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WO2006051079A1 - Procede de preparation d'hydrochlorure d'itopride - Google Patents

Procede de preparation d'hydrochlorure d'itopride Download PDF

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Publication number
WO2006051079A1
WO2006051079A1 PCT/EP2005/055839 EP2005055839W WO2006051079A1 WO 2006051079 A1 WO2006051079 A1 WO 2006051079A1 EP 2005055839 W EP2005055839 W EP 2005055839W WO 2006051079 A1 WO2006051079 A1 WO 2006051079A1
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WO
WIPO (PCT)
Prior art keywords
dimethylaminoethoxy
itopride
hydrochloride
benzylamine
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2005/055839
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English (en)
Inventor
Massimo Ferrari
Matteo Bonaldi
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Erregierre SpA
Original Assignee
Erregierre SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Erregierre SpA filed Critical Erregierre SpA
Publication of WO2006051079A1 publication Critical patent/WO2006051079A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms

Definitions

  • the present invention relates to a process for preparing itopride hydrochloride.
  • Itopride hydrochloride characterized by the following formula
  • This process has a drawback caused by the use, in the reducing step of the oxime to the corresponding amine, of hydrogen, in other words a highly explosive gas and moreover at high pressure (50 kg/cm 2 ) for which expensive equipment (autoclaves and hydrogen lines) must be used.
  • the process of the present invention differs mainly for the use in reducing step of 4-(2-dimethylaminoethoxy)-benzaldoxime to 4-(2- dimethylaminoethoxy)-benzylamine of powdered Zinc as reducing agent.
  • e) salifying itopride with hydrochloric acid to obtain itopride hydrochloride is characterized in that in the reducing step (c) of 4-(2-dimethylaminoethoxy)- benzaldoxime hydrochloride to 4-(2-dimethylaminoethoxy)-benzylamine powdered Zinc is used as reducing agent.
  • the reducing reaction is preferably carried out in an acidic aqueous solution of an organic acid, preferably concentrated acetic acid, more preferably 80% in weight. According to a particularly preferred solution, the reducing reaction (c) is carried out directly on the reaction mixture obtained from step (b) and not on the previously isolated benzaldoxime.
  • EP306827 where the reducing reaction is carried out on the previously isolated benzaldoxime.
  • 4-(2-dimethylaminoethoxy)-benzylamine obtained from reducing reaction (c) is salified with hydrochloric acid to obtain the corresponding dihydrochloride salt.
  • the benzylamine is isolated from the impurities and by-products obtained in the reducing reaction, to obtain an HPLC purity higher than 98%.
  • the itopride in step (d) is obtained with high purity; therefore, not only is it no longer necessary to purify it through crystallization prior to salification, but wet itopride separated by means of simple centrifugation of the reaction mixture obtained from step (d) of the process of the invention, is actually used as starting reactant during salification step (c).
  • Another preferred embodiment of the process forming the subject of the present invention is based on the fact that in the salification reaction of itopride, to obtain the corresponding itopride hydrochloride, concentrated aqueous hydrochloric acid (37%) in an alcohol solvent, preferably sec-butanol, is used instead of gaseous hydrochloric acid dissolved in an alcohol solvent.
  • an alcohol solvent preferably sec-butanol
