WO2008124969A1 - Méthode de préparation de rivastigmine et de ses intermédiaires - Google Patents

Méthode de préparation de rivastigmine et de ses intermédiaires Download PDF

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Publication number
WO2008124969A1
WO2008124969A1 PCT/CN2007/001248 CN2007001248W WO2008124969A1 WO 2008124969 A1 WO2008124969 A1 WO 2008124969A1 CN 2007001248 W CN2007001248 W CN 2007001248W WO 2008124969 A1 WO2008124969 A1 WO 2008124969A1
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Prior art keywords
formula
compound
compound represented
base
reaction
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Application number
PCT/CN2007/001248
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English (en)
Chinese (zh)
Inventor
Guanghui Tian
Yi Zhu
Jingshan Shen
Original Assignee
Topharman Shanghai 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 Topharman Shanghai Co., Ltd. filed Critical Topharman Shanghai Co., Ltd.
Priority to CN2007800525506A priority Critical patent/CN101707952B/zh
Priority to PCT/CN2007/001248 priority patent/WO2008124969A1/fr
Publication of WO2008124969A1 publication Critical patent/WO2008124969A1/fr

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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
    • C07C269/06—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 by reactions not involving the formation of carbamate groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a process for the preparation of rivastigmine and an intermediate thereof.
  • Rivas tigmine also known as rivastigmine
  • (S) - N-ethyl-N-methyl-3-(1-(dimethylamino)ethyl]amino Phenyl formate a drug developed by Novartis Pharmaceuticals Ltd. for the treatment of Alzheimer's disease, achieves therapeutic goals by selectively inhibiting acetylcholinesterase in the cerebral cortex and hippocampus.
  • ethylmethylcarbamoyl chloride is reacted with dimethylaminoethylphenol to obtain a racemic product, which is then separated by (+) -0, ( ⁇ -di-p-toluoyl-(D)-tartaric acid to obtain S. Configuration compound.
  • WO2005061446 discloses another preparation method in which mainly 3-acetylphenol is subjected to condensation, reduction, methylation, and then re-cleared with ethylmethylcarbamoyl chloride to obtain S-type rivastigmine.
  • WO03101917 discloses the reaction of dimethylaminoethylphenol with hydrazine-ethyl-hydrazine-methyl-4-nitrobenzamide to give the product, also using (+)-o, (-di-p-toluoyl-) (D) - Tartaric acid Perform the split.
  • WO2004037771 discloses a process for first reacting a reaction intermediate dimethylaminoethylphenol with S-(+)-camphorsulfonic acid to obtain a product of the S configuration, followed by reaction with ethylmethylcarbamoyl chloride to obtain a product.
  • CN1486973 also uses dimethylaminoethylphenol and ethylmethylcarbamoyl chloride in the S configuration to give rivastigmine with higher optical purity.
  • the present invention provides a process for preparing rivastigmine, and also provides a novel compound intermediate for the preparation of rivastig.
  • the novel method for preparing rivastigmine provided by the invention does not use ethylmethylcarbamoyl chloride which is high in preparation cost and poor in chemical stability, and reduces the preparation cost, and has great application value in industrial production.
  • the present invention provides a process for producing a compound of the formula (1), which is obtained by reacting a compound represented by the formula (2) with CH 3 X or CH 3 CH 2 X in the presence of a base.
  • X is a suitable leaving group
  • R is a methyl group or an ethyl group; when R is a methyl group, it reacts with CH 3 CH 2 X; and when R is an ethyl group, it reacts with CH 3 X.
  • the X is preferably a halogen, and more preferably Cl, Br or I.
  • the base is a metal salt of an alcohol or an amine, a metal hydride, a hydroxide, a metal oxide, or a carbon
  • the acid salt hydrogencarbonate, preferably sodium hydrogen or potassium carbonate.
  • the reaction is carried out in an organic solvent.
  • the organic solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, hydrazine, hydrazine-dimethylformamide, 1, 4-dioxane, One of 1,2-dichloroethane or a mixture of any ratio thereof.
  • the compound represented by the formula (2) is obtained by resolution of a compound represented by the formula (3) or an optically active compound represented by the formula (7).
  • R is a methyl group or an ethyl group.
  • the resolving agent is S - (+) - camphorsulfonic acid or (+) - 0, ( ⁇ - di-p-toluene) Formyl-(D)-tartaric acid;
  • the solvent is methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, one of water or a mixture thereof.
  • the compound of the formula (2) can be obtained by reacting a compound of the formula (7) with a compound of the formula (7) and a compound of the formula (5) or a compound of the formula (6).
