WO2024109438A1 - Procédé de préparation de 10-méthoxyiminostilbène de faible impureté ayant une pureté élevée - Google Patents

Procédé de préparation de 10-méthoxyiminostilbène de faible impureté ayant une pureté élevée Download PDF

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Publication number
WO2024109438A1
WO2024109438A1 PCT/CN2023/127162 CN2023127162W WO2024109438A1 WO 2024109438 A1 WO2024109438 A1 WO 2024109438A1 CN 2023127162 W CN2023127162 W CN 2023127162W WO 2024109438 A1 WO2024109438 A1 WO 2024109438A1
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Prior art keywords
methoxyiminostilbene
solvent
compound
preparation process
base
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PCT/CN2023/127162
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English (en)
Chinese (zh)
Inventor
何函蒙
何晨勇
陈斌
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浙江华洋药业有限公司
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Publication of WO2024109438A1 publication Critical patent/WO2024109438A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines

Definitions

  • the present application relates to the field of pharmaceutical chemistry and chemical engineering technology, and in particular to a preparation process of high-purity and low-impurity 10-methoxyiminostilbene.
  • o-nitrotoluene is condensed with formate and strong base to obtain 2,2'-di(2-nitrophenyl)ethane, which is reduced and phosphorylated to obtain 2,2'-di(2-aminophenyl)ethane diphosphate, and then cyclized at 260-300°C to prepare 10,11-dihydro-5H-dibenzo[b,f]azepine, which is then chlorinated, brominated and eliminated to obtain 5-chloroformyl iminostilbene, which is then bromine added, methoxylated, formiated and hydrolyzed to prepare oxcarbazepine.
  • This method of preparing 10-methoxyiminostilbene from o-nitrotoluene is complicated, has high cyclization reaction temperature, low yield, low product purity, complicated purification, and large amount of three wastes, and is not suitable for industrial production.
  • Chinese patent documents CN101386595A and CN101423496A use 5-chloroformyl-10,11-dibromoiminodibenzyl or 10,11-dibromoiminodibenzyl as raw materials, react with potassium hydroxide or potassium methoxide methanol solution to prepare 10-methoxy-5H-dibenzo[b,f]azepine crude product, and obtain 10-methoxy-5H-dibenzo[b,f]azepine fine product after refining, and then prepare oxcarbazepine through chloroformylation reaction, amidation reaction, and hydrolysis reaction.
  • This method uses 5-chloroformyl-10,11-dibromoiminodibenzyl or 10,11-dibromoiminodibenzyl as raw materials, and has the disadvantages of high raw material prices and high costs.
  • the present application provides a preparation process of high-purity and low-impurity 10-methoxyiminostilbene.
  • the present application provides a preparation process of high-purity and low-impurity 10-methoxyiminostilbene, comprising the following steps:
  • the solvent A is one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene or chlorobenzene; and the mass ratio of the solvent A to 2-benzylaminophenylacetonitrile is (4-16):1.
  • the acid binding agent is an inorganic base or an organic base
  • the inorganic base is one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or calcium bicarbonate
  • the organic base is one of triethylamine, tripropylamine, triisopropylamine or tri-n-butylamine
  • the molar ratio of the acid binding agent to 2-benzylaminophenylacetonitrile is (1.0-1.5):1.
  • the 2-halogenated benzonitrile is one of 2-bromobenzonitrile and 2-chlorobenzonitrile; and the molar ratio of the 2-halogenated benzonitrile to 2-benzylaminophenylacetonitrile is (1.0-1.3):1.
  • step S1 the substitution reaction temperature is 90-110°C.
  • the solvent B is one of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, N,N-dimethylformamide or chlorobenzene; and the mass ratio of the solvent B to compound I is (4-12):1.
  • the base 1 is one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride; and the molar ratio of the base 1 to compound I is (1.0-1.5):1.
  • step S2 the intramolecular condensation reaction temperature is 30-90°C; the hydrolysis reaction temperature is 40-80°C.
  • step S2 the hydrochloric acid acidification is performed using hydrochloric acid with a mass concentration of 30-35% until the system pH is 2-2.5.
  • the solvent C is one of tetrahydrofuran, methanol, ethanol, N,N-dimethylformamide or toluene; and the mass ratio of the solvent C to compound II is (8-20):1.
  • the base 2 is one of potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide; and the molar ratio of the base 2 to compound II is (1.0-1.8):1.
  • the methylating agent is one of dimethyl carbonate, dimethyl sulfate, methyl bromide or methyl iodide; the molar ratio of the methylating agent to compound II is (1.5-2.2):1; and the methylation reaction temperature is 70-100°C.
