JPWO2006129781A1 - Method for producing dibenzoxepin derivative - Google Patents

Abstract

(I) a step of halogenating the compound represented by the general formula (I) to obtain a compound represented by the general formula (II), (ii) a compound represented by the general formula (II) III) a step of obtaining a compound represented by the general formula (IV) by subjecting it to a coupling reaction with an alkyne compound represented by the formula (IV), and (iii) an intramolecular ring of the compound represented by the general formula (IV) And a method for producing an 11-alkylidene dibenz [b, e] oxepin derivative represented by the general formula (V) or a salt thereof, including a step of subjecting to a chemical reaction. (In the formula, R1 represents a hydrogen atom, R2 represents a lower alkyl, X1 represents a chlorine atom, X2 represents a chlorine atom, and n represents an integer of 0 to 4)

Description

  The present invention relates to a method for producing 11-alkylidene dibenz [b, e] oxepin derivatives useful as pharmaceuticals or pharmaceutical intermediates.

  Many dibenz [b, e] oxepin derivatives are known as pharmaceuticals, pharmaceutical intermediates, and the like. Among them, it is known that a compound having a vinyl group at the 11-position, for example, an 11-alkylidene dibenz [b, e] oxepin derivative as shown in the formula (VIa) has an excellent antiallergic action (Patent Document 1). 2).

  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 Medicinal Chemistry (J. Med. Chem.), 1976). (Vol.19, p.941, etc.))

(In the formula, R represents a hydrogen atom or lower alkyl, and m represents an integer of 0 to 4).
And a phosphonium salt corresponding to a Wittig reaction (see Patent Literatures 1, 2, 3 and Non-Patent Literatures 1 and 2), a method of producing a compound (VII) using a Grignard reaction, etc. (Patent Literature 1, 2 and Non-Patent Document 1) are known. However, it is known that in these production methods, it is not easy to control the configuration of the double bond site, and the target product is obtained as a mixture of geometric isomers. Also, it is not easy to purify the mixture to isolate the desired isomer, and the yield is not satisfactory.

  On the other hand, there is known a method for producing a tricyclic compound (IX) by Grigg-cyclization of an alkyne compound (VIII) (see Non-Patent Document 3).

JP 63-10784 A JP-A-62-45557 JP-A-2-250 “Journal of Medicinal Chemistry”, 1992, vol. 35, p. 2074 “Pharmacia”, 2002, 38, p. 224 “Tetrahedron Letters”, 1993, Vol. 34, p. 8353

  An object of the present invention is to provide a method for producing a desired geometric isomer with high yield in the production of an 11-alkylidene dibenz [b, e] oxepin derivative useful as a pharmaceutical or an intermediate of the pharmaceutical.

The present invention relates to the following (1) to (18).
(1) (i) General formula (I)

Wherein R ¹ represents a hydrogen atom, lower alkyl, cycloalkyl, aralkyl or aryl, X ¹ represents a chlorine atom, bromine atom, iodine atom or trifluoromethanesulfonyloxy, and n represents an integer of 0 to 4. )
The compound represented by general formula (II)

(Wherein R ¹ , X ¹ and n are as defined above, and X ² represents a chlorine atom, a bromine atom or an iodine atom)
(Ii) a compound represented by the general formula (II) is represented by the general formula (III)

Wherein R ² is selected from the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbonyl, cycloalkyl, aryl, aromatic heterocyclic group and aliphatic heterocyclic group Optionally substituted lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbonyl, oxo, aryl, aromatic heterocyclic group and aliphatic heterocyclic ring Represents a cycloalkyl optionally having a substituent selected from the group consisting of groups)
Is subjected to a coupling reaction with an alkyne compound represented by the general formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
And (iii) subjecting the compound represented by the general formula (IV) to an intramolecular cyclization reaction, the general formula (V)

(Wherein R ¹ , R ² and n are as defined above)
The manufacturing method of 11-alkylidene dibenz [b, e] oxepin derivative represented by these, or its salt.
(2) General formula (I)

(Wherein R ¹ , X ¹ and n are as defined above)
Comprising a step of halogenating the compound represented by formula (II)

(Wherein R ¹ , X ¹ , X ² and n are as defined above)
Or a salt thereof.
(3) General formula (II)

(Wherein R ¹ , X ¹ , X ² and n are as defined above)
The compound represented by general formula (III)

