WO2008078482A1 - Procédé de fabrication d'un intermédiaire de synthèse de l'asénapine - Google Patents

Procédé de fabrication d'un intermédiaire de synthèse de l'asénapine Download PDF

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Publication number
WO2008078482A1
WO2008078482A1 PCT/JP2007/072601 JP2007072601W WO2008078482A1 WO 2008078482 A1 WO2008078482 A1 WO 2008078482A1 JP 2007072601 W JP2007072601 W JP 2007072601W WO 2008078482 A1 WO2008078482 A1 WO 2008078482A1
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formula
compound
mol
compound represented
reaction
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PCT/JP2007/072601
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English (en)
Japanese (ja)
Inventor
Osamu Tokuda
Weiqi Wang
Tetsuya Ikemoto
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Sumitomo Chemical Company, Limited
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Publication of WO2008078482A1 publication Critical patent/WO2008078482A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form

Definitions

  • the present invention relates to a novel process for producing a synthetic intermediate of asenapine (A sena pine) useful as a schizophrenia drug.
  • Patent Document 1 describes a method for producing asenapine [IX] by the following reaction route.
  • Patent Document 1 International Publication 2006/1 06 1 36 Panfret Invention Disclosure
  • the object of the present invention is to use an inexpensive raw material to efficiently produce a synthesis intermediate of isenapine. Another object is to provide a method for manufacturing at low cost.
  • Patent Document 1 it was found that if 2-chlorophenylacetic acid, which can be obtained at low cost, is used instead of 2-bromophenylacetic acid ', the reaction proceeds unexpectedly well. Furthermore, as shown in the following reaction route, a compound which is an intermediate of asenapine, which is useful as a pharmaceutical, starting from 2-chlorodiphenylacetic acid (compound [I]) and 4-croxenphenol, which can be obtained at low cost, as starting materials. IV] can be manufactured.
  • R means an alkyl group having 1 to 6 carbon atoms.
  • R represents an alkyl group having 1 to 6 carbon atoms
  • R represents an alkyl group having 1 to 6 carbon atoms
  • a synthetic intermediate of isenapine can be produced by the reaction route.
  • each process will be described.
  • Compound [II] can be produced by reacting compound [I] with 4-chlorophenol. This reaction is preferably performed in the presence of a catalyst. However, the reaction between 4-chlorophenyl acetate and 4-chlorophenol does not proceed very much, and the substitution reaction proceeds only when the black mouth group is at the 2-position.
  • a base may not necessarily be added, but a base (for example, triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylpropylamine, N-methylmorpholine, pyridine, 2, 6-dione) tert Organic bases such as monobutylpyridine, imidazole, 1-methylimidazole, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium hydrogen carbonate Inorganic bases such as lithium hydrogen carbonate) may be added.
  • a base for example, triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylpropylamine, N-methylmorpholine, pyridine, 2, 6-dione
  • Organic bases such as monobutylpyridine, imidazole, 1-methylimidazole, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbon
  • the amount used is generally 1 mol-5 mol, preferably 1.2 mol-2.5 mol, per 1 mol of compound [I].
  • the base can also serve as a solvent.
  • the solvent include ester solvents (for example, ethyl acetate, propyl acetate, butyl acetate, ethyl ethyl pionate, propyl propionate, butyl propionate, etc.), ether solvents (for example, jetyl ether, tert-butyl).
  • Methyl ether diglyme (eg, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, diethylene glycol jetyl ether), 1,2-dimethylmethetane, tetrahydrofuran, etc.), amide solvent (eg, N, N-dimethylformamide, N, N.—Dimethylacetamide, N—Methylpyrrolidone, 1,3-Dimethyl-2-imidazolidinone, etc., Ketone solvent (eg, methylisobutyl ketone, methyl edyl ketone, cyclohexanone, cyclone) mouth Nitrile solvents (eg, acetonitrile, propiononitrile), alcohol solvents (eg, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.), halogen And a solvent such as methylene chloride, chloroform, etc., aromatic solvent
  • a 4-groxy phenoxy metal salt prepared by previously reacting 4-chlorophenol with the above-mentioned base can also be used.
  • the metal salt include a cesium salt, a potassium salt, a sodium salt, a lithium salt, and the like, and a cesium salt and a potassium salt are preferable.
  • the amount of 4-chlorophenol (or its metal salt) to be used is generally 1 mol-10 mol, preferably 1 mol-2 mol, per 1 mol of compound [I].
  • the catalyst used in the present invention include a compound containing a transition metal, an amino acid, or a derivative thereof.
  • Examples of 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.)
  • the halide of is particularly preferred.
  • the amount of the catalyst to be used is generally 0.01 mol to 0.5 mol, preferably 0.02 mol to 0.1 mol, per 1 mol of compound [I].
  • Examples of amino acids or derivatives thereof include glycine, N-methyldaricin, N, N-dimethyldaricin, alanine, and phenylalanine, and N-methylglycine is preferable.
  • the amount of the amino acid or derivative thereof to be used is generally 0.005 mol to 0.5 mol, preferably 0.001 mol to 0.1 mol, per 1 mol of compound [I].
  • the amount of 4-chlorophenol used is usually 1 mol to 2 mol, preferably 1 mol to 1.5 mol, per 1 mol of compound [I].
  • the reaction temperature is usually 80 to ⁇ 180T: preferably 120 to ⁇ 60. While the reaction time depends on the reaction temperature, the amount of raw materials used, etc., it is generally 1 hour to 24 hours, preferably 3 hours to 12 hours. Yield tends to decrease with increasing reaction time. There are no particular restrictions on the order of the compound [I], 4-chlorophenol (or its metal salt), base, and catalyst. 'The compound [II] produced in this way may be isolated, but can be used in the next step without isolation.
  • the method of producing compound [IV] by condensing compound [II] and compound [III] is carried out by reacting compound [II] or a reactive derivative at its carboxyl group with compound [III]. Can do.
  • the alkyl group having 1 to 6 carbon atoms represented by the symbol R may be linear or branched, and is preferably a methyl group or an ethyl group.