  • a further subject of the present invention is a salification process of itopride with hydrochloric acid characterized in that concentrated aqueous hydrochloric acid is used in an alcohol solution, in which the alcohol is preferably sec-butanol.
  • Step (a) is preferably carried out in phase transfer in the presence of a catalyst consisting of a quaternary ammonium salt.
  • step (a) a mixture of ethyl acetate, toluene and water is used as the solvent and the quaternary ammonium salt is tetrabutylammonium bromide.
  • EXAMPLE 1 Preparation of 4-(2-dimethylaminoethoxy)benzaldehyde 17.5 kg of 2-dimethylaminoethylchloride hydrochloride, 75 kg of deionized water and 2.50 kg of toluene are charged into a batch, 17.5 kg of 30% sodium hydroxide are then dropped into. The mixture obtained is kept under stirring until complete solution of the solid. The aqueous phase is removed while the organic phase is used for the following preparation.
  • This mixture is kept under stirring at 45-50°C for at least 5 hours, and then heated to 65-70°C for at least 2 hours. Upon completion of the reaction, the reaction mixture is distilled to obtain a dense but stirrable residue.
  • EXAMPLE 3 Preparation of 4-(2-dimethylaminoethoxy)benzylamine dihydrochloride 1 1.5 kg of 4-(2-dimethylaminoethoxy)-benzylamine dissolved in sec-butanol and DMF obtained as described in the previous example are charged into a reactor and 12.7 kg of 37% hydrochloric acid are added dropwise. The pH is checked to ensure it is ⁇ 1.0 and the precipitated mixture is stirred at 45-50°C for at least 30 minutes. The mixture is cooled to 0-5°C, centrifuged and the precipitate washed with 1 1.5 kg of sec-butanol. It is dried under vacuum at 70-80°C.
  • reaction mixture After adding the reaction mixture dropwise, the reaction mixture thus obtained is stirred at 75-80°C for at least two hours.
  • 40.5 kg of deionized water are added, 1 1.5 kg of 30% ammonia are added dropwise and the reaction mixture is taken to 55-60°C until complete solution.
  • the aqueous phase is separated and removed.
  • 27.0 kg of deionized water are added and the mixture is cooled to 40-45 °C until obtaining a good degree of precipitation.
  • the mixture is then centrifuged, the precipitate is washed with 10.1 kg of deionized water and the same quantity of toluene.
  • a sample of product is taken and the loss of weight determined; this analysis shows that the wet product contains 16 kg of dry itopride.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation d'hydrochlorure d'itopride consistant: a) à faire réagir du 4-hydroxybenzaldéhyde avec du 2-diméthylaminoéthyl chlorure en présence d'une base inorganique faible, de manière à obtenir du 4-(2-diméthylaminoéthoxy)- benzaldéhyde, b) à faire réagir le 4-(2-diméthylaminoéthoxy)-benzaldéhyde avec de l'hydrochlorure d'hydroxylamine dans un environnement acide, afin d'obtenir du 4-(2-diméthylaminoéthoxy)- benzaldoxime hydrochlorure, c) à réduire le 4-(2-diméthylaminoéthoxy)-benzaldoxime hydrochlorure en présence d'un agent réducteur en 4-(2-diméthylaminoéthoxy)-benzylamine, d) à faire réagir la 4-(2-diméthylaminoéthoxy)-benzylamine avec du chlorure d'acide vératique en présence d'une amine tertiaire, de manière à obtenir de l'itopride, e) à salifier l'itopride avec de l'acide hydrochlorique, de manière à obtenir de l'hydrochlorure d'itopride, caractérisé en ce que l'agent réducteur employé à l'étape (c) est du zinc en poudre.
PCT/EP2005/055839 2004-11-12 2005-11-09 Procede de preparation d'hydrochlorure d'itopride Ceased WO2006051079A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI20042168 ITMI20042168A1 (it) 2004-11-12 2004-11-12 Processo di preparazione di itopride cloridrato
ITMI2004A002168 2004-11-12