(Wherein R ² is as defined above)
Which includes a step of subjecting to a coupling reaction with an alkyne compound represented by the general formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
Or a salt thereof.
(4) General formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
A compound represented by the general formula (V) comprising a step of subjecting the compound represented by

(Wherein R ¹ , R ² and n are as defined above)
The manufacturing method of 11-alkylidene dibenz [b, e] oxepin derivative represented by these, or its salt.
(5) The method according to (1) or (2), wherein the halogenation is iodination using iodine and silver sulfate, and X ² is an iodine atom.
(6) The method according to (1) or (3), wherein the coupling reaction is a reaction performed in the presence of dichlorobis (triphenylphosphine) palladium and copper iodide.
(7) a phosphine compound in which the intramolecular cyclization reaction is selected from the group 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 palladium compound selected from the group consisting of palladium acetate, palladium chloride and palladium carbon.
(8) General formula (VI) including the method according to any one of (1) to (7) (wherein R ¹ is not a hydrogen atom)

(Wherein R ² and n are as defined above)
The manufacturing method of 11-alkylidene dibenz [b, e] oxepin derivative represented by these, or its salt.
(9) The method according to any one of (1) to (8), wherein X ¹ is a chlorine atom, a bromine atom or trifluoromethanesulfonyloxy, and X ² is an iodine atom.
(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) The method according to any one of (1) to (8), wherein X ¹ is a bromine atom and X ² is an iodine atom.
(12) Any one of (1) and (3) to (11), wherein 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 The method described.
(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) The method according to any one of (1) to (13), wherein n is 0 or 1.
(15) The method according to any one of (1) to (14), wherein R ¹ is lower alkyl.
(16) General formula (II)

(Wherein R ¹ , X ¹ , X ² and n are as defined above)
Or a salt thereof.
(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) General formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
Or a salt thereof.

  INDUSTRIAL APPLICABILITY 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.

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
In the definition of each group of the general formulas (I) to (VI),
Examples of lower alkyl and lower alkoxy of lower alkoxy, lower alkylamino, di-lower alkylamino and lower alkoxycarbonyl include, for example, linear or branched alkyl having 1 to 10 carbon atoms, more specifically methyl, Examples thereof include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. The two lower alkyl moieties of the di-lower alkylamino may be the same or different.

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.
Examples of aryl include aryl having 6 to 14 carbon atoms, and more specifically, phenyl, naphthyl, anthryl and the like.

Examples of aralkyl include aralkyl having 7 to 16 carbon atoms, and more specifically, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, naphthylmethyl, naphthylethyl, and the like.
As the aliphatic heterocyclic group, for example, 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 are condensed. A bicyclic or tricyclic condensed ring aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, Piperidino, piperidinyl, perhydroazepinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl, thiomorpholinyl, dihydroindolyl, dihydroindolyl Drill, dihydrobenzofurani , Benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H- Examples thereof include thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl and the like.

  As the aromatic heterocyclic group, for example, a 5- 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 a 3- to 8-membered ring are condensed. A bicyclic or tricyclic fused ring aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically furyl, thienyl, pyrrolyl, Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl Lil, benzotriazolyl, oxazolopyridyl pyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc. naphthyridinyl and the like.

In each group of compound (I),
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.
In each group of compound (II):
X ¹ is a chlorine atom, or X ² is a bromine atom or an iodine atom, or X ¹ is a chlorine atom, a bromine atom or trifluoromethanesulfonyloxy, preferably X ² is an iodine atom, X ¹ Is a bromine atom or trifluoromethanesulfonyloxy, X ² is more preferably an iodine atom, X ¹ is a bromine atom, and X ² is more preferably an iodine atom. R ¹ is preferably lower alkyl, more preferably methyl, ethyl or the like.

In each group of compound (IV),
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 preferably lower alkyl, more preferably methyl, ethyl or the like. R ² is preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, or the like, more preferably hydroxyethyl, dimethylaminoethyl, or the like.

  Salts of compounds (II), (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 (II), (IV), (V) and (VI) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, Examples include organic acid salts such as oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. Examples of metal salts include alkali metal salts such as sodium salts and potassium salts. , Alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like. Examples of ammonium salts include salts such as ammonium and tetramethylammonium. Examples of organic amine addition salts include Examples include addition salts such as morpholine and piperidine. Examples of amino acid addition salts include lysine, glycine, phenylalanine, aspartic acid, and glutamate. Addition salts, such as phosphate, and the like.

