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WO2007046554A1 - Procédé pour la production d'un composé de dibenzoxépinopyrrole, intermédiaire pour la production du composé et procédé pour la production de l'intermédiaire - Google Patents

Procédé pour la production d'un composé de dibenzoxépinopyrrole, intermédiaire pour la production du composé et procédé pour la production de l'intermédiaire Download PDF

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Publication number
WO2007046554A1
WO2007046554A1 PCT/JP2006/321452 JP2006321452W WO2007046554A1 WO 2007046554 A1 WO2007046554 A1 WO 2007046554A1 JP 2006321452 W JP2006321452 W JP 2006321452W WO 2007046554 A1 WO2007046554 A1 WO 2007046554A1
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formula
compound represented
compound
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Weiqi Wang
Tetsuya Ikemoto
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • TECHNICAL FIELD A process for producing a dibenzoxepinopyrrole compound, an intermediate thereof, and a process for producing the intermediate Technical Field
  • the present invention relates to a method for producing asenapine useful as a schizophrenia drug, an intermediate thereof, and a method for producing the intermediate.
  • USP 4,145,434 describes various tetracyclic derivatives including asenapine, and describes that synthetic intermediates immediately before the formation of the tetracycle can be produced by the following route.
  • J. Med. Chem. (1983), 26 (10), 1353-1360 describes that 2-phenoxy-5-chlorophenylacetic acid is synthesized by the following route.
  • An object of the present invention is to provide a method for efficiently and safely producing asenapine and a synthetic intermediate thereof starting from an inexpensive raw material, and another object is to provide a novel intermediate of asenapine. is there.
  • the present invention is as follows.
  • Formula [III] A process for producing compound [IV] comprising reacting a compound represented by the formula (hereinafter, sometimes referred to as compound [III]) with 4-monochlorophenol.
  • R represents an alkyl group having 1 to 6 carbon atoms.
  • Compound [II] has the formula [la]: A compound represented by the formula (hereinafter may be referred to as a compound [la]) or a reactive derivative of its force lpoxyl group to the formula [lb]: to CO 2 R [lb]
  • the reaction is a reaction between a reactive derivative at the carboxyl group of the compound [la] and the compound [lb], and the reactive derivative is an acid halide of the compound [la]. the method of.
  • ⁇ 1 3> The method according to any one of ⁇ 10> to ⁇ 12>, wherein the intramolecular cyclization is performed by allowing a base to act on compound [II].
  • a process comprising obtaining a compound represented by the formula (hereinafter, may be referred to as compound [IV]), wherein compound [IV] is subjected to intramolecular cyclization to formula [V]:
  • a process comprising obtaining a compound represented by formula (hereinafter sometimes referred to as compound [V]), wherein compound [V] is reduced to formula [VI]:
  • a process comprising obtaining a compound represented by the formula (hereinafter sometimes referred to as compound [VI]), and
  • ⁇ 1 7> The method according to ⁇ 15> or ⁇ 16>, wherein the reaction between compound [III] and 4-chlorophenol is performed in the presence of a base.
  • ⁇ 1 9> The method according to any one of ⁇ 15> to ⁇ 18>, wherein the intramolecular cyclization of compound [IV] is carried out in a dehydrating solvent.
  • ⁇ 20> The method according to ⁇ 19>, wherein the dehydrating solvent is sulfuric acid, phosphoric acid or polyphosphoric acid.
  • ⁇ 2 1> The method according to 19>, wherein the dehydrating solvent is polyphosphoric acid, and the polyphosphoric acid is polyphosphoric acid prepared from phosphoric acid and diphosphorus pentoxide.
  • Reduction of compound [V] is carried out by catalytic reduction in the presence of a noble metal catalyst or by reaction with an alkali metal or alkaline earth metal in lower alcohol or ammonia ⁇ 1
  • ⁇ 24> The method according to any one of ⁇ 15> to ⁇ 23>, wherein the reduction of the carbonyl group of compound [VI] is carried out by reacting with a reducing agent.