Publications (1)

Publication Number Publication Date
WO2006051079A1 true WO2006051079A1 (fr) 2006-05-18

Family

ID=35840312

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/055839 Ceased WO2006051079A1 (fr) 2004-11-12 2005-11-09 Procede de preparation d'hydrochlorure d'itopride

Country Status (2)

Country Link
IT (1) ITMI20042168A1 (fr)
WO (1) WO2006051079A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101000362B1 (ko) 2008-07-22 2010-12-13 하나제약 주식회사 이토프라이드의 새로운 제조방법
CN103351305A (zh) * 2013-05-24 2013-10-16 浙江金伯士药业有限公司 一种4-(2-二甲氨基乙氧基)苄胺的制备方法
KR101374939B1 (ko) 2013-10-18 2014-03-14 제일약품주식회사 이토프라이드 염산염 제조에 사용되는 신규 중간체염, 이의 제조방법 및 이를 이용한 이토프라이드 염산염의 제조방법
KR101508565B1 (ko) 2008-05-27 2015-04-03 이범찬 이토프라이드의 신규한 제조 방법 및 이로부터 얻은 신규의중간체 화합물
CN105985257A (zh) * 2015-10-13 2016-10-05 威海迪素制药有限公司 一种盐酸伊托必利的制备方法
CN106748821A (zh) * 2016-12-14 2017-05-31 安徽省诚联医药科技有限公司 4‑（2‑二甲氨基乙氧基）苄胺的制备方法
KR101819771B1 (ko) * 2013-01-10 2018-01-18 연세대학교 산학협력단 마이크로 플로우 리액터를 이용한 이토프라이드의 제조방법
CN111679029A (zh) * 2020-07-29 2020-09-18 珠海润都制药股份有限公司 一种盐酸伊托必利中对羟基苯甲醛的检测方法
CN113009003A (zh) * 2019-12-22 2021-06-22 珠海润都制药股份有限公司 一种盐酸伊托必利制剂中有关物质的检测方法
CN113720947A (zh) * 2021-10-18 2021-11-30 珠海润都制药股份有限公司 一种去甲基伊托必利亚硝胺的检测方法
CN117843518A (zh) * 2023-09-23 2024-04-09 迪嘉药业集团股份有限公司 一种盐酸伊托必利的制备方法及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306827A1 (fr) * 1987-09-05 1989-03-15 Hokuriku Pharmaceutical Co.,Ltd Amides, procédé pour leur préparation et composition pour l'activation des fonctions gastromotrices
EP0388188A1 (fr) * 1989-03-15 1990-09-19 Suntory Limited Dérivés de benzoxépine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306827A1 (fr) * 1987-09-05 1989-03-15 Hokuriku Pharmaceutical Co.,Ltd Amides, procédé pour leur préparation et composition pour l'activation des fonctions gastromotrices
EP0388188A1 (fr) * 1989-03-15 1990-09-19 Suntory Limited Dérivés de benzoxépine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JUN SAKAGUCHI ET AL: "Synthesis, Gastrointestinal Prokinetic Activity and Structure-Activity Relationships of Novel N-[[2-(Dialkylamino)ethoxy]benzyl]- benzamide Derivatives", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 40, no. 1, 1992, pages 202 - 211, XP002152593, ISSN: 0009-2363 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101508565B1 (ko) 2008-05-27 2015-04-03 이범찬 이토프라이드의 신규한 제조 방법 및 이로부터 얻은 신규의중간체 화합물
KR101000362B1 (ko) 2008-07-22 2010-12-13 하나제약 주식회사 이토프라이드의 새로운 제조방법
KR101819771B1 (ko) * 2013-01-10 2018-01-18 연세대학교 산학협력단 마이크로 플로우 리액터를 이용한 이토프라이드의 제조방법
CN103351305A (zh) * 2013-05-24 2013-10-16 浙江金伯士药业有限公司 一种4-(2-二甲氨基乙氧基)苄胺的制备方法
CN103351305B (zh) * 2013-05-24 2014-10-08 浙江金伯士药业有限公司 一种4-(2-二甲氨基乙氧基)苄胺的制备方法
KR101374939B1 (ko) 2013-10-18 2014-03-14 제일약품주식회사 이토프라이드 염산염 제조에 사용되는 신규 중간체염, 이의 제조방법 및 이를 이용한 이토프라이드 염산염의 제조방법
CN105985257B (zh) * 2015-10-13 2018-04-17 威海迪素制药有限公司 一种盐酸伊托必利的制备方法
CN105985257A (zh) * 2015-10-13 2016-10-05 威海迪素制药有限公司 一种盐酸伊托必利的制备方法
CN106748821A (zh) * 2016-12-14 2017-05-31 安徽省诚联医药科技有限公司 4‑（2‑二甲氨基乙氧基）苄胺的制备方法
CN113009003A (zh) * 2019-12-22 2021-06-22 珠海润都制药股份有限公司 一种盐酸伊托必利制剂中有关物质的检测方法
CN111679029A (zh) * 2020-07-29 2020-09-18 珠海润都制药股份有限公司 一种盐酸伊托必利中对羟基苯甲醛的检测方法
CN113720947A (zh) * 2021-10-18 2021-11-30 珠海润都制药股份有限公司 一种去甲基伊托必利亚硝胺的检测方法
CN117843518A (zh) * 2023-09-23 2024-04-09 迪嘉药业集团股份有限公司 一种盐酸伊托必利的制备方法及其应用

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