  The 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. More specifically, for example, the reaction step shown in Step 1 of the following production method is mentioned. It is done. The coupling reaction in the present invention is a reaction for coupling an aryl halide and an alkyne compound, and includes, for example, the Sonogashira reaction. More specifically, for example, the reaction step shown in Step 2 of the following production method Can be given. 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, a reaction step shown in Step 3 of the following production method.

  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.

(Wherein R ¹ , R ² , X ¹ , X ² and n are as defined above)
Process 1
This step is a known method for halogenating a benzene ring (for example, Organic Synthesis, 1963, Vol. 4, p. 872; Organic Synthesis, 1973, Vol. 5, p. 117). Organic Synthesis, 1963, volume 4, p. 547; Tetrahedron Letters, 1993, volume 34, p. 6223; Angewante Chemi International Edition (Angew. Chem.); Int. Ed.), 2001, 40, p.1967).

Compound (II) 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 10 hours.
Compound (I) can be obtained, for example, by the method described in WO2005 / 009104 or according thereto.

  Examples of the halogenating agent include chlorinating agents such as chlorine and sulfuryl chloride, brominating agents such as bromine and N-bromosuccinimide, iodine, iodine chloride, bis (pyridineiodonium) tetrafluoroborate (F-TEDA), bis ( (Iodine pyridine iodonium) boron tetrafluoride and the like can be mentioned, and these can be used in combination. Examples of the combination 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, still more preferably 1 to 2 equivalents, and still more preferably 1 to 1.5 equivalents, relative to Compound (I). These halogenating agents can also be used in combination with various additives, and various additives can be used depending on the type of halogenating agent used. Examples of the combinations include, for example, a combination of chlorine and hydrogen chloride, bromine And a combination of Lewis acid such as aluminum chloride, a combination of bromine and iron, a combination of iodine and silver sulfate, a combination of iodine and potassium iodide, and a combination of iodine and silver trifluoroacetate. Among these, a combination of iodine and silver sulfate is preferable. The amount of the additive used when used in combination varies depending on the halogenating agent used and the type of additive used. For example, when bromine and aluminum chloride are used in combination, the aluminum chloride is preferably 2 to 2 bromine. 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 0.8 to 2 equivalents, relative to iodine. 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, still more preferably iodine. One equivalent is used.

  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), and hydrocarbon solvents such as hexane. Ester solvents such as ethyl acetate, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, halogen solvents such as dichloromethane and chloroform, basic solvents such as pyridine, acetic acid, etc. An acidic solvent, water, etc. are mentioned, These can be used individually or in mixture. In the case of using iodine and an iodinating agent such as silver sulfate or iodine chloride as the halogenating agent, an alcohol solvent such as methanol is preferred.

The treatment in this step is usually performed at a temperature between −78 ° C. and 150 ° C., preferably at a temperature between 0 ° C. and 100 ° C., more preferably at a temperature between 10 ° C. and 70 ° C.
Process 2
This step is in accordance with a known method (for example, Tetrahedron Letters, 1975, 16, p. 4467; Tetrahedron Letters, 1993, 34, p. 8353). Can be done.

Compound (IV) is compound (II) 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 Can be prepared by reacting with 1 to 3 equivalents of compound (III) for 5 minutes to 72 hours, preferably 1 to 24 hours.
Compound (III) can be obtained as a commercial product, or can be obtained by a known method (for example, Journal of Organic Chemistry (J. Org. Chem.), 1999, Vol. 64, p. 1798) or the like. Can be obtained.

Examples of the copper compound include copper iodide. The copper compound is preferably used in an amount of 0.001 to 1 equivalent, more preferably 0.01 to 0.2 equivalent, relative to compound (II).
Examples of the palladium catalyst having a phosphine ligand include a compound in which a phosphine ligand is coordinated to palladium. Examples of the phosphine ligand include triphenylphosphine, tri (o-tolyl) phosphine, tri ( m-tolyl) phosphine, tri (p-tolyl) phosphine, tris (2,4-dimethoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine, tris (dimethylamino) phosphine, tri (tert-butyl) phosphine, tri Cyclohexylphosphine, ethylenebis (diphenylphosphine), 1,3-bis (diphenylphosphino) propane, 1,1′-bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1 '-Binaphthyl. As the palladium catalyst having these phosphine ligands, for example, those produced in the reaction solution by adding the above-described phosphine ligand and palladium compound to 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. Examples of the palladium compound include palladium acetate, palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium carbon, and the like. The palladium catalyst having a phosphine ligand is usually used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalent, relative to compound (II). As the palladium catalyst having a phosphine ligand, for example, commercially available dichlorobis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium acetate, tetrakis (triphenylphosphine) palladium and the like can be used. Triphenylphosphine) palladium and the like are preferable.