  • the reducing agent is Li A l H 4 , Na a 1 H 2 (OCH 2 CH 2 0 CH 3 ) 2 , Li A 1 H (t 1 Bu 0) 3 , A 1 H 3 , B 2 H 6 , BH 3 'THF, BH 3 ' OE t 2 , Na BH 4 / BF 3 'THF, KBH 4 / BF 3- THF, Li BH 4 / BF 3 ⁇ TH F, Na B H 4 / (CH 3) 2 S0 4 or method according to NaBH 4 / H 2 S_ ⁇ is 4 ⁇ 24>.
  • asenapine or a pharmacologically acceptable salt thereof can be produced by the route shown in the following scheme 1.
  • Compound [II] can be produced by reacting compound [la] or a reactive derivative at its carboxyl group with compound [lb].
  • R represents a linear or branched alkyl group having 1 to 6 carbon atoms, particularly preferably a methyl group or an ethyl group.
  • This step can be performed by a method employed in a general amidation reaction.
  • a method using a condensing agent can be employed.
  • a reactive derivative at the galboxyl group of compound [la] is used, a reactive derivative derived from compound [la], for example, a method of reacting the corresponding acid halide with compound [lb] can be mentioned.
  • the amount of the compound. [Ib] is usually 0.8 to 5 mol, preferably 1 with respect to 1 mol of the compound [la]. ⁇ 1.5 moles.
  • Condensation agents include N, N'-dicyclohexyl carpositimide (DCC), N- (3-Jetylamino-1_propyl) -N'-ethyl carpositimide hydrochloride (WSCI ⁇ HC 1), etc.
  • Diphenylphosphoryl azide DP PA
  • Jetyl cyanophosphate DEPC
  • N ⁇ 'One bis (2-oxo-1-3-xazolidinyl) Phosphinic chloride (BOP— C 1)
  • organic phosphorus condensing agents methyl carbonates such as methyl carbonate, ethyl carbonate, and isopropyl carbonate
  • pivaloyl chloride thionyl chloride
  • phosphorus oxychloride phosphorus oxychloride and the like.
  • the amount of the condensing agent is usually 0.8 to 5 mol, preferably 1 to 1.5 mol, per 1 mol of the compound [la].
  • a base is not necessarily used, but a base (for example, triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropyl) is used.
  • Organic pyrethylamine, N-methylmorpholine, pyridine, 2,6-di-tert-butylpyridine, imidazole, 1-methylimidazole and other organic bases, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, Inorganic bases such as sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, etc.) may be added to the reaction system, with triethylamine being particularly preferred.
  • the base the amount is usually 0.1 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of the compound [la].
  • the base is liquid, it can also serve as a solvent.
  • the solvent examples include ester solvents (for example, ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, propyl propionate, butyl propionate, etc.); ether solvents (for example, jetyl ether, tert butyl) Methyl ether, 1,2-dimethoxyethane, diglyme, tetrahydrofuran, etc.) Amide solvent (eg, N, N-dimethylformamide, N, N-dimethylacetylamide, N-methylpyrrolidone, 1,3-dimethyl-2) —Imidazolidinones, etc.); Ketone solvents (eg, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone, cyclopentanone, etc.); Nitryl solvents.
  • ester solvents for example, ethyl acetate, propyl acetate,
  • Alcohol solvent for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2_butanol, etc .; halogenated solvents (eg, methylene chloride, black, etc.); aromatic solvents (eg, toluene, xylene, black mouth) Benzene, nitro benzene, etc.); water, etc.
  • halogenated solvents eg, methylene chloride, black, etc.
  • aromatic solvents eg, toluene, xylene, black mouth
  • water etc.
  • the amount of the solvent is usually 1 to 100 L, preferably 3 to 30 L, relative to 1 kg of the compound [la].
  • a catalyst such as 4-N, N-dimethylaminopyridine or 4-pyrrolidinopyridine to the reaction system, and 4-N, N-dimethylaminopyridine is added. It is particularly preferable to add them.
  • the amount of the catalyst is usually from 0.001 to 1 mol, preferably from 0.1 to 0.5 mol, per 1 mol of the compound [la].
