好ましくは 1〜10時間処理することにより製造することができる。 [0062] Compound (V) is compound (IV) in a suitable solvent in the presence of a suitable base and a hydrogen source. It can be produced by treating with a noradium catalyst, preferably a palladium catalyst having a phosphine ligand, for 5 minutes to 72 hours, preferably 1 to 10 hours.
ノラジウム触媒としては、例えばホスフィン配位子を有するパラジウム触媒があげら れ、該ホスフィン配位子を有するパラジウム触媒としては、例えばホスフィン配位子が ノ ラジウムに配位した化合物があげられる。該ホスフィン配位子としては、例えばトリ フエ-ルホスフィン、トリ（o—トリル）ホスフィン、トリ（m—トリル）ホスフィン、トリ（ρ—トリ ル）ホスフィン、トリス（2, 4—ジメトキシフエ-ル）ホスフィン、トリス（4—メトキシフエ- ル）ホスフィン、トリス（ジメチルァミノ）ホスフィン、トリ（tert—ブチル）ホスフィン、トリシ クロへキシルホスフィン、エチレンビス（ジフエ二ノレホスフィン）、 1, 3—ビス（ジフエ- ルホスフイノ）プロパン、 1, 1， 一ビス（ジフエ-ルホスフイノ）フエ口セン、 2, 2， 一ビス（ ジフエ-ルホスフイノ）一 1, 1，一ビナフチルなどがあげられ、好ましくはトリフエ-ルホ スフイン、トリ（o—トリル）ホスフィン、トリ（m—トリル）ホスフィン、トリ（p—トリル）ホスフィ ン、トリシクロへキシルホスフィンなどがあげられ、より好ましくはトリ（o—トリル)ホスフィ ンなどがあげられる。これらホスフィン配位子を有するパラジウム触媒は、例えば上記 であげたホスフィン配位子とパラジウム化合物とを反応溶液中に添加することで反応 溶液中に生成したものを用いることができる。このとき、ホスフィン配位子としては、例 えばトリフエニルホスフィン、トリ（o—トリル）ホスフィン、トリ（m—トリル）ホスフィン、トリ（ P—トリル）ホスフィン、トリシクロへキシルホスフィンなどが好ましぐトリ（o—トリル）ホス フィンなどがより好ましぐこれらはパラジウム化合物に対して 1〜4当量用いるのが好 ましい。該パラジウム化合物としては、例えば酢酸パラジウム、塩化パラジウム、トリス（ ジベンジリデンアセトン)ジパラジウム、パラジウム炭素などがあげられ、好ましくは酢 酸パラジウム、塩化パラジウム、パラジウム炭素などがあげられ、より好ましくは酢酸パ ラジウムなどがあげられる。また、ホスフィン配位子を有するパラジウム触媒としては、 例えば市販のジクロ口ビス（トリフエ-ルホスフィン)パラジウム、テトラキス（トリフエ-ル ホスフィン)パラジウムなどを利用することもできる。なお、ノ ラジウム触媒は、化合物（ IV)に対して通常 0. 001〜： L当量、好ましくは 0. 01〜0. 2当量用いられる。  Examples of the noradium catalyst include a palladium catalyst having a phosphine ligand, and examples of the palladium catalyst having the phosphine ligand include a compound in which the phosphine ligand is coordinated to noradium. Examples of the phosphine ligand include triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (ρ-tolyl) phosphine, tris (2,4-dimethoxyphenol). ) Phosphine, tris (4-methoxyphenol) phosphine, tris (dimethylamino) phosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, ethylenebis (diphenylenophosphine), 1,3-bis (diphenyl-) Ruphosphino) propane, 1,1,1bis (diphenylphosphino) phenol, 2,2,1bis (diphosphosphino) 1,1,1, binaphthyl, etc., preferably triphenylphosphine, triphenyl (O-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, tricyclohexylphosphine Like fins and the like, and more preferable, tri (o-tolyl) phosphine emission and the like. As the palladium catalyst having these phosphine ligands, for example, those produced in the reaction solution by adding the phosphine ligand and palladium compound mentioned above to the reaction solution can be used. At this time, preferred examples of the phosphine ligand include triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (P-tolyl) phosphine, and tricyclohexylphosphine. (O-Tolyl) phosphine and the like are more preferable. These are preferably used in an amount of 1 to 4 equivalents with respect to the palladium compound. Examples of the palladium compound include palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon and the like, preferably palladium acetate, palladium chloride, palladium carbon and the like, and more preferably acetate acetate. For example, radium. As the palladium catalyst having a phosphine ligand, for example, commercially available dichroic bis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium and the like can be used. In addition, the radium catalyst is usually used in an amount of 0.001 to L equivalents, preferably 0.01 to 0.2 equivalents, relative to the compound (IV).
塩基としては、例えば水酸化リチウム、水酸ィ匕カリウム、水酸化ナトリウム、炭酸ナトリ ゥム、炭酸カリウム、カリウム tert—ブトキシド、ナトリウムメトキシドなどの無機塩基、 メチルァミン、ジメチルァミン、ピリジン、ピロリジン、ピぺリジン、モルホリン、 N—メチ ルモルホリン、トリエチルァミン、ジイソプロピルェチルァミン、 DBUなどの有機塩基な どがあげられ、好ましくはピペリジンなどがあげられる。該塩基は、化合物 (IV)に対し て、好ましくは 0. 5〜30当量、より好ましくは 1〜20当量、更に好ましくは 1〜10当量 用いられる。 Examples of bases include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, Examples thereof include organic bases such as methylamine, dimethylamine, pyridine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, triethylamine, diisopropylethylamine, DBU, and preferably piperidine. The base is preferably used in an amount of 0.5 to 30 equivalents, more preferably 1 to 20 equivalents, still more preferably 1 to 10 equivalents, relative to compound (IV).