  Examples of the base include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5. 4.0] undec-7-ene (DBU), piperidine, organic bases such as N-methylmorpholine, and the like, preferably triethylamine and the like. The base is preferably used in an amount of 0.5 to 20 equivalents, more preferably 1 to 10 equivalents, and still more preferably 1 to 5 equivalents, relative to compound (II).

  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, ester solvents such as ethyl acetate, diethyl Examples include ether solvents such as ether, THF, 1,4-dioxane, dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. These can be used alone or in combination. Preferably, DMF etc. are mentioned.

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 at a temperature between 10 ° C. and 70 ° C.
Process 3
This step is in accordance with a known method (for example, Tetrahedron Letters, 1993, 34, p. 8353; Tetrahedron Letters, 1988, 29, p. 4325). Can be done.

Compound (V) is obtained by reacting compound (IV) with a palladium catalyst, preferably a palladium catalyst having a phosphine ligand, in a suitable solvent in the presence of a suitable base and a hydrogen source for 5 minutes to 72 hours, preferably 1 to It can manufacture by processing for 10 hours.
Examples of the palladium catalyst include a palladium catalyst having a phosphine ligand, and examples of the palladium catalyst having the phosphine ligand include a compound in which a phosphine ligand is coordinated to palladium. Examples of the phosphine ligand include triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, tris (2,4-dimethoxyphenyl) phosphine, tris ( 4-methoxyphenyl) phosphine, tris (dimethylamino) phosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, ethylenebis (diphenylphosphine), 1,3-bis (diphenylphosphino) propane, 1,1′- Bis (diphenylphosphino) ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl and the like are preferable, and triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) are preferable. ) Phosphine, tri (p-tolyl) phosphie And tricyclohexylphosphine and the like, and more preferable, tri (o-tolyl) phosphine and the like. As the palladium catalyst having these phosphine ligands, for example, those produced in the reaction solution by adding the above-described phosphine ligand and palladium compound to the reaction solution can be used. In this case, as the phosphine ligand, for example, triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine, tricyclohexylphosphine, and the like are preferable. Tolyl) phosphine and the like are more preferable, and these are preferably used in an amount of 1 to 4 equivalents relative 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, more preferably palladium acetate and the like. Can be given. Moreover, as a palladium catalyst which has a phosphine ligand, commercially available dichlorobis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) palladium, etc. can also be utilized, for example. In addition, a palladium catalyst is 0.001-1 equivalent normally with respect to compound (IV), Preferably 0.01-0.2 equivalent is used.

  Examples of the base include lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, and other inorganic bases, methylamine, dimethylamine, pyridine, pyrrolidine, piperidine, morpholine, Examples thereof include organic bases such as N-methylmorpholine, triethylamine, diisopropylethylamine, and 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, ammonium salts of the organic acids and ammonia, methylamine, dimethylamine, triethylamine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, and the like. Metal salts such as sodium, potassium, calcium, etc., preferably ammonium formate, ammonium acetate, pyrrolidinium formate, piperidium formate, and the like, more preferably piperidium formate. Examples of these organic acid ammonium salts and organic acid metal salts include, for example, organic acids such as acetic acid and formic acid and ammonia, organic amines mentioned above, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, and the like. What was produced | generated in the reaction solution can also be used by adding in a reaction solution, It is preferable to use what was produced | generated by adding formic acid and a piperidine in a reaction solution. These organic acids, ammonium salts of organic acids and metal salts of organic acids are preferably used in an amount of 1 to 10 equivalents relative to 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, ester solvents such as ethyl acetate, diethyl Examples include ether solvents such as ether, THF, 1,4-dioxane, dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. These can be used alone or in combination. 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 at a temperature between 10 ° C. and 100 ° C.
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, Comprehensive Organic Transformations 2nd edition, R. C. The method described in Larock, Vch Verlagsgesellschaft Mbh (1999), etc.] or in conformity thereto.