  • the solvent D is one of tetrahydrofuran, methanol, ethanol or isopropanol; and the mass ratio of the solvent D to compound III is (5-12):1.
  • the hydrogenation catalyst is one of palladium carbon or Raney nickel; the mass of the palladium carbon catalyst is 1%-6% of the mass of compound III, and the mass of the Raney nickel catalyst is 10%-18% of the mass of compound III.
  • step S4 the catalytic hydrogenolysis reaction temperature is 30-60° C., and the hydrogen pressure is 0.2-0.4 MPa.
  • the present invention includes at least one of the following beneficial technical effects:
  • the obtained 10-methoxyiminostilbene has high purity and low impurities
  • the preparation process conditions are easy to achieve, the operation is simple and safe, the reaction conditions are mild, the process flow is short, and the post-processing is simple;
  • the raw materials used are cheap and easy to obtain, the cost is low, the amount of three wastes generated is small, and it is green and environmentally friendly.
  • the raw materials and equipment used in the present invention are conventional raw materials and equipment (conventional commercial products) in the art and can be purchased on the market.
  • the present application designs a preparation process of high-purity and low-impurity 10-methoxyiminostilbene, comprising the following steps:
  • the 10-methoxyiminostilbene prepared by the preparation process has high purity and low impurities; the preparation process conditions are easy to achieve, the operation is simple and safe, the reaction conditions are mild, the process flow is short, and the post-treatment is simple.
  • the layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane.
  • the aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 18.1 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 90.7% and a liquid phase purity of 99.4%.
  • the layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane.
  • the aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 13.8 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 91.8% and a liquid phase purity of 99.5%.
  • the layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane.
  • the resulting aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 10.9 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 91.5% and a liquid phase purity of 99.5%.
  • the layers were separated, and the aqueous layer was washed once with 20 g of dichloromethane.
  • the aqueous phase was acidified with 35 wt% hydrochloric acid to a pH value of 2.0-2.5, filtered, and dried to obtain 8.93 g of 5-benzyl-10-oxa-10,11-dihydro-5H-dibenzo[b,f]azepine with a yield of 90.8% and a liquid purity of 99.4%.
  • the obtained 10-methoxyiminostilbene has a high purity, with a liquid phase purity of more than 99.3%.
  • the purity of the obtained 10-methoxyiminostilbene using the preparation process described in Example 3 is slightly higher than that of other examples.
  • the embodiments of the present application are simple and safe to operate, with mild reaction conditions and more selectivity. Most of the solvents and palladium-carbon catalysts can be recycled, the raw materials are cheap and easy to obtain, the cost is low, the amount of three wastes generated is small, and it is green and environmentally friendly, and suitable for industrial production.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente demande concerne un procédé de préparation de 10-méthoxyiminostilbène de faible impureté ayant une pureté élevée, comprenant les étapes suivantes : S1, qui consiste à ajouter du cyanure de 2-aminobenzyle, un agent de liaison acide et du benzonitrile 2-halogéné dans un solvant A, et à effectuer une réaction de substitution pour préparer un composé I ; S2, qui consiste à effectuer, dans un solvant B, sous l'action de l'alcali 1, une réaction de condensation intramoléculaire sur le composé I, et à effectuer une réaction d'hydrolyse et une acidification de l'acide chlorhydrique pour obtenir un composé II ; S3, qui consiste à effectuer, dans un solvant C, sous l'action de l'alcali 2, une réaction de méthylation sur le composé II et un réactif de méthylation pour obtenir un composé III ; et S4, qui consiste à effectuer, dans un solvant D, sous l'action d'un catalyseur d'hydrogénation, une réaction d'hydrogénolyse catalytique sur le composé III afin d'obtenir du 10-méthoxyiminostilbène. Le 10-méthoxyiminostilbène préparé par le procédé de préparation selon la présente demande a une pureté élevée et une faible impureté ; les conditions du procédé de préparation sont faciles à mettre en œuvre, le mode opératoire est simple, pratique et sûr, les conditions de réaction sont modérées, le flux de traitement est court, et le post-traitement est simple ; les matières premières utilisées sont bon marché et facilement disponibles, et le coût est faible.
PCT/CN2023/127162 2022-11-23 2023-10-27 Procédé de préparation de 10-méthoxyiminostilbène de faible impureté ayant une pureté élevée WO2024109438A1 (fr)