[0064] 水素源としては、例えば酢酸、ギ酸などの有機酸、該有機酸とアンモニア、メチルァ ミン、ジメチルァミン、トリエチルァミン、ピロリジン、ピぺリジン、モルホリン、 N—メチル モルホリンなどの有機ァミンとのアンモ-ゥム塩、該有機酸のナトリウム、カリウム、力 ルシゥムなどの金属塩などがあげられ、好ましくは、ギ酸アンモ-ゥム、酢酸アンモ- ゥム、ギ酸ピロリジゥム、ギ酸ピペリジゥムなどがあげられ、より好ましくはギ酸ピベリジ ゥムなどがあげられる。これら有機酸のアンモ-ゥム塩および有機酸の金属塩として は、例えば酢酸、ギ酸などの有機酸とアンモニア、上記であげた有機ァミン、水酸ィ匕 ナトリウム、水酸ィ匕カリウム、水酸ィ匕カルシウム、炭酸カリウムなどとを反応溶液中に添 加することで、反応溶液中に生成したものを用いることもでき、ギ酸とピぺリジンを反 応溶液中に添加して生成したものを用いることが好ましい。これら有機酸、有機酸の アンモ-ゥム塩および有機酸の金属塩は、化合物 (IV)に対して好ましくは 1〜： LO当 量用いられる。また、水素ガスも該水素源として利用できる。  [0064] Examples of the hydrogen source include organic acids such as acetic acid and formic acid, and organic acids such as ammonia, methylamine, dimethylamine, triethylamine, pyrrolidine, piperidine, morpholine, and N-methylmorpholine. Ammonium salts, metal salts of the organic acids such as sodium, potassium, strength, and the like, preferably ammonium formate, ammonium acetate, pyrrolidinium formate, piperidium formate, etc. More preferably, for example, pyridium formate. These organic acid ammonium salts and organic acid metal salts include, for example, organic acids such as acetic acid and formic acid and ammonia, the organic amines mentioned above, sodium hydroxide, potassium hydroxide, and hydroxide.匕 Calcium, potassium carbonate, etc. added to the reaction solution can be used in the reaction solution. Formic acid and piperidine can be added to the reaction solution. It is preferable to use it. These organic acids, ammonium salts of organic acids and metal salts of organic acids are preferably used in an amount equivalent to 1 to LO for compound (IV). Hydrogen gas can also be used as the hydrogen source.
[0065] 溶媒としては、例えばメタノール、エタノール、プロパノールなどのアルコール系溶 媒、アセトン、ァセトニトリル、 DMF、 NMPなどの親水性溶媒、トルエン、キシレン、 へキサンなどの炭化水素系溶媒、酢酸ェチルなどのエステル系溶媒、ジェチルエー テル、 THF、 1, 4 ジォキサン、ジメトキシェタンなどのエーテル系溶媒、ジクロロメ タン、クロ口ホルムなどのハロゲン系溶媒、ピリジンなどの塩基性溶媒などがあげられ 、これらを単独でまたは混合して用いることができ、好ましくは DMF、ァセトニトリルな どがあげられる。  [0065] Examples of the solvent include alcohol solvents such as methanol, ethanol, and propanol, hydrophilic solvents such as acetone, acetonitrile, DMF, and NMP, hydrocarbon solvents such as toluene, xylene, and hexane, and ethyl acetate. Examples include ester solvents, ether solvents such as jetyl ether, THF, 1,4 dioxane, and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. Alternatively, they can be used as a mixture, and preferred examples include DMF and acetonitrile.
[0066] 本工程の処理は、通常 78°C〜用いる溶媒の沸点の間の温度で、好ましくは 0°C 〜 120°Cの間の温度で、より好ましくは 10°C〜 100°Cの間の温度で行われる。  [0066] The treatment in this step is usually performed at a temperature between 78 ° C and the boiling point of the solvent used, preferably at a temperature between 0 ° C and 120 ° C, more preferably between 10 ° C and 100 ° C. Between temperatures.
化合物 (IV)、 (V)および (VI)における R2に含まれる官能基の変換は、公知の方法 [例えば、コンプリへンシブ 'オーガニック 'トランスフォーメーションズ 第 2版（Compr ehensive Organic Transformations 2nd edition)、 R. C.ラロック (Larock) 著、 Vch Verlagsgesellschaft Mbh (1999年）などに記載の方法]でまたはそれ らに準じて行うこともできる。 The conversion of the functional group contained in R 2 in the compounds (IV), (V) and (VI) can be carried out by a known method [for example, Complicative 'Organic' Transformations 2nd Edition (Compr ehensive Organic Transformations 2nd edition), RC Larock, Vch Verlagsgesellschaft Mbh (1999), etc.] or similar methods.
[0067] 例えば、化合物（V)のうち、 R1が水素原子であり、 R2がジメチルアミノエチルである 抗アレルギー剤として知られている化合物 (Vc)は、上記製造方法で得られた化合物 (Va)より、例えば以下に示す公知の方法によっても製造することができる。 For example, among compounds (V), R 1 is a hydrogen atom and R 2 is dimethylaminoethyl. Compound (Vc) known as an antiallergic agent is a compound obtained by the above production method From (Va), for example, it can also be produced by a known method shown below.
[0068] [化 20]  [0068] [Chemical 20]
Figure imgf000020_0001
Figure imgf000020_0001
( Vc )  (Vc)
[0069] (式中、 R1および nはそれぞれ前記と同義である） [0069] (wherein R 1 and n are as defined above)
工程 4  Process 4
化合物 (Vb)は、上記工程 3で得られる化合物 (Va)を、（1)適当な溶媒中、必要に より 1〜20当量の適当な塩基の存在下、 1〜 10当量の塩化メタンスルホ -ル、無水ト リフルォロメタンスルホ -ル、塩化ベンゼンスルホ -ル、塩化 p—トルエンスルホ-ル などのスルホ -ル化剤と— 20°Cと用いる溶媒の沸点の間の温度で、 5分間〜 72時 間反応させ、（2)次いで得られたィ匕合物を、無溶媒でまたは適当な溶媒中、必要に より 1〜20当量の適当な塩基の存在下、 1当量〜大過剰量、好ましくは 1〜20当量 のジメチルァミンと、—20°Cと 100°Cの間の温度で、 5分間〜 72時間反応させること により製造することができる。  Compound (Vb) is obtained by converting Compound (Va) obtained in Step 3 above into (1) 1 to 10 equivalents of methanesulfonyl chloride in an appropriate solvent, if necessary in the presence of 1 to 20 equivalents of an appropriate base. 5 to 72 minutes at a temperature between 20 ° C and the boiling point of the solvent used, and a sulfonating agent such as trifluoromethanesulfuric anhydride, benzenesulfuric chloride, and p-toluenesulfuric chloride (2) The obtained compound is then reacted in the absence of solvent or in a suitable solvent, optionally in the presence of 1 to 20 equivalents of a suitable base, preferably 1 equivalent to a large excess, preferably Can be produced by reacting with 1 to 20 equivalents of dimethylamine at a temperature between -20 ° C and 100 ° C for 5 minutes to 72 hours.
[0070] (1)で用いる溶媒としては、例えばアセトン、ァセトニトリル、 DMF、 NMPなどの親 水性溶媒、トルエン、キシレン、へキサンなどの炭化水素系溶媒、酢酸ェチルなどの エステル系溶媒、ジェチルエーテル、 THF、 1, 4 ジォキサン、ジメトキシェタンなど のエーテル系溶媒、ジクロロメタン、クロ口ホルムなどのハロゲン系溶媒、ピリジンなど の塩基性溶媒などがあげられ、これらを単独でまたは混合して用いられる。 [0070] Examples of the solvent used in (1) include hydrophilic solvents such as acetone, acetonitrile, DMF, and NMP, hydrocarbon solvents such as toluene, xylene, and hexane, and ethyl acetate. Examples include ester solvents, ether solvents such as jetyl ether, THF, 1,4 dioxane and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. Or mixed.