For example, among compounds (V), compound (Vc) known as an antiallergic agent in which R ¹ is a hydrogen atom and R ² is dimethylaminoethyl is compound (Va) obtained by the above production method. For example, it can also be produced by a known method shown below.

(Wherein R ¹ and n are as defined above)
Process 4
Compound (Vb) is obtained by subjecting compound (Va) obtained in the above step 3 to (1) 1 to 10 equivalents of methanesulfonyl chloride, anhydrous, in the presence of 1 to 20 equivalents of an appropriate base as required in an appropriate solvent. Reaction with a sulfonylating agent such as trifluoromethanesulfonyl, benzenesulfonyl chloride, p-toluenesulfonyl chloride at a temperature between −20 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours, (2) In the absence of solvent or in a suitable solvent, optionally in the presence of 1 to 20 equivalents of a suitable base, 1 equivalent to a large excess, preferably 1 to 20 equivalents of dimethylamine, and between -20 ° C and 100 ° C. At a temperature of 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, ester solvents such as ethyl acetate, diethyl ether, THF, 1, Examples include ether solvents such as 4-dioxane and dimethoxyethane, halogen solvents such as dichloromethane and chloroform, and basic solvents such as pyridine. These may be used alone or in combination.

Examples of the base used in (1) include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, pyridine, triethylamine, diisopropylethylamine, DBU and the like. Organic bases.
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. Examples include ester solvents, ether solvents such as diethyl ether, THF, 1,4-dioxane, dimethoxyethane, halogen solvents such as dichloromethane and chloroform, basic solvents such as pyridine, water, and the like. Used as a mixture.

Examples of the base used in (2) include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, pyridine, triethylamine, diisopropylethylamine, DBU and the like. Organic bases.
Process 5
Compound (Vc) is produced by treating compound (Vb) with 1 to 20 equivalents, preferably 1 to 3 equivalents of an appropriate base in a water-containing solvent for 5 minutes to 72 hours, preferably 10 minutes to 6 hours. be able to.

  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, hydrophilic solvents such as acetone, acetonitrile, DMF, and NMP. Hydrocarbon solvents such as toluene, xylene, hexane, ester solvents such as ethyl acetate, ether solvents such as diethyl ether, THF, 1,4-dioxane, dimethoxyethane, halogen solvents such as dichloromethane and chloroform, pyridine, etc. These may be used alone or as a mixture, and preferred examples include methanol and ethanol.

Examples of the base include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium methoxide, and organic bases such as pyridine, triethylamine, diisopropylethylamine, and DBU. can give.
The treatment in this step is usually performed at a temperature between 0 ° C. and the boiling point of the solvent used, preferably at a temperature between 10 ° C. and 70 ° C.

The intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. In addition, the intermediate can be subjected to the next reaction without any particular purification.
In addition, compounds (II), (IV), (V) and (VI) and salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. It is included in the target object manufactured by the manufacturing method of this invention.

  When it is desired to obtain a salt of compound (II), (IV), (V) or (VI), it is purified as it is when compound (II), (IV), (V) or (VI) is obtained in the form of a salt. When it is obtained in a free form, the salt is obtained by dissolving or suspending the compound (II), (IV), (V) or (VI) in an appropriate solvent and adding an acid or a base. It may be formed and isolated and purified.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Preparation of methyl 4- (2-bromobenzyloxy) -3-iodophenylacetate (Compound IIA) Iodine (7.28 g, 28.1 mmol) and silver sulfate (8.76 g, 28.1 mmol) were added to methanol (127 mL). Added and stirred at 18 ° C. until iodine was dissolved. Next, 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 by using the iodine and sulfuric acid prepared above. Added to the silver methanol solution. After stirring at 18 ° C. for 2 hours, the insoluble material was filtered off, and the insoluble material was washed with ethyl acetate (38 mL). 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 IIA (11.00 g, 86%) as white crystals.
¹ H-NMR (CDCl ₃ , δ ppm): 7.78 (d, 1H, J = 7.7 Hz), 7.75 (d, 1H, J = 2.0 Hz), 7.59 (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] ^- .

