WO2006129781A1 - Procede de production d'un derive de la dibenzoxepine - Google Patents

Procede de production d'un derive de la dibenzoxepine Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
chemical
atom
defined above
formula
Prior art date
Application number
PCT/JP2006/311060
Other languages
English (en)
Japanese (ja)
Inventor
Koichiro Nishimura
Masahiko Kinugawa
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to JP2007519078A priority Critical patent/JP5099830B2/ja
Priority to CN2006800106989A priority patent/CN101151256B/zh
Publication of WO2006129781A1 publication Critical patent/WO2006129781A1/fr

Links

Classifications

    • 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.

Abstract

L'invention porte sur un procédé de production d'un dérivé de la 11-alkylidène dibenz[b,e]oxépine de formule générale (V) ou l'un de ses sels comportant les étapes suivantes: (i) halogénation d'un composé de formule générale (I) pour obtenir un composé de formule générale (II); (ii) soumission du composé de formule générale (II) à une réaction de couplage avec un composé d'alkyne de formule générale (III) pour obtenir un composé de formule générale (IV); et (iii) soumission du composé de formule générale (IV) à une cyclisation intramoléculaire pour obtenir un composé de formule générale (V). Dans les formules (I), (II); (III) (IV) et (V) des étapes (i), (ii) et (iii), R1 représente un atome d'hydrogène ou analogue; R2 représente alkyle inférieur ou analogue; X1 représente un atome de chlore ou analogue; X2 représente un atome de chlore ou analogue; et n représente un entier de 0 à 4.
PCT/JP2006/311060 2005-06-02 2006-06-02 Procede de production d'un derive de la dibenzoxepine WO2006129781A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2007519078A JP5099830B2 (ja) 2005-06-02 2006-06-02 ジベンズオキセピン誘導体の製造方法
CN2006800106989A CN101151256B (zh) 2005-06-02 2006-06-02 二苯并*庚因衍生物的制造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005162240 2005-06-02
JP2005-162240 2005-06-02

Publications (1)

Publication Number Publication Date
WO2006129781A1 true WO2006129781A1 (fr) 2006-12-07

Family

ID=37481708

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2006/311060 WO2006129781A1 (fr) 2005-06-02 2006-06-02 Procede de production d'un derive de la dibenzoxepine

Country Status (5)

Country Link
JP (1) JP5099830B2 (fr)
KR (1) KR101001129B1 (fr)
CN (1) CN101151256B (fr)
TW (1) TW200716588A (fr)
WO (1) WO2006129781A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099900A1 (fr) * 2007-02-16 2008-08-21 Sumitomo Chemical Company, Limited Procédé de production de composé de dibenzoxépine
JP2009114166A (ja) * 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd ジベンゾオキセピン化合物の製造方法
WO2011033532A1 (fr) 2009-09-17 2011-03-24 Indoco Remedies Limited Procédé de préparation d'hydrochlorure d'olopatadine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5821679A (ja) * 1981-07-31 1983-02-08 メルク　エンド　カムパニー　インコーポレーテツド ジベンツ〔ｂ，ｅ〕オキセピン化合物
WO2003070686A1 (fr) * 2002-02-21 2003-08-28 Asahi Kasei Pharma Corporation Derive de l'acide phenylalcanoyle substitue et son utilisation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4282365A (en) * 1978-11-24 1981-08-04 Merck & Co., Inc. Dibenz[b,e]oxepin compounds
WO2001036351A2 (fr) * 1999-11-19 2001-05-25 Corvas International, Inc. Antagonistes de l'inhibiteur des activateurs du plasminogène