  • the reaction temperature is usually ⁇ 30 to 15 ° C., preferably 0 to 50 ° C. There is no particular restriction on the order of charging with Compound [Ia], Compound [lb] and the condensing agent.
  • the acid halide examples include an acid chloride and an acid chloride, and an acid chloride is preferable.
  • the acid group and the ride can be produced by reacting the compound [la] with a halogenating agent.
  • the halogenating agent include thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride, thionyl bromide, and ⁇ phosphorous bromide, with thionyl chloride being preferred.
  • the amount of thionyl chloride is usually;! '-5 mol, preferably 1-1.'5 mol, relative to compound [la] ⁇ mol.
  • Solvents are not necessarily used, but halogenated solvents (eg, methylene chloride, chloroform, etc.), aromatic solvents (eg, benzene, toluene, xylene, chloroform, nitrobenzene, etc.) are used. Of these, toluene is preferred.
  • the amount of the solvent is usually 1 to 100 L, preferably 3 to 30 L, per 1 kg of the compound [la].
  • N, N-dimethylformamide, ⁇ ,, ⁇ -dimethylaniline, etc. as a catalyst, and it is particularly preferable to add ⁇ , ⁇ -dimethylformamide to the reaction system.
  • the amount of the catalyst is usually from 0.001 to 1 mol, preferably from 0.01 to 0.05 mol, per 1 mol of the compound [la].
  • the reaction temperature is usually ⁇ 30 to 1.5 ° C., preferably 20 to 90 ° C.
  • the acid halide of the compound [la] is used in the form of a solution, a concentrated product or a distilled product obtained by distillation after removing the excess amount of the halogenating agent as the solvent is distilled off, preferably in the form of a concentrated compound. Used for reactions with [lb].
  • the reaction between the acid halide of compound [la] and compound [lb] can be suitably carried out usually in the presence of a base.
  • the amount of compound [lb] is usually 0.8 to 5 mol, preferably 1 to 1.5 mol, per 1 mol of compound [la].
  • bases examples include ⁇ ethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, N_methylmorpholine, pyridine, 2,6-di-tert-butylpyridine, imidazole, 1- Organic bases such as methylimidazole, inorganic bases such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, lithium bicarbonate ⁇ Liethylamine and N-methylmorpholine are preferred.
  • the amount of the base is usually 0.8 to 5 mol, preferably 1 to 3 mol, relative to 1 mol of the compound [la].
  • Base as solvent It can also be used.
  • the solvent examples include ester solvents (eg, ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, propyl propionate, butyl propionate, etc.); ether media (eg, jetyl ether, tert-butyl methyl ether, 1, 2 _ Dimethichetetane, diglyme, tetrahydrofuran, etc.); Amide solvent (eg, N, N-dimethylformamide, N, N-dimethylacetylamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc.); Ketone Solvents (eg, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone, cyclopentanone, etc.); diaryl solvents (eg, acetonitrile, propionitryl, etc.); alcohol solvents (eg, methanol,
  • a mixed solvent of two or more Preferably, toluene and tetrahydrofuran are used.
  • a catalyst such as 4-N, N-dimethylaminopyridine or 4-pyrrolidinopyridine to the reaction system, and the amount of the catalyst is 1 mol of the compound [la].
  • the amount is usually from 0.001 to 1 mol, preferably from 0.1 to 0.5 mol.
  • the reaction temperature is usually ⁇ 30 to 15 O: preferably 0 to 80 ° C.
  • the order in which the acid halide of compound [la] and the compound [Ib ⁇ and base are charged is not particularly limited, but the acid halide of compound [la] is preferably added dropwise to the solution of compound [lb] and base.
  • Compound [ ⁇ ] can be purified by conventional post-treatment of the reaction solution (for example, neutralization, extraction, washing, drying, concentration, chromatography, etc.), but without any particular purification. It can also be used in the next step. (Process 2)
  • Compound [ ⁇ ] can be produced by intramolecular cyclization of compound [II].
  • the reaction in this step can be suitably carried out by reacting compound [II] with a base.