Preparation of methyl 4- (2-bromobenzyloxy) -3- (4-hydroxybut-1-ynyl) phenylacetate (Compound IVA) To compound IIA (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 the mixture was stirred at 25 ° C. for 5 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture 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 / hexane = 1/1) to give the title compound IVA (4.34 g, 99%) as a brown oil.
¹ H-NMR (CDCl ₃ , δ ppm): 7.64 (dd, 1H, J = 7.7, 1.7 Hz), 7.57 (dd, 1H, J = 7.7, 1.1 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).
¹³ C-NMR (CDCl ₃ , δ ppm): 171.9, 158.1, 136.1, 134.1, 132.5, 130.1, 129.2, 128.6, 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 .
MS ESI (+) m / z: 405, 403 [M + H] ^< +>.

Preparation of (Z) -11- (3-hydroxypropylidene) -6,11-dihydrobenz [b, e] oxepin-2-acetic acid methyl (Compound VA) Compound IVA obtained in Example 2 under nitrogen atmosphere To (200 mg, 0.496 mmol), palladium acetate (11.1 mg, 0.0496 mmol) and tri (o-tolyl) phosphine (37.7 mg, 0.124 mmol) were added, and DMF (2.0 mL) was added. Dissolved. Piperidine (344 μL, 4.93 mmol) and formic acid (20.5 μL, 0.545 mmol) were sequentially added, and the mixture was 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 / hexane = 1/2) to give the title compound VA (114 mg, 71%) as a white solid.
¹ H-NMR (CDCl ₃ , δ ppm): 7.43-7.24 (m, 4H), 7.17 (d, 1H, J = 2.2 Hz), 7.04 (dd, 1H, 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, 2H), 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 Hz).
MS ESI (+) m / z: 325 [M + H] ^< +>.

Preparation of methyl 4- (2-bromobenzyloxy) -3- (4-dimethylaminobut-1-ynyl) phenylacetate (Compound IVB) Compound IIA obtained in Example 1 (1.00 g, 2.17 mmol) Dichlorobis (triphenylphosphine) palladium (76.1 mg, 0.108 mmol) and copper iodide (21.0 mg, 0.108 mmol) were added, and DMF (10 mL) was added and dissolved. But-3-ynyldimethylamine (609 mg, 4.34 mmol) and triethylamine synthesized according to known methods (Journal of Organic Chemistry (J. Org. Chem.), 1999, 64, p. 1798) (1.22 mL, 8.68 mmol) was 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 (eluent: chloroform / methanol = 20/1) to give the title compound IVB (728 mg, 78%) as a brown oil.
¹ H-NMR (CDCl ₃ , δ ppm): 7.64 (dd, 1H, J = 7.7, 1.7 Hz), 7.57 (dd, 1H, J = 7.7, 1.1 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).
MS ESI (+) m / z: 432, 430 [M + H] ^< +>.

Preparation of (Z) -11- [3- (dimethylamino) propylidene] -6,11-dihydrobenz [b, e] oxepin-2-acetic acid methyl (Compound VB) Obtained in Example 4 under nitrogen atmosphere To compound IVB (161 mg, 0.374 mmol) was added palladium acetate (8.40 mg, 0.0374 mmol) and tri (o-tolyl) phosphine (22.8 mg, 0.0748 mmol), and DMF (3.2 mL) was added. In addition, it was dissolved. Piperidine (148 μL, 1.50 mmol) and formic acid (42.0 μL, 1.12 mmol) were sequentially added, and the mixture was 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.

Preparation of hydrochloric acid (Z) -11- [3- (dimethylamino) propylidene] -6,11-dihydrobenz [b, e] oxepin-2-acetic acid (Compound VIa) Compound VA (21) obtained in Example 3 (0.0 g, 64.7 mmol) was dissolved by adding pyridine (160 mL) and cooled to 5 ° C. Methanesulfonyl chloride (28.0 g, 244 mmol) was gradually added at 5 ° C., followed by stirring 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 under reflux for 3 hours. 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 the reaction mixture was concentrated, 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- (2-Bromobenzyloxy) phenyl acetate methyl (Compound IA)
DMF (50.0 mL) was added to and dissolved in methyl 4-hydroxyphenylacetate (5.00 g, 30.1 mmol), and potassium carbonate (6.28 g, 45.1 mmol) and 2-bromobenzyl bromide (7.50 g, 30.1 mmol) was sequentially added, and the mixture was stirred at 25 ° C. for 4 hours. Water (70 mL) was added to the reaction mixture, extraction was performed 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 give the title compound IA (10.25 g, quantitative).
¹ H-NMR (CDCl ₃ , δ ppm): 7.58 (dd, 1 H, J = 7.7, 1.1 Hz), 7.53 (dd, 1 H, J = 7.7, 1.3 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] ^< +>.