[0071] (1)で用いる塩基としては、例えば水酸化リチウム、水酸ィ匕カリウム、水酸化ナトリウ ム、炭酸ナトリウム、炭酸カリウム、カリウム tert—ブトキシド、ナトリウムメトキシドなど の無機塩基、ピリジン、トリェチルァミン、ジイソプロピルェチルァミン、 DBUなどの有 機塩基などがあげられる。  [0071] Examples of the base used in (1) include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, and other inorganic bases, pyridine, and triethylamine. And organic bases such as diisopropylethylamine and DBU.
(2)で用いる溶媒としては、例えばメタノール、エタノール、プロパノールなどのアル コール系溶媒、アセトン、ァセトニトリル、 DMF、 NMPなどの親水性溶媒、トルエン、 キシレン、へキサンなどの炭化水素系溶媒、酢酸ェチルなどのエステル系溶媒、ジェ チルエーテル、 THF、 1, 4 ジォキサン、ジメトキシェタンなどのエーテル系溶媒、 ジクロロメタン、クロ口ホルムなどのハロゲン系溶媒、ピリジンなどの塩基性溶媒、水な どがあげられ、これらを単独でまたは混合して用いられる。  Examples of the solvent used in (2) include alcohol solvents such as methanol, ethanol and propanol, hydrophilic solvents such as acetone, acetonitrile, DMF and NMP, hydrocarbon solvents such as toluene, xylene and hexane, and ethyl acetate. Such as ester solvents such as diethyl ether, THF, 1,4 dioxane and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, basic solvents such as pyridine, water, etc. These may be used alone or in combination.
[0072] (2)で用いる塩基としては、例えば水酸化リチウム、水酸ィ匕カリウム、水酸化ナトリウ ム、炭酸ナトリウム、炭酸カリウム、カリウム tert ブトキシド、ナトリウムメトキシドなど の無機塩基、ピリジン、トリェチルァミン、ジイソプロピルェチルァミン、 DBUなどの有 機塩基などがあげられる。  [0072] Examples of the base used in (2) include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert butoxide, sodium methoxide, and other inorganic bases, pyridine, triethylamine, Organic bases such as diisopropylethylamine and DBU.
工程 5  Process 5
化合物 (Vc)は、化合物 (Vb)を含水溶媒中、 1〜20当量好ましくは 1〜3当量の適 当な塩基で、 5分間〜 72時間、好ましくは 10分間〜 6時間処理することにより製造す ることがでさる。  Compound (Vc) is produced by treating compound (Vb) in an aqueous solvent with 1 to 20 equivalents, preferably 1 to 3 equivalents of a suitable base for 5 minutes to 72 hours, preferably 10 minutes to 6 hours. It can be done.
[0073] 含水溶媒としては、例えば各種有機溶媒と水との混合溶媒があげられ、該有機溶 媒としては、例えばメタノール、エタノール、プロパノールなどのアルコール系溶媒、 アセトン、ァセトニトリル、 DMF、 NMPなどの親水性溶媒、トルエン、キシレン、へキ サンなどの炭化水素系溶媒、酢酸ェチルなどのエステル系溶媒、ジェチルエーテル 、 THF、 1, 4 ジォキサン、ジメトキシェタンなどのエーテル系溶媒、ジクロロメタン、 クロ口ホルムなどのハロゲン系溶媒、ピリジンなどの塩基性溶媒などがあげられ、これ らを単独でまたは混合して用いることができ、好ましくはメタノール、エタノールなどが あげられる。 [0073] Examples of the hydrous solvent include mixed solvents of various organic solvents and water. Examples of the organic solvent include alcohol solvents such as methanol, ethanol, and propanol, acetone, acetonitrile, DMF, and NMP. Hydrophilic solvents, hydrocarbon solvents such as toluene, xylene, hexane, ester solvents such as ethyl acetate, ether solvents such as jetyl ether, THF, 1,4 dioxane, dimethoxyethane, dichloromethane, black mouth Examples thereof include halogen solvents such as form, basic solvents such as pyridine, and the like. These can be used alone or as a mixture, preferably methanol, ethanol, etc. can give.
[0074] 塩基としては、例えば水酸化リチウム、水酸ィ匕カリウム、水酸化ナトリウム、炭酸ナトリ ゥム、炭酸カリウム、カリウム tert ブトキシド、ナトリウムメトキシドなどの無機塩基、 ピリジン、トリェチルァミン、ジイソプロピルェチルァミン、 DBUなどの有機塩基などが あげられる。  [0074] Examples of the base include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert butoxide, sodium methoxide, and other inorganic bases such as pyridine, triethylamine, diisopropyl ether. And organic bases such as min and DBU.
本工程の処理は、通常 0°C〜用いる溶媒の沸点の間の温度で、好ましくは 10°C〜 The treatment in this step is usually at a temperature between 0 ° C and the boiling point of the solvent used, preferably 10 ° C to
70°Cの間の温度で行われる。 Performed at a temperature between 70 ° C.
[0075] 上記各製造法における中間体および目的化合物は、有機合成化学で常用される 分離精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィ 一などに付して単離精製することができる。また、中間体においては特に精製するこ となく次の反応に供することも可能である。 [0075] The intermediates and target compounds in each of the above production methods are simply separated and purified commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. It can be separated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.
また、化合物 (Π)、（IV)、（V)および (VI)ならびにそれらの塩は、水または各種溶 媒との付加物の形で存在することもあるが、これらの付加物も本発明に包含されるか In addition, the compounds (Π), (IV), (V) and (VI) and their salts may exist in the form of adducts with water or various solvents, and these adducts are also present in the present invention. Is included in
、本発明の製造方法で製造される目的物に包含される。 It is included in the object manufactured by the manufacturing method of the present invention.
[0076] 化合物 (Π)、 (IV)、 (V)または (VI)の塩を取得した 、とき、化合物 (Π)、 (IV)、 (V[0076] Obtaining a salt of compound (Π), (IV), (V) or (VI), when compound (Π), (IV), (V
)または (VI)が塩の形で得られるときはそのまま精製すればよぐまた、遊離の形で 得られるときは、化合物 (Π)、（IV)、（V)または (VI)を適当な溶媒に溶解または懸濁 し、酸または塩基を加えることにより塩を形成させて単離、精製すればよい。 ) Or (VI) can be purified as it is in the form of a salt, and when it is obtained in a free form, the compound (、), (IV), (V) or (VI) can be appropriately converted. It can be isolated or purified by dissolving or suspending in a solvent and adding an acid or base to form a salt.
