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WO2003106440A3 - PROCESS FOR THE SYNTHESIS OF A BENZAMIDE DERIVATIVE - Google Patents

PROCESS FOR THE SYNTHESIS OF A BENZAMIDE DERIVATIVE Download PDF

Info

Publication number
WO2003106440A3
WO2003106440A3 PCT/HU2003/000042 HU0300042W WO03106440A3 WO 2003106440 A3 WO2003106440 A3 WO 2003106440A3 HU 0300042 W HU0300042 W HU 0300042W WO 03106440 A3 WO03106440 A3 WO 03106440A3
Authority
WO
WIPO (PCT)
Prior art keywords
formula
represented
base
compound
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/HU2003/000042
Other languages
French (fr)
Other versions
WO2003106440A2 (en
Inventor
Krisztina Vukics
Janos Fischer
Sandor Levai
Peter Erdelyi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
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 Richter Gedeon Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Priority to AU2003242867A priority Critical patent/AU2003242867A1/en
Priority to EP03760090A priority patent/EP1515958A2/en
Publication of WO2003106440A2 publication Critical patent/WO2003106440A2/en
Publication of WO2003106440A3 publication Critical patent/WO2003106440A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Cette invention concerne un procédé de synthèse de citrate de mosapride représenté par la formule (I) et portant le nom chimique : dihydrate de citrate de (R,S)-4-amino-5-chloro-2-éthoxy-N-{[4-(4-fluoro-benzyl)-2-morpholinyl]-méthyl}benzamide. Le procédé de cette invention consiste à faire réagir le composé représenté par la formule (II) avec du di-tert-butyl-dicarbonate dans un alcool en présence d'une base ; à éthyler le produit obtenu dans un solvant inerte en présence d'une base ; puis à hydrolyser le composé obtenu avec un alkyl-hydroxyde et à neutraliser le sel obtenu avec un acide. Ce procédé consiste ensuite à chlorer le produit obtenu, puis à faire réagir le composé obtenu représenté par la formule (VI) avec le composé représenté par la formule (VII) dans laquelle BOC désigne un groupe protecteur de tert-butoxy-carbonyl ; et à retirer le groupe protecteur du composé obtenu représenté par la formule (VIII) dans laquelle BOC est tel que défini ci-dessus. Il s'agit ensuite de préparer la base mosapride, et éventuellement de produire, au moyen d'un acide et de préférence de l'acide citrique, un sel pharmaceutiquement acceptable, de préférence le dihydrate de citrate de mosapride représenté par la formule (I).This invention relates to a process for the synthesis of mosapride citrate represented by the formula (I) and having the chemical name: (R, S) -4-amino-5-chloro-2-ethoxy-N - {- citrate dihydrate 4- (4-fluoro-benzyl) -2-morpholinyl] methyl} benzamide. The method of this invention comprises reacting the compound represented by formula (II) with di-tert-butyl-dicarbonate in an alcohol in the presence of a base; ethylating the product obtained in an inert solvent in the presence of a base; then hydrolyzing the compound obtained with an alkyl hydroxide and neutralizing the salt obtained with an acid. This process then consists in chlorinating the product obtained, then reacting the compound obtained represented by formula (VI) with the compound represented by formula (VII) in which BOC denotes a protective group of tert-butoxy-carbonyl; and removing the protecting group from the compound obtained represented by the formula (VIII) in which BOC is as defined above. It is then a question of preparing the mosapride base, and optionally of producing, by means of an acid and preferably citric acid, a pharmaceutically acceptable salt, preferably the mosapride citrate dihydrate represented by the formula (I ).