  • the reaction between compound [I I] and compound [I I I] is preferably carried out in the presence of a condensing agent.
  • the amount of compound [I I I] to be used is generally 1 mol to 2 mol, preferably 1 mol to 1.5 mol, per 1 mol of compound [I I].
  • condensing agent examples include calpositimide condensing agents (for example, N, N'-dicyclohexyl carpositimide (DCC), N- (3-jetylamino-1-propyl) -N'-ethyl carpositimide hydrochloride ( WS CI ⁇ HC 1)), pentavalent organic phosphorus condensing agents (eg diphenylphosphoryl azide (DPPA), cyanoethyl jetyl (DEPC), N, N '—bis (2-oxo-3— Oxazolidinyl) phosphinic chloride (BOP— C 1), etc., black mouth carbonic acid esters (eg, black mouth methyl carbonate, black mouth carbonic acid ester, black mouth carbonic acid isopropyl, etc.), pivaloyl chloride mouth lid, Examples include thionyl chloride and phosphorus oxychloride.
  • DCC N, N'-dicyclohexyl carpositimide
  • the amount of the condensing agent to be used is generally 1 mol-2 mol, preferably 1 mol-1.5 mol, per 1 mol of compound [II].
  • a base for example, tridylamine, tri-n-propylamine, tri-n-butylamine, diisopropylpropylamine, N-methylmorpholine, pyridine, 2,6-di-tert
  • Organic bases such as monobutylpyridine, imidazole, 1-methylimidazole, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium hydrogen carbonate Or an inorganic base such as lithium hydrogen carbonate) may be added.
  • the amount used is generally 1 mol to 10 mol, preferably 1 mol to 5 mol, per 1 mol of compound [II].
  • the solvent 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) Diglyme (eg, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, diethylene glycol jetyl ), 1,2-dimethoxetane, tetrahydrofuran, etc.), amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3— Dimethyl-1,2-imidazolidinone, etc.), ketone solvents (eg, methylis
  • halogenating agent examples include thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride, thionyl bromide, phosphorus tribromide, and thionyl chloride is preferable.
  • the amount of thionyl chloride used is usually 1 mol to 2 mol, preferably 1 mol to 1.5 mol, per 1 mol of compound [II]. Solvents are not necessarily used.
  • Solvents such as halogenated solvents (eg, methylene chloride, black mouth form) and aromatic solvents (eg, benzene, toluene, xylene, black mouth benzene, nitrobenzene) are used. It may be used and is preferably toluene.
  • the amount of the solvent to be used is generally 1 L-50 L, preferably 2 L-20 L, per 1 kg of compound [II].
  • the amount of compound [III] used is usually 1 to 2 mol, preferably 1 mol, per 1 mol of compound [II]. ⁇ 1.5 moles.
  • This reaction is preferably carried out in the presence of a base when an acid halide is used as the reactive derivative.
  • a base include triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-di-tert-butylpyridine, imidazole, and 1-methylimidazole.
  • Organic bases such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate, etc.
  • sodium bicarbonate is preferable.
  • the amount of the base group to be used is generally 1 mol to 10 mol, preferably 1 mol to 5 mol, per 1 mol of compound [II].
  • the base can also serve as a solvent.
  • the solvent include ester solvents (eg, ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, propyl propionate, butyl propionate), ether solvents (eg, jetyl ether, tert-butyl methyl ether, diglyme) (Eg, diethylene glycol dimethyl ether, diethylene glycol dibutyl ether, diethylene glycol jetyl ether), 1,2-dimethoxetane, tetrahydrofuran, etc.), amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamine) , N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone
  • the compound [IV] can be purified by post-treatment of the reaction solution by a conventional method (for example, neutralization, extraction, washing, drying, concentration, chromatography, etc.). Can be used.
  • the compound [IV] obtained by the method of the present invention is converted into a compound [V], [VI], [VII] as shown in the following scheme by the method described in International Publication No. 2006Z1 0 6 1 36 pamphlet. , [VIII] via isenapine (trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1H-dibenzo [2,3: 6,7] oxepino [4, 5-c] Pillar).
  • 2-Black mouth phenylacetic acid [I] (l. O g, 5.9 mmo 1), 4-Black mouth phenol (0.78 g, 6.5 mmo 1), Cesium carbonate (3.8 g, 1 1. 7 mm o 1), copper bromide (I) (42 mg, 0.29 mm o 1), and ethylene glycol dimethyl ether (5 m 1) were mixed and heated at 145 for 8 hours. After cooling, water (15 ml) was poured into the reaction mass, acidified with concentrated hydrochloric acid (about 2 g), and extracted with toluene (20 ml X 2).
  • the toluene layer was washed with water (20 ml) and saturated brine (20 ml), dehydrated with anhydrous magnesium sulfate, and then magnesium sulfate was removed by filtration to obtain a toluene solution of [II] (the sample was used). Quantitative yield 59%). After concentration for partial spectral data, purification was performed by silica gel column chromatography to obtain compound [II]. In place of cesium carbonate, potassium carbonate (1.6 g, 11.7 mmol) was used as described above. The yield was 62% under the same conditions, and the reaction was carried out under the same conditions as above using copper chloride (I) (29 mg, 0.29 mm o 1) instead of copper bromide (I).
  • the toluene layer was washed with water (30 m 1 X 2) and saturated brine (30 ml), dehydrated with anhydrous magnesium sulfate, and then magnesium sulfate was removed by filtration to obtain a toluene solution of compound [I I]. This solution was used as such for the next step. After concentration for partial spectral data, purification by silica gel column chromatography yielded compound [I I].
  • N, N-dimethylformamide (0.5 ml) was added to the toluene solution of the compound [II] obtained in Example (1-13) above, and then the temperature was maintained at 50 to 65, while chlorinated. Thionyl (8.4 g, 70.3 mmo 1) was added dropwise over about 30 minutes. The reaction was further carried out at 50 to 65 for 2 hours after the completion of the dropwise addition. After cooling, toluene (about 25 ml) was distilled off under reduced pressure to obtain a toluene solution of compound [II] in acid chloride.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne un procédé de fabrication de l'acide 2-(2-(4-chlorophénoxy)phényl)acétique [II] par la réaction de l'acide 2-chlorophénylacétique [I] avec du 4-chlorophénol.
PCT/JP2007/072601 2006-12-22 2007-11-15 Procédé de fabrication d'un intermédiaire de synthèse de l'asénapine WO2008078482A1 (fr)