[0077] 以下、実施例により本発明をさらに具体的に説明するが、本発明はこれらの実施例 に何ら限定されるものではな 、。  [0077] Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
実施例 1  Example 1
[0078] 4一（2 ブロモベンジルォキシ） 3 ョードフエ-ル酢酸メチル（ィ匕合物 ΠΑ)の製 造  [0078] 4 (2 Bromobenzyloxy) 3 Manufactured Methyl Phodoacetate (Compound)
メタノーノレ（127 mL)にヨウ素（7.28 g, 28.1 mmol)および硫酸銀（8.76 g, 28.1 mmol )を添加し、 18°Cでヨウ素が溶解するまで撹拌した。次いで、メタノール（15 mL)に溶 解した参考例 1で得られた 4一（2 ブロモベンジルォキシ)フ ニル酢酸メチル (ィ匕合 物 IA) (9.44 g, 28.1 mmol)を、先に調製したヨウ素と硫酸銀のメタノール溶液に添カロ した。 18°Cで 2時間撹拌した後、不溶物を濾別し、該不溶物を酢酸ェチル (38 mL)で 洗浄した。濾液および洗浄液を集め、 50°Cで濃縮乾固した。得られた残渣にメタノー ル (47 mL)を添加して 1時間撹拌した。不溶物を濾取し、 30°Cで減圧乾燥することで 標記化合物 ΠΑ (11.00 g, 86%)を白色結晶として得た。 To methanol (127 mL), iodine (7.28 g, 28.1 mmol) and silver sulfate (8.76 g, 28.1 mmol) were added and stirred at 18 ° C. until iodine was dissolved. Next, the methyl 4- (2-bromobenzyloxy) phenylacetate (Compound IA) (9.44 g, 28.1 mmol) obtained in Reference Example 1 dissolved in methanol (15 mL) was prepared in advance. The solution was added to a methanol solution of iodine and silver sulfate. After stirring at 18 ° C for 2 hours, the insoluble material was filtered off, and the insoluble material was filtered with ethyl acetate (38 mL). Washed. The filtrate and washings were collected and concentrated to dryness at 50 ° C. Methanol (47 mL) was added to the resulting residue and stirred for 1 hour. The insoluble material was collected by filtration and dried under reduced pressure at 30 ° C. to give the title compound ΠΑ (11.00 g, 86%) as white crystals.
1H-NMR (CDC1 , δ ppm): 7.78 (d, 1H, J = 7.7 Hz), 7.75 (d, 1H, J = 2.0 Hz), 7.59 (  1H-NMR (CDC1, δ ppm): 7.78 (d, 1H, J = 7.7 Hz), 7.75 (d, 1H, J = 2.0 Hz), 7.59 (
3  Three
dd, 1H, J = 7.9, 1.0 Hz), 7.37 (td, 1H, J= 7.9, 1.0 Hz), 7.25-7.21 (m, 2H), 6.83 (d, 1H, J = 8.3 Hz), 5.18 (s, 2H), 3.70 (s, 3H), 3.55 (s, 2H).  dd, 1H, J = 7.9, 1.0 Hz), 7.37 (td, 1H, J = 7.9, 1.0 Hz), 7.25-7.21 (m, 2H), 6.83 (d, 1H, J = 8.3 Hz), 5.18 (s , 2H), 3.70 (s, 3H), 3.55 (s, 2H).
MS ESI (-) m/z: 461, 459 [M- H]— .  MS ESI (-) m / z: 461, 459 [M- H] —.
実施例 2  Example 2
[0079] 4一（2 ブロモベンジルォキシ）一 3—（4ーヒドロキシブト一 1ーィ -ル）フエ-ル酢酸 メチル (化合物 IVA)の製造  [0079] Production of methyl 4- (2-bromobenzyloxy) 3- (4-hydroxybut-1-yl) phenol acetate (compound IVA)
実施例 1で得られた化合物 ΠΑ (5.00 g, 10.8 mmol)に、ジクロロビス（トリフエ-ルホ スフイン）パラジウム（381 mg, 0.542 mmol)およびヨウ化銅（103 mg, 0.542 mmol)を添 加し、 DMF (50 mL)をカ卩えて溶解させた。 3 ブチン— 1—オール（1.64 mL, 21.7 m mol)およびトリェチルァミン（6.06 mL, 43.4 mmol)を順次添カ卩し、 25°Cで 5時間撹拌 した。反応混合物に酢酸ェチル（100 mL)をカ卩え、水（300 mL)および飽和塩ィ匕ナトリ ゥム水溶液で順次洗浄した。有機層を濾過した後、濾液を濃縮した。残渣をシリカゲ ルカラムクロマトグラフィー (溶出溶媒:酢酸ェチル Zへキサン = 1/1)で精製し、標 記化合物 IVA(4.34 g, 99%)を褐色油状物として得た。  To compound ΠΑ (5.00 g, 10.8 mmol) obtained in Example 1, dichlorobis (triphenylphosphine) palladium (381 mg, 0.542 mmol) and copper iodide (103 mg, 0.542 mmol) were added, and DMF (50 mL) was added and dissolved. 3 Butyn-1-ol (1.64 mL, 21.7 mmol) and triethylamine (6.06 mL, 43.4 mmol) were sequentially added and stirred at 25 ° C. for 5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, which was washed successively with water (300 mL) and saturated aqueous sodium chloride solution. After the organic layer was filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate Z-hexane = 1/1) to give the title compound IVA (4.34 g, 99%) as a brown oil.
1H-NMR (CDC1 , δ ppm): 7.64 (dd, 1H, J = 7.7, 1.7 Hz), 7.57 (dd, 1H, J = 7.7, 1.1  1H-NMR (CDC1, δ ppm): 7.64 (dd, 1H, J = 7.7, 1.7 Hz), 7.57 (dd, 1H, J = 7.7, 1.1
3  Three
Hz), 7.34 (td, 1H, J = 7.7, 1.1 Hz), 7.33 (d, 1H, J = 2.2 Hz), 7.18 (td, 1H, J = 7.7, 1.7 Hz), 7.14 (dd, 1H, J = 8.6, 2.2 Hz), 6.85 (d, 1H, J = 8.6 Hz), 5.18 (s, 2H), 3.80 (t, 2H, J = 6.1 Hz), 3.69 (s, 3H), 3.53 (s, 2H), 2.73 (t, 2H, J = 6.1 Hz).  Hz), 7.34 (td, 1H, J = 7.7, 1.1 Hz), 7.33 (d, 1H, J = 2.2 Hz), 7.18 (td, 1H, J = 7.7, 1.7 Hz), 7.14 (dd, 1H, J = 8.6, 2.2 Hz), 6.85 (d, 1H, J = 8.6 Hz), 5.18 (s, 2H), 3.80 (t, 2H, J = 6.1 Hz), 3.69 (s, 3H), 3.53 (s, 2H ), 2.73 (t, 2H, J = 6.1 Hz).