PCT/HU2003/000042 2002-06-13 2003-06-12 Process for the synthesis of a benzamide derivative Ceased WO2003106440A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003242867A AU2003242867A1 (en) 2002-06-13 2003-06-12 Process for the synthesis of mosapride
EP03760090A EP1515958A2 (en) 2002-06-13 2003-06-12 Process for the synthesis of mosapride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0201980 2002-06-13
HU0201980A HUP0201980A3 (en) 2002-06-13 2002-06-13 Process for preparing a benzamide derivative and intermediates thereof

Publications (2)

Publication Number Publication Date
WO2003106440A2 WO2003106440A2 (en) 2003-12-24
WO2003106440A3 true WO2003106440A3 (en) 2004-06-17

Family

ID=89980512

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2003/000042 Ceased WO2003106440A2 (en) 2002-06-13 2003-06-12 Process for the synthesis of a benzamide derivative

Country Status (4)

Country Link
EP (1) EP1515958A2 (en)
AU (1) AU2003242867A1 (en)
HU (1) HUP0201980A3 (en)
WO (1) WO2003106440A2 (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100750593B1 (en) * 2006-03-16 2007-08-20 동우신테크 주식회사 Process for preparing substituted benzamide derivatives
JP2008247753A (en) * 2007-03-29 2008-10-16 Dainippon Sumitomo Pharma Co Ltd Process for producing 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide
KR100986734B1 (en) * 2008-03-21 2010-10-13 하나제약 주식회사 Method for producing intermediate for producing mosapride
WO2011107903A1 (en) 2010-03-04 2011-09-09 Ranbaxy Laboratories Limited Highly pure mosapride citrate dihydrate and processes for its preparation
CN105301118B (en) * 2014-07-02 2018-05-25 成都康弘药业集团股份有限公司 A kind of detection method of mosapride citrate in relation to substance
KR102275045B1 (en) * 2019-02-13 2021-07-08 한국바이오켐제약 주식회사 Methods for preparing mosapride citrate hydrate and pharmaceutical composition comprising the same
CN114671826B (en) * 2020-12-24 2025-07-15 鲁南制药集团股份有限公司 A kind of mosapride organic acid crystal

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243959A1 (en) * 1986-04-30 1987-11-04 Dainippon Pharmaceutical Co., Ltd. Substituted benzamide derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same
EP0640601A1 (en) * 1991-02-15 1995-03-01 Hokuriku Seiyaku Co., Ltd. Benzamide derivative
WO1996034851A1 (en) * 1995-05-03 1996-11-07 Abbott Laboratories Benzene, pyridine, naphtalene or benzophenone derivatives as inhibitors of squalene synthetase and protein farnesyltransferase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0243959A1 (en) * 1986-04-30 1987-11-04 Dainippon Pharmaceutical Co., Ltd. Substituted benzamide derivatives, processes for the preparation thereof, and pharmaceutical compositions containing the same
EP0640601A1 (en) * 1991-02-15 1995-03-01 Hokuriku Seiyaku Co., Ltd. Benzamide derivative
WO1996034851A1 (en) * 1995-05-03 1996-11-07 Abbott Laboratories Benzene, pyridine, naphtalene or benzophenone derivatives as inhibitors of squalene synthetase and protein farnesyltransferase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KATO S ET AL: "NOVEL BENZAMIDES AS SELECTIVE AND POTENT GASTROKINETIC AGENTS 2. SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF 4-AMINO-5-CHLORO-2-ETHOXY-N-4-(4-FLUOROBENZYL)-2-MORPHOLINYL METHYLBENZAMIDE CITRATE (AS-4370) AND RELATED COMPOUNDS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 34, no. 2, February 1991 (1991-02-01), pages 616 - 624, XP001037842, ISSN: 0022-2623 *

Also Published As

Publication number Publication date
WO2003106440A2 (en) 2003-12-24
AU2003242867A8 (en) 2003-12-31
HU0201980D0 (en) 2002-08-28
AU2003242867A1 (en) 2003-12-31
HUP0201980A3 (en) 2008-06-30
EP1515958A2 (en) 2005-03-23
HUP0201980A2 (en) 2004-03-01

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