  • Bases include metal hydrides (eg, potassium hydride, sodium hydride, lithium hydride, etc.), Metal carbonates (eg cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, etc.), metal alkoxides (eg tert-butoxy potassium, tert-butoxy sodium, potassium potassium, ethoxy sodium) ), Tertiary amines (eg, triethyla, min, 1,8-diazabicyclo [4.3.0] — 5-nonene, etc.), and metal alkoxides are preferred.
  • metal hydrides eg, potassium hydride, sodium hydride, lithium hydride, etc.
  • Metal carbonates eg cesium carbonate, potassium carbonate, potassium bicarbonate, sodium carbonate,
  • the amount of the base is usually 0.5 to 5 mol, preferably 1 to 1.5 mol, per 1 mol of the compound [II].
  • the reaction solvent include ether solvents (eg, jetyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, diglyme, tetrahydrofuran, etc.); amide solvents (eg, N, N-dimethylformamide, N, N-dimethyla Cetylamide, N-methylpyrrolidone, 1,3-dimethyl_ 2 -imidazolidinone, etc .; halogenated solvents (eg methylene chloride, black mouth form, etc.); aromatic solvents (eg benzene, toluene, etc.) Xylene, black benzene, nitrobenzene, etc.); alcohol solvents (eg, methanol, ethanol, 1-propanol, 2_propanol, 1-butane, etc.); amide solvents (
  • the amount of the solvent is usually 1 to 100 L, preferably 3 to 30 L, per 1 kg of the compound [II].
  • the reaction temperature is usually from 30 to 150 ° C, preferably from -10 to 50 ° C.
  • the reaction time depends on the reaction temperature and the amount of raw materials, it is usually 1 to 48 hours, preferably 2 to 10 hours.
  • Compound [III] can be isolated by post-treatment of the reaction solution by a conventional method (for example, neutralization, extraction, washing, drying, crystallization, etc.).
  • Step 3) Compound [IV] can be produced by reacting Compound [III] with 4-chlorophenol.
  • the reaction in this step can be suitably performed in the presence of a base, and is preferably performed in the presence of a catalyst.
  • Examples of the base include, for example, triethylamine, tri_n-propylamine, tri-n-butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-di-tert-butylpyridine, imidazole, and 1-methylimidazole.
  • Organic bases such as: metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide, metal carbonates such as cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, bicarbonate Inorganic bases such as metal bicarbonates such as lithium can be mentioned, and cesium carbonate and potassium carbonate are preferred.
  • the amount of the base is usually 0.5 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of the compound [HI].
  • 4-Chlorophenol can be used in place of 4-chlorophenol and a base, which is prepared by previously reacting 4-chlorophenol with the above-mentioned metal hydroxide.
  • the metal salt include a cesium salt, a potassium salt, a sodium salt, and a lithium salt, and a cesium salt and a potassium salt are preferable.
  • the catalyst examples include a compound containing a transition metal, an amino acid or a derivative thereof.
  • the compound containing a transition metal include compounds containing a transition metal such as rhodium, nickel, iron and copper, and a compound containing copper (0) or copper (I) is preferable.
  • Compounds containing copper (I) include copper (I) halides (eg, copper chloride (I), copper bromide (I), copper iodide (I), etc.), oxides, mineral salts (eg, , Sulfates, nitrates, phosphates, carbonates, etc.), organic acid salts, complexes of copper (0) and copper (I), etc., but copper iodide (I) and copper chloride (I) are Particularly preferred.
  • the amount of the catalyst is usually 0.001 to 0.5 mol, preferably 0.01 to 0.1 mol, relative to 1 mol of the compound [III].
  • amino acids and derivatives thereof include glycine, N-methylglycine, N, N-dimethylglycine, alanine, phenylalanine and the like can be mentioned, and N, N-dimethyldaricin is preferable.
  • the amount of the amino acid and its derivative is usually from 0.001 to 0.5 mol, preferably from 0.005 to 0.1 mol, per 1 mol of the compound [III].
  • the amount of monophenol is usually 1 to 5 mol, preferably 1 to L. 5 mol, per 1 mol of compound [II].