13C-NMR (CDC1 , δ ppm): 171.9, 158.1, 136.1, 134.1, 132.5, 130.1, 129.2, 128.6, 1 3 C-NMR (CDC1, δ ppm): 171.9, 158.1, 136.1, 134.1, 132.5, 130.1, 129.2, 128.6,
3  Three
127.6, 126.6, 121.8,113.4, 112.7, 91.0, 78.7, 70.0, 61.1, 52.1, 40.0, 24.2.  127.6, 126.6, 121.8, 113.4, 112.7, 91.0, 78.7, 70.0, 61.1, 52.1, 40.0, 24.2.
IR (KBr): 3322, 1739, 1507, 1429, 1264, 1151, 1037, 744 cm"1. IR (KBr): 3322, 1739, 1507, 1429, 1264, 1151, 1037, 744 cm " 1 .
MS ESI (+) m/z: 405, 403 [M+H]+. MS ESI (+) m / z: 405, 403 [M + H] + .
実施例 3  Example 3
[0080] (Z)—11— (3—ヒドロキシプロピリデン） 6, 11—ジヒドロべンズ [b, e]ォキセピン -2-酢酸メチル (ィ匕合物 VA)の製造 [0080] (Z) —11— (3-Hydroxypropylidene) 6, 11-Dihydrobens [b, e] oxepin -2-Production of methyl acetate (compound VA)
窒素雰囲気下、実施例 2で得られた化合物 IVA (200 mg, 0.496 mmol)に、酢酸パ ラジウム（11.1 mg, 0.0496 mmol)およびトリ（o トリル）ホスフィン（37.7 mg, 0.124 mm ol)を添カ卩し、 DMF (2.0 mL)をカ卩えて溶解させた。ピぺリジン（344 μ L, 4.93 mmol) およびギ酸 (20.5 μ L, 0.545 mmol)を順次添カ卩し、 92°Cで 3時間撹拌した。反応混合 物に酢酸ェチルを加え、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄した。有機 層を濃縮し、残渣をシリカゲルカラムクロマトグラフィー (溶出溶媒:酢酸ェチル Zへキ サン = 1Z2)で精製し、標記化合物 VA(114 mg, 71%)を白色固体として得た。  In a nitrogen atmosphere, compound IVA (200 mg, 0.496 mmol) obtained in Example 2 was added with palladium acetate (11.1 mg, 0.0496 mmol) and tri (o-tolyl) phosphine (37.7 mg, 0.124 mmol). Then, DMF (2.0 mL) was added and dissolved. Piperidine (344 μL, 4.93 mmol) and formic acid (20.5 μL, 0.545 mmol) were sequentially added and stirred at 92 ° C. for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated aqueous sodium chloride solution. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate Z-hexane = 1Z2) to obtain the title compound VA (114 mg, 71%) as a white solid.
JH-NMR (CDC1 , δ ppm): 7.43-7.24 (m, 4H), 7.17 (d, 1H, J = 2.2 Hz), 7.04 (dd, 1 JH-NMR (CDC1, δ ppm): 7.43-7.24 (m, 4H), 7.17 (d, 1H, J = 2.2 Hz), 7.04 (dd, 1
3  Three
H, J = 8.4, 2.2 Hz), 6.80 (d, 1H, J = 8.4 Hz), 5.74 (d, 1H, J = 7.5 Hz), 5.18 (brs, 2 H), 3.80 (t, 2H, J = 6.1 Hz), 3.69 (s, 3H), 3.53 (s, 2H), 2.68 (dt, 2H, J = 7.5 , 6.1 H z).  H, J = 8.4, 2.2 Hz), 6.80 (d, 1H, J = 8.4 Hz), 5.74 (d, 1H, J = 7.5 Hz), 5.18 (brs, 2 H), 3.80 (t, 2H, J = 6.1 Hz), 3.69 (s, 3H), 3.53 (s, 2H), 2.68 (dt, 2H, J = 7.5, 6.1 H z).
MS ESI (+) m/z: 325 [M+H]+. MS ESI (+) m / z: 325 [M + H] + .
実施例 4 Example 4
4一（2 ブロモベンジルォキシ） 3—（4ージメチルアミノブトー 1ーィ -ル）フエ-ル 酢酸メチル (ィ匕合物 IVB)の製造 4- (2-Bromobenzyloxy) 3- (4-Dimethylaminobuto-1-yl) phenol Production of methyl acetate (compound IVB)
実施例 1で得られた化合物 ΠΑ(1.00 g, 2.17 mmol)に、ジクロロビス（トリフエ-ルホ スフイン）ノ《ラジウム（76.1 mg, 0.108 mmol)およびヨウ化銅（21.0 mg, 0.108 mmol)を 添加し、 DMF (10 mL)を加えて溶解させた。公知の方法（ジャーナル'ォブ 'オーガ ニック ·ケミストリー (J. Org. Chem. )、 1999年、 64卷、 p. 1798)【こ従!ヽ合成したブ ト— 3—ィ-ルジメチルァミン（609 mg, 4.34 mmol)およびトリェチルァミン（1.22 mL, 8 .68 mmol)を順次添加し、 25°Cで 3時間撹拌した。反応混合物に酢酸ェチルを加え、 水および飽和塩ィ匕ナトリウム水溶液で順次洗浄した。有機層を濃縮し、残渣をシリカ ゲルカラムクロマトグラフィー (溶出溶媒:クロ口ホルム Zメタノール = 20/1)で精製 することにより、標記化合物 IVB (728 mg, 78%)を褐色油状物として得た。  To the compound ΠΑ (1.00 g, 2.17 mmol) obtained in Example 1, dichlorobis (triphenylphosphine) no << radium (76.1 mg, 0.108 mmol) and copper iodide (21.0 mg, 0.108 mmol) were added, DMF (10 mL) was added and dissolved. Known method (Journal 'Ob' Organic Chemistry (J. Org. Chem.), 1999, 64 卷, p. 1798) [According to the synthesized but-3-yldimethylamine (609 mg) , 4.34 mmol) and triethylamine (1.22 mL, 8.68 mmol) were sequentially added, and the mixture was stirred at 25 ° C for 3 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated aqueous sodium chloride solution. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (elution solvent: Kuroguchi Form Z methanol = 20/1) to give the title compound IVB (728 mg, 78%) as a brown oil. .
JH-NMR (CDC1 , δ ppm): 7.64 (dd, 1H, J = 7.7, 1.7 Hz), 7.57 (dd, 1H, J = 7.7, 1.1 JH-NMR (CDC1, δ ppm): 7.64 (dd, 1H, J = 7.7, 1.7 Hz), 7.57 (dd, 1H, J = 7.7, 1.1
3  Three
Hz), 7.34 (td, 1H, J = 7.7, 1.1 Hz), 7.33 (d, 1H, J = 2.2 Hz), 7.18 (td, 1H, J = 7.7, Hz), 7.34 (td, 1H, J = 7.7, 1.1 Hz), 7.33 (d, 1H, J = 2.2 Hz), 7.18 (td, 1H, J = 7.7,
I.7 Hz), 7.14 (dd, 1H, J = 8.6, 2.2 Hz), 6.85 (d, 1H, J = 8.6 Hz), 5.18 (s, 2H), 3.80 (t, 2H, J = 6.1 Hz), 3.69 (s, 3H), 3.53 (s, 2H), 2.73 (t, 2H, J = 6.1 Hz). MS ESI (+) m/z: 432, 430 [M+H]+. I.7 Hz), 7.14 (dd, 1H, J = 8.6, 2.2 Hz), 6.85 (d, 1H, J = 8.6 Hz), 5.18 (s, 2H), 3.80 (t, 2H, J = 6.1 Hz), 3.69 (s, 3H), 3.53 (s, 2H), 2.73 (t, 2H, J = 6.1 Hz). MS ESI (+) m / z: 432, 430 [ M + H] + .
