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WO2006068386A1 - Procédé de synthèse d'un dérivé de phénylcarbamate - Google Patents

Procédé de synthèse d'un dérivé de phénylcarbamate Download PDF

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Publication number
WO2006068386A1
WO2006068386A1 PCT/KR2005/004364 KR2005004364W WO2006068386A1 WO 2006068386 A1 WO2006068386 A1 WO 2006068386A1 KR 2005004364 W KR2005004364 W KR 2005004364W WO 2006068386 A1 WO2006068386 A1 WO 2006068386A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
rivastigmine
hydrochloride
salt
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/KR2005/004364
Other languages
English (en)
Inventor
Kyung Hoi Cha
Dae Sung Lim
Han Won Lee
In Kyu Lee
Hyun Ki Paeng
Seun Soon Park
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.)
Dong Kook Pharmaceutical Co Ltd
Original Assignee
Dong Kook Pharmaceutical Co Ltd
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 Dong Kook Pharmaceutical Co Ltd filed Critical Dong Kook Pharmaceutical Co Ltd
Publication of WO2006068386A1 publication Critical patent/WO2006068386A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/08—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals

Definitions

  • Rivastigmine is a common name for (S)-N-ethyl-3-[(l-dimethylamino)ethyl]-N -methyl-phenylcarbamate represented by the following Formula 1 :
  • this process involves many-times-repeated recrystallization in the final step to achieve increased enantiomeric excess (ee).
  • Such many-times-repeated recrystallization indicates a great disadvantage in yield, and it means there is a difficulty in ensuring high enantiomeric excess. Accordingly, the process has a limitation in terms of economical efficiency.
  • Rivastigmine exhibits a negative optical rotation value in its free-base form, and exhibits either a positive or negative optical rotation value in the form of an acid addition salt.
  • r ivastigmine in the form of the tartaric acid salt exhibits a positive optical rotation value.
  • the free base and acid addition salts are included in the present invention, irrespective of their optical rotation value.
  • Formula 1 or an acid addition salt thereof comprises the steps of: subjecting the compound of Formula 7 below to N-methylation to obtain the compound of Formula 8 below or an acid addition salt thereof; and subjecting the compound of Formula 8 or an acid addition salt thereof to 0-carbamoylation to obtain the compound of Formula 1 or an acid addition salt thereof.
  • the method of the present invention is depicted in Reaction Scheme 4 below: [24] Reaction Scheme 4
  • the method of the present invention is characterized by the use of the already known (S)-enantiomeric compound as a starting material, rather than by resolution of a compound in a racemic form to obtain final compound.
  • the method of the obtaining (S)-enantiomer of this series it is difficult to resolve the compound of Formula 1 in racemic mixture and to obtain (S)-enantiomer of the compound of Formula 2 by the following reasons. Since there is no difference in solubility between two diastereomers of the dimethyl compound of Formula 2, the diastereomers cannot be separated from each other by resolution.
  • N-methylation is performed using formaldehyde/formic acid.
  • the 0-carbamoylation is performed using one of N-ethyl-N-methyl carbamoyl halogenide, such as N-ethyl-N-methyl carbamoyl chloride, and N-ethyl-N - methyl-4-nitrophenyl carbamate as an 0-carbamoylating reagent in the presence of a base.
  • N-ethyl-N-methyl carbamoyl halogenide such as N-ethyl-N-methyl carbamoyl chloride
  • N-ethyl-N -methyl-4-nitrophenyl carbamate as an 0-carbamoylating reagent in the presence of a base.
  • the base used in the 0-carbamoylation is selected from metal hydrides, e.g., sodium hydride, alkali, and alkaline metal oxides, hydroxides, e.g., sodium hydroxide and potassium hydroxide, carbonates, e.g., sodium carbonate and potassium carbonate, and secondary and tertiary amines, e.g., 4-dimethylaminopyridine (DMAP), ⁇ - ethyldiisopropylamine and triethylamine.
  • metal hydrides e.g., sodium hydride, alkali, and alkaline metal oxides
  • hydroxides e.g., sodium hydroxide and potassium hydroxide
  • carbonates e.g., sodium carbonate and potassium carbonate
  • secondary and tertiary amines e.g., 4-dimethylaminopyridine (DMAP), ⁇ - ethyldiisopropylamine and triethyl
  • the pH of the concentrate was adjusted to 11 using water and NaOH solution, followed by extraction with ether and concentration.
  • To the concentrate were added water and cone. HCl.
  • the mixture was stirred at room temperature for one hour, and washed twice with ether.
  • the obtained aqueous layer was concentrated, and re- crystallized from ethylacetate, yielding racemic rivastigmine hydrochloride (50.6 g, 58%).
  • the racemic rivastigmine hydrochloride (20 g, 69 mmol) was dissolved in water (60 ml), and then NaOH (3.3 g, 1.2 eq.) was added thereto.
  • the mixture was stirred at room temperature for one hour.
  • the resulting mixture was extracted five times with ether, dried over anhydrous MgSO , and concentrated under reduced pressure.
  • DTTA -p-toluoyl tartaric acid monohydrate
  • methanol/water (2/1) 180 ml
  • the precipitate was filtered, and recrystallized four times to afford rivastigmine DTTA salt (11.4 g, 26% (from the racemic rivastigmine hydrochloride)).
  • the obtained rivastigmine DTTA salt (4.7 g, 7.4 mmol) was suspended in a IM NaOH solution (8 ml) and dichloromethane (30 ml). The suspension was stirred for 30 minutes, followed by phase separation.