  • reaction solvent examples include ether solvents (eg, jetyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, diglyme, tetrahydrofuran, etc.); amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetylamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, etc .; ketone solvents (eg, methylisoptylketone, methylethylketone, cyclohexanone, cyclopentanone, etc.); Nitrile solvents (eg, acetonitrile, propionitrile, etc.); alcohol solvents (eg, 1-propanol, 2-monopropanol, 1-butanol, 2-butanol, etc.); halogenated solvents (eg, methylene chloride, Chloroform, etc.); aromatic solvents (eg, Ene
  • the amount of the solvent is usually 1 to: 100 L, preferably 3 to 30 L, relative to 1 kg of the compound [III].
  • the reaction temperature is usually 0 to 200 ° C., preferably 50 to 150 ° C. While the reaction time depends on the reaction temperature, the amount of raw materials, etc., it is usually 0.5 to 48 hours, preferably 0.5 to 6 hours. If the reaction time is too long, the yield tends to decrease.
  • Compound [IV] can be isolated by post-treatment of the reaction solution by a conventional method (for example, neutralization, extraction, washing, drying, crystallization, etc.). After adding water to the reaction solution, it is washed with an organic solvent (for example, an alcohol such as methanol or ethanol, or a mixed solvent of the alcohol and tetrahydrofuran, tert-butylmethylether or toluene), and separated. Neutralize the resulting aqueous layer to PH 1-8, preferably pH 6-8, A method of isolating the product [IV] by crystallization is preferred.
  • a conventional method for example, neutralization, extraction, washing, drying, crystallization, etc.
  • Compound [IV] may be a tautomer of the formula [IV '] depending on conditions.
  • Compound [V] can be produced by intramolecular ring closure of compound [IV].
  • the intramolecular ring closure reaction in this step can be preferably carried out in a dehydrating solvent.
  • the dehydrating solvent include sulfuric acid, phosphoric acid, and polyphosphoric acid.
  • Polyphosphoric acid, especially polyphosphoric acid prepared from phosphoric acid and nitric pentoxide is preferred because of its adjustable viscosity.
  • the amount of phosphoric acid is usually 1 to: L 0 0 kg, preferably 3 to 30 kg, per 1 kg of compound [IV]
  • the amount of diphosphorus pentaoxide is usually 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound [IV].
  • the reaction temperature is usually from 20 to 25 ° C., preferably from 1 20 to 20 ° C.
  • the reaction time depends on the reaction temperature and the amount of raw materials, but is usually 10 to 48 hours, preferably 15 to 25 hours.
  • the compound [V] extracted by post-treatment of the reaction solution by a conventional method for example, neutralization, extraction, purification, drying, concentration, etc.
  • the product may be used in the next step as it is.
  • Compound [VI] can be produced by reducing the carbon-carbon double bond of compound [V].
  • Examples of the reduction reaction in this step include a method of catalytic reduction in the presence of a noble metal catalyst such as platinum and palladium, and a method of reacting with an alkali metal or alkaline earth metal in a lower alcohol or ammonia.
  • a method of reacting with alkali metal or alkaline earth metal in lower alcohol or ammonia More preferred is a method of reacting with magnesium in a lower alcohol, a method of reacting with lithium or sodium in ammonia, and most preferred is a method of reacting with magnesium in methanol or ethanol.
  • the amount of the lower alcohol or ammonia is usually 4 to 100, preferably 5 to 30 L per 1 kg of the compound [V].
  • the amount of the alkali metal or alkaline earth metal is usually 2 to 25 mol, preferably 4 to 7 mol, per 1 mol of the compound [V].
  • the reaction temperature is usually 0-100 ° C, preferably 40-70 ° C.
  • the reaction time is usually 1 to 48 hours, preferably 4 to 10 hours, although it depends on the reaction temperature and the amount of raw materials.
  • Compound [V] can be purified by conventional post-treatment of the reaction solution (for example, neutralization, extraction, washing, drying, concentration, chromatography, etc.), and without any particular purification. The liquid can also be used in the next step as it is.
  • Compound [VII] can be produced by reducing the carbonyl group of compound [VI].
  • the reduction reaction in this step can be suitably carried out in the presence of a reducing agent.