実施例 5  Example 5
[0082] (Z) - l l - [3- (ジメチルァミノ）プロピリデン ]—6, 11—ジヒドロべンズ [b, e]ォキ セピン 2—酢酸メチル (ィ匕合物 VB)の製造  [0082] Preparation of (Z) -l l- [3- (dimethylamino) propylidene] -6,11-dihydrobens [b, e] oxepin 2-methyl acetate (compound VB)
窒素雰囲気下、実施例 4で得られた化合物 IVB ( 161 mg, 0.374 mmol)に、酢酸パ ラジウム（8.40 mg, 0.0374 mmol)およびトリ（o トリル）ホスフィン（22.8 mg, 0.0748 m mol)を添カ卩し、 DMF (3.2 mL)をカ卩えて溶解させた。ピぺリジン（148 μ L, 1.50 mmol )およびギ酸 (42.0 n 1.12 mmol)を順次添カ卩し、 60°Cで 4時間撹拌した。反応混合 物に酢酸ェチルを加え、水および飽和塩ィ匕ナトリウム水溶液で順次洗浄した。有機 層を濃縮し、標記化合物 VBを含む油状物質 90 mgを得た。  In a nitrogen atmosphere, compound IVB (161 mg, 0.374 mmol) obtained in Example 4 was added with palladium acetate (8.40 mg, 0.0374 mmol) and tri (o-tolyl) phosphine (22.8 mg, 0.0748 mmol). Then, DMF (3.2 mL) was added and dissolved. Piperidine (148 μL, 1.50 mmol) and formic acid (42.0 n 1.12 mmol) were sequentially added and stirred at 60 ° C. for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated aqueous sodium chloride solution. The organic layer was concentrated to obtain 90 mg of an oily substance containing the title compound VB.
実施例 6  Example 6
[0083] 塩酸（Z)—11— [3 （ジメチルァミノ）プロピリデン ]—6, 11—ジヒドロべンズ [b, e] ォキセピン 2—酢酸 (ィ匕合物 Via)の製造  [0083] Hydrochloric acid (Z) -11— [3 (Dimethylamino) propylidene] —6, 11-Dihydrobens [b, e] Oxepin 2-acetic acid (I compound Via)
実施例 3で得られた化合物 VA (21.0 g, 64.7 mmol)に、ピリジン（160 mL)をカ卩えて 溶解し、 5°Cに冷却した。塩化メタンスルホ-ル（28.0 g, 244 mmol)を 5°Cで徐々に添 加した後、室温で 2時間撹拌した。反応混合物に水（1.0 L)を加え、約 500 mLまで濃 縮を行い、残渣に水（500 mL)をカ卩え、酢酸ェチル (500 mL)で抽出した。有機層を 硫酸マグネシウムで乾燥し、濃縮した。残渣にメタノール (400 mL)および 50%ジメチ ルァミン水溶液（120 mL, 1.14 mol)をカ卩え、 3時間還流下で撹拌した。反応混合物を 冷却した後、濃縮した。残渣にメタノール (400 mL)および 2 mol/L水酸ィ匕ナトリウム水 溶液（100 mL)を加え、 2時間還流下で撹拌した。反応混合物を濃縮後、水（200 mL )および酢酸ブチル（200 mL)をカ卩え、 2 mol/L塩酸で水層の pHを 2に調整した。酢酸 ブチルで抽出し、有機層を濃縮することにより、化合物 Via (21.4 g, 88.4%)を得た。 参考例 1  In the compound VA (21.0 g, 64.7 mmol) obtained in Example 3, pyridine (160 mL) was added and dissolved, and cooled to 5 ° C. Methanesulfuryl chloride (28.0 g, 244 mmol) was gradually added at 5 ° C, and the mixture was stirred at room temperature for 2 hours. Water (1.0 L) was added to the reaction mixture, and the mixture was concentrated to about 500 mL. Water (500 mL) was added to the residue, and the mixture was extracted with ethyl acetate (500 mL). The organic layer was dried over magnesium sulfate and concentrated. Methanol (400 mL) and 50% aqueous dimethylamine solution (120 mL, 1.14 mol) were added to the residue, and the mixture was stirred for 3 hours under reflux. The reaction mixture was cooled and then concentrated. Methanol (400 mL) and 2 mol / L aqueous sodium hydroxide solution (100 mL) were added to the residue, and the mixture was stirred for 2 hours under reflux. After concentration of the reaction mixture, water (200 mL) and butyl acetate (200 mL) were added, and the pH of the aqueous layer was adjusted to 2 with 2 mol / L hydrochloric acid. Extraction with butyl acetate and concentration of the organic layer gave Compound Via (21.4 g, 88.4%). Reference example 1
4一（2 ブロモベンジルォキシ）フエ-ル酢酸メチル（ィ匕合物 IA)  4-Methyl acetate (2-bromobenzyloxy) phenyl acetate (IA compound IA)
4 ヒドロキシフエ-ル酢酸メチル（5.00 g, 30.1 mmol)に DMF (50.0 mL)をカ卩えて 溶解し、炭酸カリウム（6.28 g, 45.1 mmol)および 2 ブロモベンジルブロミド（7.50 g, 30.1 mmol)を順次添カ卩し、 25°Cで 4時間撹拌した。反応混合物に水（70 mL)をカロえ、 酢酸ェチル (50 mL)で抽出し、有機層を飽和食塩水溶液 (70 mL)で洗浄した。有機 層を 50°Cで濃縮することにより、標記化合物 IA(10.25 g,定量的）を得た。 4 Dissolve DMF (50.0 mL) in methyl hydroxyphenol acetate (5.00 g, 30.1 mmol) and dissolve with potassium carbonate (6.28 g, 45.1 mmol) and 2 bromobenzyl bromide (7.50 g, 30.1 mmol) was added successively and stirred at 25 ° C for 4 hours. Water (70 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated brine solution (70 mL). The organic layer was concentrated at 50 ° C to obtain the title compound IA (10.25 g, quantitative).