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JP2006346735 2006-12-22
JP2006-346735 2006-12-22

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012038975A2 (fr) * 2010-09-22 2012-03-29 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
CN103760258A (zh) * 2014-01-07 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马来酸阿塞那平有关物质的方法
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101851242B (zh) * 2010-05-25 2013-07-24 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
CN102746209A (zh) * 2012-06-20 2012-10-24 盛世泰科生物医药技术(苏州)有限公司 一种3-（2-（4-氯苯氧基）苯基）-1-甲基-2,4-二酮的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5775948A (en) * 1980-10-28 1982-05-12 Ihara Chem Ind Co Ltd Production of 2-(substituted phenoxy)phenylacetic acid
JPS5775947A (en) * 1980-10-28 1982-05-12 Ihara Chem Ind Co Ltd Production of 2-(substituted phenoxy)phenylacetic acid
WO2006106136A1 (fr) * 2005-04-07 2006-10-12 N.V. Organon Composés intermédiaires pour la synthèse du trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1h-dibenz[2,3:6,7]oxépino[4,5-c]pyrrole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5775948A (en) * 1980-10-28 1982-05-12 Ihara Chem Ind Co Ltd Production of 2-(substituted phenoxy)phenylacetic acid
JPS5775947A (en) * 1980-10-28 1982-05-12 Ihara Chem Ind Co Ltd Production of 2-(substituted phenoxy)phenylacetic acid
WO2006106136A1 (fr) * 2005-04-07 2006-10-12 N.V. Organon Composés intermédiaires pour la synthèse du trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1h-dibenz[2,3:6,7]oxépino[4,5-c]pyrrole

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012038975A2 (fr) * 2010-09-22 2012-03-29 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
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
CN103760258A (zh) * 2014-01-07 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马来酸阿塞那平有关物质的方法
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
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

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CN101563312A (zh) 2009-10-21
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