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

Abstract

La présente invention décrit une méthode de synthèse du composé de Formule 1 ou d'un sel d'addition acide dudit composé. Ladite méthode comprend les étapes suivantes : N-méthylation du composé de Formule 7 pour aboutir au composé de Formule 8 ou un sel d'addition acide de ce composé ; et O-carbamoylation du composé de Formule 8 ou d'un sel d'addition acide dudit composé afin d'obtenir le composé de Formule 1 ou un sel d'addition acide dudit composé.
PCT/KR2005/004364 2004-12-23 2005-12-16 Procédé de synthèse d'un dérivé de phénylcarbamate Ceased WO2006068386A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020040110897A KR20060072326A (ko) 2004-12-23 2004-12-23 페닐카바메이트 유도체의 새로운 합성 방법
KR10-2004-0110897 2004-12-23

Publications (1)

Publication Number Publication Date
WO2006068386A1 true WO2006068386A1 (fr) 2006-06-29

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Application Number Title Priority Date Filing Date
PCT/KR2005/004364 Ceased WO2006068386A1 (fr) 2004-12-23 2005-12-16 Procédé de synthèse d'un dérivé de phénylcarbamate

Country Status (2)

Country Link
KR (1) KR20060072326A (fr)
WO (1) WO2006068386A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014973A3 (fr) * 2005-08-04 2007-05-03 Ragactives Sl Procede d'obtention de carbamates de phenyle
WO2008020452A1 (fr) * 2006-08-17 2008-02-21 Alembic Limited Procédé pour la préparation de rivastigmine amélioré
EP1980552A3 (fr) * 2007-04-10 2008-10-29 Dr. Reddy's Laboratories Ltd. Processus pour la préparation de rivastigmine ou sel correspondant
WO2009086705A1 (fr) 2008-01-10 2009-07-16 Shanghai Institute Of Pharmaceutical Industry Procédé de préparation de rivastigmine, ses intermédiaires et procédé de préparation des intermédiaires
WO2011159910A2 (fr) 2010-06-17 2011-12-22 Codexis, Inc. Biocatalyseurs et procédés pour la synthèse de (s)-3-(1-aminoéthyl)-phénol
CN104987294A (zh) * 2015-07-27 2015-10-21 浙江京新药业股份有限公司 一种3-[1-(二甲基氨基)乙基]苯酚的制备方法
CN105439906A (zh) * 2015-12-08 2016-03-30 哈药集团三精制药有限公司 一种重酒石酸卡巴拉汀的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101917A2 (fr) * 2002-05-31 2003-12-11 Sun Pharmaceutical Industries Limited Procede de preparation de phenylcarbamates
WO2004037771A1 (fr) * 2002-10-24 2004-05-06 Zentiva, A.S. Procede de production de (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003101917A2 (fr) * 2002-05-31 2003-12-11 Sun Pharmaceutical Industries Limited Procede de preparation de phenylcarbamates
WO2004037771A1 (fr) * 2002-10-24 2004-05-06 Zentiva, A.S. Procede de production de (-)-(s)-3-[1-(dimethylamino)ethyl]phenyl-n-ethyl-n-methylcarbamate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NORMAN ET AL.: "Principles of Organic Synthesis", 1993, 3TH CHELTENHAM: NELSON THOMES, pages: 669 - 670 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014973A3 (fr) * 2005-08-04 2007-05-03 Ragactives Sl Procede d'obtention de carbamates de phenyle
EP1939172A4 (fr) * 2005-08-04 2011-03-23 Interquim Sa Procede d'obtention de carbamates de phenyle
WO2008020452A1 (fr) * 2006-08-17 2008-02-21 Alembic Limited Procédé pour la préparation de rivastigmine amélioré
US7683205B2 (en) 2006-08-17 2010-03-23 Alembic Limited Process for the preparation of Rivastigmine
EP1980552A3 (fr) * 2007-04-10 2008-10-29 Dr. Reddy's Laboratories Ltd. Processus pour la préparation de rivastigmine ou sel correspondant
WO2009086705A1 (fr) 2008-01-10 2009-07-16 Shanghai Institute Of Pharmaceutical Industry Procédé de préparation de rivastigmine, ses intermédiaires et procédé de préparation des intermédiaires
US8324429B2 (en) 2008-01-10 2012-12-04 Shanghai Institute Of Pharmaceutical Industry Preparation method of rivastigmine, its intermediates and preparation method of the intermediates
WO2011159910A2 (fr) 2010-06-17 2011-12-22 Codexis, Inc. Biocatalyseurs et procédés pour la synthèse de (s)-3-(1-aminoéthyl)-phénol
CN104987294A (zh) * 2015-07-27 2015-10-21 浙江京新药业股份有限公司 一种3-[1-(二甲基氨基)乙基]苯酚的制备方法
CN105439906A (zh) * 2015-12-08 2016-03-30 哈药集团三精制药有限公司 一种重酒石酸卡巴拉汀的合成方法

Also Published As

Publication number Publication date
KR20060072326A (ko) 2006-06-28

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