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CN202211473593.4A CN115650918A (zh) 2022-11-23 2022-11-23 一种高纯度低杂质10-甲氧基亚氨基芪的制备工艺
CN202211473593.4 2022-11-23

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115650918A (zh) * 2022-11-23 2023-01-31 浙江华洋药业有限公司 一种高纯度低杂质10-甲氧基亚氨基芪的制备工艺
CN116354884B (zh) * 2023-03-02 2024-05-10 浙江华洋药业有限公司 一种高纯度10-甲氧基亚氨基芪及其高收率的制备方法

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GB943277A (en) * 1959-11-16 1963-12-04 Geigy Ag J R Dibenz[b,f]azepines and process for their preparation
WO2007141798A1 (fr) * 2006-06-07 2007-12-13 Jubilant Organosys Limited Procédé de production d'oxcarbazépine via un intermédiaire 11-alcoxy-10-halogéno-dihydroiminostilbène
US20080269480A1 (en) * 2004-03-11 2008-10-30 Mandakini Muthukumaran Process for the Preparation of 10,11-Dihydro-10-Oxo-5H-Dibenz[B,F] Azepine-5-Carboxamide
CN101423496A (zh) * 2008-12-02 2009-05-06 浙江九洲药业股份有限公司 10-甲氧基-5H-二苯并[b,f]氮杂卓的化学合成方法
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CN110563652A (zh) * 2018-06-06 2019-12-13 新发药业有限公司 一种中间体化合物、卡马西平及其衍生物及奥卡西平及其衍生物的制备方法
CN114957122A (zh) * 2022-05-14 2022-08-30 浙江华洋药业有限公司 一种10-甲氧基亚氨基芪的制备方法
CN115304547A (zh) * 2022-08-16 2022-11-08 山东金吉利新材料有限公司 一种10-甲氧基亚氨基芪化合物的制备方法
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EP1678140A2 (fr) * 2003-10-20 2006-07-12 Amoli Organics Ltd. Nouveau procede de preparation de 10-oxo-10, 11-dihydro-5h-dibenz [b,f]azepine-5-carboxamide (oxcarbazepine) via le chlorure de 10-methoxy-5h-dibenz [b,f] azepine-5-carbonyle comme intermediaire
US20070032647A1 (en) * 2004-10-15 2007-02-08 Amoli Organics Ltd. Novel process for preparation of 10-oxo-10, 11-dihydro-5h-dibenz [b,f] azepine-5-carbox- amide (oxcarbazepine) via intermediate, 10-methoxy-5h-debenz[b,f] azepine-5-carbonyl- chloride

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB943277A (en) * 1959-11-16 1963-12-04 Geigy Ag J R Dibenz[b,f]azepines and process for their preparation
US20080269480A1 (en) * 2004-03-11 2008-10-30 Mandakini Muthukumaran Process for the Preparation of 10,11-Dihydro-10-Oxo-5H-Dibenz[B,F] Azepine-5-Carboxamide
WO2007141798A1 (fr) * 2006-06-07 2007-12-13 Jubilant Organosys Limited Procédé de production d'oxcarbazépine via un intermédiaire 11-alcoxy-10-halogéno-dihydroiminostilbène
CN101423496A (zh) * 2008-12-02 2009-05-06 浙江九洲药业股份有限公司 10-甲氧基-5H-二苯并[b,f]氮杂卓的化学合成方法
CN102807528A (zh) * 2012-08-07 2012-12-05 常州华生精细化工有限公司 10-甲氧基亚氨基芪的制备方法
CN106467491A (zh) * 2015-08-15 2017-03-01 浙江华洲药业有限公司 一种10-甲氧基-5H-二苯并[b,f]氮杂*的制备方法
CN110563652A (zh) * 2018-06-06 2019-12-13 新发药业有限公司 一种中间体化合物、卡马西平及其衍生物及奥卡西平及其衍生物的制备方法
CN114957122A (zh) * 2022-05-14 2022-08-30 浙江华洋药业有限公司 一种10-甲氧基亚氨基芪的制备方法
CN115304547A (zh) * 2022-08-16 2022-11-08 山东金吉利新材料有限公司 一种10-甲氧基亚氨基芪化合物的制备方法
CN115650918A (zh) * 2022-11-23 2023-01-31 浙江华洋药业有限公司 一种高纯度低杂质10-甲氧基亚氨基芪的制备工艺

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