1H-NMR (CDC1 , δ ppm): 7.58 (dd, 1H, J = 7.7, 1.1 Hz), 7.53 (dd, 1H, J = 7.7, 1.3 1H-NMR (CDC1, δ ppm): 7.58 (dd, 1H, J = 7.7, 1.1 Hz), 7.53 (dd, 1H, J = 7.7, 1.3
3  Three
Hz), 7.32 (td, 1H, J = 7.7, 1.3 Hz), 7.21 (d, 2H, J = 8.8 Hz), 7.17 (td, 1H, J = 7.7, 1.1 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.17 (s, 2H), 3.68 (s, 3H), 3.57 (s, 2H).  Hz), 7.32 (td, 1H, J = 7.7, 1.3 Hz), 7.21 (d, 2H, J = 8.8 Hz), 7.17 (td, 1H, J = 7.7, 1.1 Hz), 6.93 (d, 2H, J = 8.8 Hz), 5.17 (s, 2H), 3.68 (s, 3H), 3.57 (s, 2H).
MS ESI (+) m/z: 337, 335 [M+H]+. MS ESI (+) m / z: 337, 335 [M + H] + .
産業上の利用可能性 Industrial applicability
本発明により、医薬品または医薬品の中間体として有用な 11 アルキリデンジベン ズ [b, e]ォキセピン誘導体の製造において、望む幾何異性体を収率よく製造する方 法など提供することができる。  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a method for producing a desired geometric isomer in a high yield in the production of 11 alkylidene dibenz [b, e] oxepin derivatives useful as pharmaceuticals or pharmaceutical intermediates.

Claims

請求の範囲 The scope of the claims
(i)一般式 (I)  (i) General formula (I)
[化 21]  [Chemical 21]
Figure imgf000027_0001
Figure imgf000027_0001
( I )  (I)
(式中、 R1は水素原子、低級アルキル、シクロアルキル、ァラルキルまたはァリールを 表し、 X1は塩素原子、臭素原子、ヨウ素原子またはトリフルォロメタンスルホ二ルォキ シを表し、 nは 0〜4の整数を表す） (In the formula, R 1 represents a hydrogen atom, lower alkyl, cycloalkyl, aralkyl or aryl, X 1 represents a chlorine atom, a bromine atom, an iodine atom or trifluoromethanesulfonyloxy, and n is 0-4. Represents an integer)
で表される化合物を、ハロゲンィ匕して、一般式 (II) A compound represented by general formula (II)
[化 22] [Chemical 22]
Figure imgf000027_0002
( II )
Figure imgf000027_0002
(II)
(式中、
Figure imgf000027_0003
X1および nはそれぞれ前記と同義であり、 X2は塩素原子、臭素原子また はヨウ素原子を表す） (Where
Figure imgf000027_0003
X 1 and n are as defined above, and X 2 represents a chlorine atom, a bromine atom or an iodine atom)
で表される化合物を得る工程、 (ii)一般式 (Π)で表される化合物を一般式 (III) [化 23] (Ii) converting the compound represented by the general formula (Π) into the general formula (III) [Chemical Formula 23]
H = R2 H = R 2
( III )  (III)
(式中、 R2はヒドロキシ、低級アルコキシ、アミ入低級アルキルァミノ、ジ低級アルキ ルァミノ、カルボキシ、低級アルコキシカルボ-ル、シクロアルキル、ァリール、芳香族 複素環基および脂肪族複素環基からなる群から選ばれる置換基を有して!/、てもよ 、 低級アルキル、またはヒドロキシ、低級アルコキシ、アミ入低級アルキルァミノ、ジ低 級アルキルアミ入カルボキシ、低級アルコキシカルボ-ル、ォキソ、ァリール、芳香 族複素環基および脂肪族複素環基からなる群から選ばれる置換基を有していてもよ Vヽシクロアルキルを表す） (Wherein R 2 is hydroxy, lower alkoxy, amino-containing lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbole, cycloalkyl, aryl, aromatic It has a substituent selected from the group consisting of a heterocyclic group and an aliphatic heterocyclic group! /, May be lower alkyl, or hydroxy, lower alkoxy, ami-substituted lower alkylamino, di-lower alkylami-substituted carboxy, lower (It may have a substituent selected from the group consisting of alkoxycarbox, oxo, aryl, aromatic heterocyclic group and aliphatic heterocyclic group, and represents V ヽ cycloalkyl)
で表されるアルキンィ匕合物とのカップリング反応に付して、一般式 (IV)  Is subjected to a coupling reaction with an alkyne compound represented by the general formula (IV)
[化 24]  [Chemical 24]
Figure imgf000028_0001
Figure imgf000028_0001
( IV )  (IV)
(式中、
Figure imgf000028_0002
R2、 X1および nはそれぞれ前記と同義である） (Where
Figure imgf000028_0002
R 2 , X 1 and n are as defined above)
で表される化合物を得る工程、および (iii)一般式 (IV)で表される化合物を分子内環 化反応に付す工程、を含む一般式 (V)  And (iii) subjecting the compound represented by the general formula (IV) to an intramolecular cyclization reaction.
[化 25]  [Chemical 25]
Figure imgf000028_0003
Figure imgf000028_0003
( V )  (V)
(式中、
Figure imgf000028_0004
R2および nはそれぞれ前記と同義である） (Where
Figure imgf000028_0004
R 2 and n are as defined above)
で表される 11—アルキリデンジベンズ [b, e]ォキセピン誘導体またはその塩の製造 方法。  A process for producing 11-alkylidene dibenz [b, e] oxepin derivatives represented by the formula:
[2] 一般式 (I) (CH2)n COOR1 [2] General formula (I) (CH 2 ) n COOR 1
( I)  (I)
(式中、 R X1および nはそれぞれ前記と同義である） で表される化合物をハロゲンィ匕する工程を含む一般式 (II) [化 27](Wherein RX 1 and n are as defined above, respectively), comprising a step of halogenating a compound represented by the general formula (II) [Chemical Formula 27]
Figure imgf000029_0001
Figure imgf000029_0001
( II)  (II)
(式中、 R X1、 X2および nはそれぞれ前記と同義である) で表される化合物またはその塩の製造方法。 (Wherein RX 1 , X 2 and n are as defined above) or a salt thereof.
一般式 (Π)  General formula (Π)
[化 28] [Chemical 28]
Figure imgf000029_0002
Figure imgf000029_0002
( II)  (II)
(式中、 R X1、 X2および nはそれぞれ前記と同義である) で表される化合物を一般式 (III) (III) (Wherein, RX 1 , X 2 and n are as defined above), a compound represented by the general formula (III) (III)
(式中、 R2は前記と同義である） (Wherein R 2 has the same meaning as above)
で表されるアルキンィ匕合物とのカップリング反応に付す工程を含む一般式 (IV)Including the step of subjecting to a coupling reaction with an alkyne compound represented by formula (IV)
[化 30] [Chemical 30]
Figure imgf000030_0001
Figure imgf000030_0001
(IV)  (IV)
(式中、 R R2、 X1および nはそれぞれ前記と同義である) (Wherein, RR 2 , X 1 and n are as defined above)
で表される化合物またはその塩の製造方法。 Or a salt thereof.