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5821679A (ja) * 1981-07-31 1983-02-08 メルク　エンド　カムパニー　インコーポレーテツド ジベンツ〔ｂ，ｅ〕オキセピン化合物
WO2003070686A1 (fr) * 2002-02-21 2003-08-28 Asahi Kasei Pharma Corporation Derive de l'acide phenylalcanoyle substitue et son utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FINCH H. ET AL.: "The synthesis of a conformationally restrained, combined thromboxane antagonist/synthase inhibitor using an intramolecular Stille- or Grigg-palladium-catalyzed cyclization strategy", TETRAHEDRON LETTERS, vol. 34, no. 51, 1993, pages 8353 - 8356, XP002352271 *
OHSHIMA E. ET AL.: "Dibenzoxepin derivatives: thromboxane A2 synthase inhibition and thromboxane A2 receptor antagonism combined in one molecule", JOURNAL OF MEDICINAL CHEMISTRY, vol. 36, no. 11, 1993, pages 1613 - 1618, XP003004421 *
SUGAYA T. ET AL.: "Stereoselective synthesis of novel thromboxane A2 receptor antagonists via stereoselective 1-azadiene isomerization", CHEMISTRY LETTERS, no. 12, 1990, pages 2181 - 2182, XP008073376 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008099900A1 (fr) * 2007-02-16 2008-08-21 Sumitomo Chemical Company, Limited Procédé de production de composé de dibenzoxépine
JP2009114166A (ja) * 2007-02-16 2009-05-28 Sumitomo Chemical Co Ltd ジベンゾオキセピン化合物の製造方法
WO2011033532A1 (fr) 2009-09-17 2011-03-24 Indoco Remedies Limited Procédé de préparation d'hydrochlorure d'olopatadine

Also Published As

Publication number Publication date
JP5099830B2 (ja) 2012-12-19
CN101151256A (zh) 2008-03-26
KR20080011652A (ko) 2008-02-05
TW200716588A (en) 2007-05-01
JPWO2006129781A1 (ja) 2009-01-08
CN101151256B (zh) 2011-02-09
KR101001129B1 (ko) 2010-12-14

Similar Documents

Publication Publication Date Title
JPH0570463A (ja) Ｎ−アシル−２，３−ベンゾジアゼピン誘導体、その製造法、それを含有する製剤組成物、およびその製造法
JP2008534657A (ja) トランス−５−クロロ−２−メチル−２，３，３ａ，１２ｂ−テトラヒドロ−１Ｈ−ジベンズ［２，３：６，７］−オキセピノ［４，５−ｃ］ピロールの調製のための中間体化合物
JP2009543838A (ja) インドール化合物
HU190541B (en) Process for preparing disubstituted proline derivatives
WO2006129781A1 (fr) Procede de production d'un derive de la dibenzoxepine
WO2006129626A1 (fr) Procede de fabrication d'un derive de [1,2,4]triazolo[1,5-c]pyrimidine
AU722147B2 (en) N-(benzothiazol-2-yl) piperidine-1-ethanamine derivatives, their preparation and application in therapeutics
PL117107B1 (en) Process for preparing novel 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido/4,3-b/indoles-geksagirdid 1h-pirido 4,3-b ionidolov
CN107108604B (zh) 制备三环内酰胺化合物的方法
JP2006083085A (ja) 二環性ピリミジン誘導体の製造法およびその合成中間体
Pedrosa et al. Synthesis of enantiopure mono-and disubstituted tetrahydroisoquinolines by 6-exo radical cyclizations
GB2030133A (en) Tetrahydrothiopyrano (2,3-b) indole derivatives
JP5130211B2 (ja) ３−ヒドラジノ−２，５−ジオキソピロリジン−３−カルボキシレート類およびその製造方法ならびにその使用
JP2008094744A (ja) ビスアミノールエーテル化合物を用いるピペリジン−４−オン誘導体の製造方法
JP2549931B2 (ja) ピリミドベンズイミダゾール誘導体
JP4011819B2 (ja) インドール誘導体の製造法およびその中間体
JPH07121931B2 (ja) ベンゾ〔ｂ〕フラン誘導体
JP3017338B2 (ja) インドールアルカロイド誘導体製造用の新規中間体化合物
OMURA et al. Studies on the Syntheses of N-Heterocyclic Compounds. XXVIII. Syntheses of Pyrido [3, 4-d] pyridazine Derivatives.(4)
CN109776388B (zh) 一种具有c2季碳中心的吲哚啉衍生物的合成方法
JPH0733374B2 (ja) フエニルイミダゾ−ル誘導体
JP3496979B2 (ja) 置換インドール−３−酢酸化合物および置換ベンゾフラニル−３−酢酸化合物の製造方法
JP4922761B2 (ja) 置換された複素環化合物の合成
JP3454435B2 (ja) ４−アミノピリジン誘導体の製造方法
CA3214107A1 (fr) Nouveau procede de synthese de derives de 5-{5-chloro-2-[(3s)-3-[(morpholin-4-yl)methyl]-3,4-dihydroisoquinoleine-2(1h)-carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-acide carboxylique et son application pour la production de composes pharmaceutiques

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680010698.9

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2007519078

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 1020077022592

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06747104

Country of ref document: EP

Kind code of ref document: A1