  • the reducing agent include Li A 1 H 4 , NaA 1 H 2 (OCH 2 CH 2 OCH 3 ) 2 , L i A 1 H (t -BuO) 3 , A 1 H 3 , B 2 H 6 , BH 3 'THF, BH 3 * OE t 2, N'a BH 4, / BF 3 ⁇ THF, KBH down BF 3 ⁇ THF, L i BH 4 / BF 3 ⁇ TH F, Na BH 4 Z (CH 3) 2 S0 4 , And so on.
  • the amount of the reducing agent is usually 1 to 5 mol per 1 mol of compound [VI].
  • the reaction solvent include ether solvents such as jetyl ether, tert-butyl methyl ether, 1,2-dimethoxyethane, diglyme, and tetrahydrofuran, and tetrahydrofuran is preferred.
  • the amount of the solvent is usually 1 to 100, preferably 3 to 30 L per 1 kg of the compound [VI].
  • the reaction temperature is usually from 80 to 100.
  • Compound [VII] can be purified by conventional post-treatment of the reaction solution (for example, neutralization, extraction, washing, drying, concentration, crystallization, chromatography, etc.). It is preferred to do both.
  • the extraction method is preferably an acid-base extraction method
  • the crystallization method is preferably a salt-forming crystallization method. After acid-base extraction first, It is more preferable to pray.
  • Acid-base extraction refers to crude compound [VII] converted from mineral acid (eg, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, etc.) or organic acid (eg, methanesulfonic acid, trichloromethanesulfonic acid, formic acid, acetic acid, etc.) ) And the resulting acidic aqueous solution of compound [VII] is washed with an organic solvent (for example, ethyl acetate, tert-butyl methyl ether, toluene, etc.), and then added to a neutral to basic base. If necessary, further extract, dry, concentrate, etc. and isolate.
  • mineral acid eg, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, etc.
  • organic acid eg, methanesulfonic acid, trichloromethanesulfonic acid, formic acid, acetic acid, etc.
  • an organic solvent for example,
  • the salt crystallization method is an organic solvent (for example, an alcohol solvent such as methanol or ethanol, a cane solvent such as acetone or methylisobutyl ketone, an aromatic hydrocarbon solvent such as benzene, toluene or xylene, N, Amide solvents such as N-dimethylformamide and 1-methylpyrrolidinone, i ⁇ ryl solvents such as acetonitrile and propionitol, halogenated solvents such as methylene chloride and blackform), water, and a mixture of two or more of these In the solvent of [VII] and a mineral acid (for example, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, etc.) or an organic acid (for example, methanesulfonic acid, p-toluenesulfonic acid, maleic acid
  • an organic solvent for example, methanesulfonic acid, p-toluenesul
  • Example 2 The compound obtained in Example 2 (compound [III]) (20.0 g, 89.6 mmo 1), 4 monochlorophenol (17.3 g, 1 34 mmo 1), cesium carbonate (59.3 g, 1 82mmo 1), copper iodide (I) (0.34 g, 1.9 mm o 1), N, N-dimethyldalysin hydrochloride (0.94 g, 6.7 mmo 1) and diglyme (190 m 1) After the mixture was heated in an nitrogen atmosphere at an internal temperature of 114 to 116 ° C. for 50 minutes, the disappearance of raw materials was confirmed by HP. The reaction mass was cooled to about 10 ° C, and water (190 ml) was gradually introduced.
  • Solution B concentration 20% to 70% for 20 minutes. 70% for 5 minutes.
  • asenapine useful as a pharmaceutical, a pharmacologically acceptable salt thereof, and a synthetic intermediate thereof can be efficiently and safely produced.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour la production d'un composé [VII] ou d'un sel acceptable du point de vue pharmacologique de celui-ci, lequel comprend les étapes consistant à faire réagir un composé [III] avec du 4-chlorophénol pour produire un composé [IV], à soumettre le composé [IV] à une réaction de cyclisation intramoléculaire pour produire un composé [V], à effectuer la réduction du composé [V] pour produire un composé [VI] et à effectuer la réduction d'un groupe carbonyle présent dans le composé [VI] pour produire le composé [VII] souhaité. L'invention concerne également un intermédiaire pour la production du composé [VII]. L'invention concerne également un procédé pour la production de l'intermédiaire.