一般式 (IV)  Formula (IV)
[化 31]  [Chemical 31]
Figure imgf000030_0002
Figure imgf000030_0002
(IV)  (IV)
(式中、
Figure imgf000030_0003
R2、 X1および nはそれぞれ前記と同義である） (Where
Figure imgf000030_0003
R 2 , X 1 and n are as defined above)
で表される化合物を分子内環化反応に付す工程を含む一般式 (V) Including the step of subjecting the compound represented by the formula to an intramolecular cyclization reaction (V)
[化 32] [Chemical 32]
r (CH2)n COOR1 (式中、 R\ R2および nはそれぞれ前記と同義である） r (CH 2 ) n COOR 1 (Wherein R \ R 2 and n are as defined above)
で表される 11—アルキリデンジベンズ [b, e]ォキセピン誘導体またはその塩の製造 方法。  A process for producing 11-alkylidene dibenz [b, e] oxepin derivatives represented by the formula:
[5] ノ、ロゲン化が、ヨウ素と硫酸銀を用いるヨウ素化であり、 X2がヨウ素原子である請求 項 1または 2記載の方法。 [5] Bruno, halogenated is a iodinated using iodine and silver sulfate, according to claim 1 or 2 wherein X 2 is an iodine atom.
[6] カップリング反応力 ジクロロビス（トリフエ-ルホスフィン)パラジウムおよびヨウ化銅 の存在下で行う反応である請求項 1または 3記載の方法。 [6] The method according to claim 1 or 3, wherein the reaction is carried out in the presence of dichlorobis (triphenylphosphine) palladium and copper iodide.
[7] 分子内環化反応が、トリフエニルホスフィン、トリ（o—トリル)ホスフィン、トリ（m—トリ ル）ホスフィン、トリ（p—トリル）ホスフィンおよびトリシクロへキシルホスフィンからなる群 力も選ばれるホスフィンィ匕合物ならびに酢酸パラジウム、塩化パラジウムおよびパラジ ゥム炭素力 なる群力 選ばれるパラジウム化合物の存在下で行う反応である請求 項 1または 4記載の方法。 [7] Phosphines in which intramolecular cyclization is also selected from the group force consisting of triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine and tricyclohexylphosphine The method according to claim 1 or 4, wherein the reaction is performed in the presence of a compound and a group power of palladium acetate, palladium chloride, and palladium carbon power.
[8] 請求項 1〜7の 、ずれかに記載の方法 (但し、 R1は水素原子ではな 、）を含む一般 式 (VI) [8] General formula (VI) comprising the method according to any one of claims 1 to 7, wherein R 1 is not a hydrogen atom
[化 33]  [Chemical 33]
Figure imgf000031_0001
Figure imgf000031_0001
( VI )  (VI)
(式中、 R2および nはそれぞれ前記と同義である） (Wherein R 2 and n are as defined above)
で表される 11—アルキリデンジベンズ [b, e]ォキセピン誘導体またはその塩の製造 方法。  A process for producing 11-alkylidene dibenz [b, e] oxepin derivatives represented by the formula:
[9] X1が塩素原子、臭素原子またはトリフルォロメタンスルホニルォキシであり、 X2がョ ゥ素原子である請求項 1〜8のいずれかに記載の方法。 [9] X 1 is a chlorine atom, a bromine atom or a triflate Ruo b methanesulfonyl O carboxymethyl method according to claim 1 which is X 2 Gayo © atom.
[10] X1が塩素原子であり、 X2が臭素原子またはヨウ素原子である請求項 1〜8のいずれ かに記載の方法。 [10] X 1 is a chlorine atom, method of any crab of claims 1 to 8 X 2 is a bromine atom or an iodine atom.
[11] X1が臭素原子であり、 X2がヨウ素原子である請求項 1〜8のいずれかに記載の方 法。 [11] The method according to any one of claims 1 to 8, wherein X 1 is a bromine atom and X 2 is an iodine atom. Law.
[12] R2が低級アルキル、ヒドロキシ置換低級アルキル、ァミノ置換低級アルキル、低級ァ ルキルアミノ置換低級アルキルまたはジ低級アルキルアミノ置換低級アルキルである 請求項 1および 3〜： L 1のいずれかに記載の方法。 [12] R 2 is a lower alkyl, hydroxy substituted lower alkyl, Amino substituted lower alkyl, lower § alkylamino substituted lower alkyl or di-lower alkylamino substituted lower alkyl claims 1 and 3: according to any one of L 1 Method.
[13] R2がヒドロキシ置換低級アルキルまたはジ低級アルキルアミノ置換低級アルキルで ある請求項 1および 3〜： L 1のいずれかに記載の方法。 [13] The method according to any one of [1] and [3]: [R1], wherein R 2 is hydroxy-substituted lower alkyl or di-lower alkylamino-substituted lower alkyl.
[14] nが 0または 1である請求項 1〜13のいずれかに記載の方法。  [14] The method according to any one of claims 1 to 13, wherein n is 0 or 1.
[15] R1が低級アルキルである請求項 1〜14のいずれかに記載の方法。 15. The method according to any one of claims 1 to 14, wherein R 1 is lower alkyl.
[16] 一般式 (II)  [16] General formula (II)
[化 34]  [Chemical 34]
Figure imgf000032_0001
( II )
Figure imgf000032_0001
(II)
(式中、
Figure imgf000032_0002
X1、 X2および nはそれぞれ前記と同義である） (Where
Figure imgf000032_0002
X 1 , X 2 and n are as defined above)
で表される化合物またはその塩。  Or a salt thereof.
X1が臭素原子であり、 X2がヨウ素原子である請求項 16記載の化合物またはその塩 一般式 (IV) The compound or a salt thereof according to claim 16, wherein X 1 is a bromine atom, and X 2 is an iodine atom.
[化 35]  [Chemical 35]
Figure imgf000032_0003
(式中、 R R2、 X1および nはそれぞれ前記と同義である) で表される化合物またはその塩。
Figure imgf000032_0003
Wherein RR 2 , X 1 and n are as defined above, or a salt thereof.
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JP2009114166A (en) * 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd Method for producing dibenzoxepin compound
WO2011033532A1 (en) 2009-09-17 2011-03-24 Indoco Remedies Limited Process for preparation of olopatadine hydrochloride

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Publication number Priority date Publication date Assignee Title
WO2008099900A1 (en) * 2007-02-16 2008-08-21 Sumitomo Chemical Company, Limited Process for production of dibenzoxepin compound
JP2009114166A (en) * 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd Method for producing dibenzoxepin compound
WO2011033532A1 (en) 2009-09-17 2011-03-24 Indoco Remedies Limited Process for preparation of olopatadine hydrochloride

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