  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 (18)

(I) General formula (I)

Wherein R ¹ represents a hydrogen atom, lower alkyl, cycloalkyl, aralkyl or aryl, X ¹ represents a chlorine atom, bromine atom, iodine atom or trifluoromethanesulfonyloxy, and n represents an integer of 0 to 4. )
The compound represented by general formula (II)

(Wherein R ¹ , X ¹ and n are as defined above, and X ² represents a chlorine atom, a bromine atom or an iodine atom)
(Ii) a compound represented by the general formula (II) is represented by the general formula (III)

Wherein R ² is selected from the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbonyl, cycloalkyl, aryl, aromatic heterocyclic group and aliphatic heterocyclic group Optionally substituted lower alkyl, hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbonyl, oxo, aryl, aromatic heterocyclic group and aliphatic heterocyclic ring Represents a cycloalkyl optionally having a substituent selected from the group consisting of groups)
Is subjected to a coupling reaction with an alkyne compound represented by the general formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
And (iii) subjecting the compound represented by the general formula (IV) to an intramolecular cyclization reaction, the general formula (V)

(Wherein R ¹ , R ² and n are as defined above)
The manufacturing method of 11-alkylidene dibenz [b, e] oxepin derivative represented by these, or its salt. Formula (I)

(Wherein R ¹ , X ¹ and n are as defined above)
Comprising a step of halogenating the compound represented by formula (II)

(Wherein R ¹ , X ¹ , X ² and n are as defined above)
Or a salt thereof. Formula (II)

(Wherein R ¹ , X ¹ , X ² and n are as defined above)
The compound represented by general formula (III)

(Wherein R ² is as defined above)
Which includes a step of subjecting to a coupling reaction with an alkyne compound represented by the general formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
Or a salt thereof. Formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
A compound represented by the general formula (V) comprising a step of subjecting the compound represented by

(Wherein R ¹ , R ² and n are as defined above)
The manufacturing method of 11-alkylidene dibenz [b, e] oxepin derivative represented by these, or its salt. Halogenation, a iodinated using iodine and silver sulfate, according to claim 1 or 2 wherein X ² is an iodine atom.   The method according to claim 1 or 3, wherein the coupling reaction is a reaction performed in the presence of dichlorobis (triphenylphosphine) palladium and copper iodide.   A phosphine compound selected from the group consisting of triphenylphosphine, tri (o-tolyl) phosphine, tri (m-tolyl) phosphine, tri (p-tolyl) phosphine and tricyclohexylphosphine, and palladium acetate; The method according to claim 1 or 4, wherein the reaction is carried out in the presence of a palladium compound selected from the group consisting of palladium chloride and palladium carbon. A general formula (VI) comprising the method according to claim 1, wherein R ¹ is not a hydrogen atom.

(Wherein R ² and n are as defined above)
The manufacturing method of 11-alkylidene dibenz [b, e] oxepin derivative represented by these, or its salt. The method according to claim 1, wherein X ¹ is a chlorine atom, a bromine atom or trifluoromethanesulfonyloxy, and X ² is an iodine atom. The method according to claim 1, wherein X ¹ is a chlorine atom and X ² is a bromine atom or an iodine atom. The method according to claim 1, wherein X ¹ is a bromine atom and X ² is an iodine atom. The method according to any one of claims 1 and 3 to 11, wherein 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. The method according to any one of claims 1 and 3 to 11, wherein R ² is hydroxy-substituted lower alkyl or di-lower alkylamino-substituted lower alkyl.   The method according to claim 1, wherein n is 0 or 1. The method of any of claims 1 to 14 R ¹ is lower alkyl. Formula (II)

(Wherein R ¹ , X ¹ , X ² and n are as defined above)
Or a salt thereof. The compound or a salt thereof according to claim 16, wherein X ¹ is a bromine atom and X ² is an iodine atom. Formula (IV)

(Wherein R ¹ , R ² , X ¹ and n are as defined above)
Or a salt thereof.