PCT/JP2006/321452 2005-10-21 2006-10-20 Procédé pour la production d'un composé de dibenzoxépinopyrrole, intermédiaire pour la production du composé et procédé pour la production de l'intermédiaire Ceased WO2007046554A1 (fr)

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JP2005307588 2005-10-21
JP2005-307588 2005-10-21

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WO2007046554A1 true WO2007046554A1 (fr) 2007-04-26

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PCT/JP2006/321452 Ceased WO2007046554A1 (fr) 2005-10-21 2006-10-20 Procédé pour la production d'un composé de dibenzoxépinopyrrole, intermédiaire pour la production du composé et procédé pour la production de l'intermédiaire

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008081010A1 (fr) * 2007-01-05 2008-07-10 Synthon B.V. Procede de fabrication d'asenapine
WO2009087058A1 (fr) * 2008-01-04 2009-07-16 N.V. Organon Procédé de préparation d'asénapine et produits intermédiaires utilisés dans ledit procédé
CN101851242A (zh) * 2010-05-25 2010-10-06 上海皓元生物医药科技有限公司 阿塞那平中间体的制备方法
WO2012038975A3 (fr) * 2010-09-22 2012-05-18 Msn Laboratories Limited Procédé de préparation de maléate de (3ars,12brs)-5-chloro-2-méthyl- 2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole et composition pharmaceutique le contenant
EP2468751A3 (fr) * 2010-12-24 2012-08-01 Medichem, S.A. Processus de préparation de 5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1H-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole
CN103254201A (zh) * 2012-02-21 2013-08-21 四川科伦药物研究有限公司 一种阿塞那平的制备方法
CN103351393A (zh) * 2013-07-03 2013-10-16 华裕(无锡)制药有限公司 用于制备阿森那平之还原剂及阿森那平之制备方法
CN103760280A (zh) * 2014-01-10 2014-04-30 万特制药(海南)有限公司 一种用液相色谱法分离测定阿塞那平中间体有关物质的方法
JP2014513117A (ja) * 2011-05-02 2014-05-29 オロン ソシエタ ペル アチオニ アセナピンの結晶塩
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008081010A1 (fr) * 2007-01-05 2008-07-10 Synthon B.V. Procede de fabrication d'asenapine
WO2009087058A1 (fr) * 2008-01-04 2009-07-16 N.V. Organon Procédé de préparation d'asénapine et produits intermédiaires utilisés dans ledit procédé
US7964739B2 (en) 2008-01-04 2011-06-21 N.V. Organon Process for the preparation of asenapine and intermediate products used in said process
CN101851242A (zh) * 2010-05-25 2010-10-06 上海皓元生物医药科技有限公司 阿塞那平中间体的制备方法
WO2012038975A3 (fr) * 2010-09-22 2012-05-18 Msn Laboratories Limited Procédé de préparation de maléate de (3ars,12brs)-5-chloro-2-méthyl- 2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole et composition pharmaceutique le contenant
EP2468751A3 (fr) * 2010-12-24 2012-08-01 Medichem, S.A. Processus de préparation de 5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1H-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole
JP2014513117A (ja) * 2011-05-02 2014-05-29 オロン ソシエタ ペル アチオニ アセナピンの結晶塩
CN103254201A (zh) * 2012-02-21 2013-08-21 四川科伦药物研究有限公司 一种阿塞那平的制备方法
CN103254201B (zh) * 2012-02-21 2016-04-13 四川科伦药物研究有限公司 一种阿塞那平的制备方法
CN103351393B (zh) * 2013-07-03 2016-04-06 华裕(无锡)制药有限公司 用于制备阿森那平之还原剂及阿森那平之制备方法
CN103351393A (zh) * 2013-07-03 2013-10-16 华裕(无锡)制药有限公司 用于制备阿森那平之还原剂及阿森那平之制备方法
CN103760280A (zh) * 2014-01-10 2014-04-30 万特制药(海南)有限公司 一种用液相色谱法分离测定阿塞那平中间体有关物质的方法
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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