  • reaction solvent is benzene, toluene, dichloromethane or chloroform
  • reaction temperature is 30 ° C - 120 ° C, preferably 50 ° C - 100 .
  • the reaction of the compound of the formula (7) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base, and the inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1, 2 a mixture of dichloroacetamidine, tetrahydrofuran, I, 4 -dioxane, 1,2-dichloroethane or any ratio thereof;
  • the base is a metal hydride, hydroxide, metal oxide , carbonate, bicarbonate, organic base or a combination thereof.
  • the organic base is an organic amine, a metal salt of an amine, or a combination thereof.
  • the compound represented by the formula (3) is obtained by reacting a compound represented by the formula (4).
  • the method is as follows: a compound represented by the formula (4) is obtained by reacting a compound represented by the formula (5), or a compound represented by the formula (4) with a compound of the formula (6).
  • R is a methyl group or an ethyl group.
  • reaction solvent is tetrahydrofuran, DMF, benzene, toluene, dichloromethane, chloroform, and the reaction temperature is 30 ° C - 120 ° C, preferably 60 . C - 100 ° C.
  • the reaction of the compound of the formula (4) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base, and the inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, One of 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane or a mixture thereof in any ratio; the base is a metal hydride, a hydroxide, Metal oxides, carbonates, bicarbonates, organic bases or combinations thereof.
  • the organic base is an organic amine, a metal salt of an amine, or a combination thereof.
  • the present invention also provides a compound of the formula (2):
  • R is an ethyl group.
  • the invention also provides a compound represented by formula (3)
  • R is an ethyl group.
  • the compound of the structural formula (4) according to the present invention can be referred to the literature (Journal of East China Normal University, Nature Scientific version, 2001, 1, 61-65), the method is as follows:
  • the method for preparing rivastigmine provided by the invention does not use ethylmethylcarbamoyl chloride which is high in preparation cost and poor in chemical stability, and reduces the preparation cost, and has great application value in industrial production. Detailed ways
  • the invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention.
  • the technical solutions of the present invention described above are all technical solutions for achieving the object of the present invention. That is, the temperatures and reagents used in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.
  • the solvents or reagents used in the tests were produced by Sinopharm Chemical Reagent Co., Ltd. unless otherwise indicated; the NMR spectra were performed on a Varian Mercury 300 instrument, and all spectra were consistent with the predicted structure, and the characteristic peaks were represented by conventional abbreviations. : s, single peak; d, doublet; t, triplet; q, quartet; m, multiplet.
  • Room temperature means 20 - 25 °C.
  • Methyl chloride diluted R is a compound of the formula (6) (N-methylcarbamoyl chloride) 9.77 g (0.105 fflol) was slowly added dropwise to the above solution, and the addition was completed, and the mixture was returned to room temperature and stirred for 2 hours.
  • Example 1 Preparation of compound 11. lg (0.05 mol), dissolved in llOmL methanol, added D (+) 10- 10-camphorsulfonic acid 12. lg (0.053 mol), heated at 60 ° C for 2 hours, returned to room temperature, Ethyl acetate (50 mL) was added to precipitate a solid, and the obtained solid was filtered, and then recrystallized three times with methanol/ethyl acetate, and dried at 50 ° C for 2 hours, weighing 7.3 g of product, dissolved in 20 mL of water, sodium hydroxide 0.64 g (0.016 mol), stirring at room temperature for 30 minutes, adding 100 mL of dichloromethane, separating the liquid, and washing the dichloromethane phase three times with 60 mL of distilled water, and evaporating the solvent under reduced pressure to obtain the formula (2) wherein R is a methyl group.
  • Example 2 The compound of Example 2, lg (4.5 mmol), was dissolved in 10 mL of THF, and potassium carbonate (0.35 g (5.0 lb ol) was added thereto, and 0.54 g (5.0 leg ol) of bromoacetone was slowly added dropwise thereto, and the mixture was heated at 80 ° C for 1.5 hours. After returning to room temperature, most of the THF was evaporated under reduced pressure. The product was obtained by adding 30 mL of dichloromethane, and washed with 5 mL of distilled water. The organic phase was dried over anhydrous sodium sulfate and evaporated to give the compound of formula (1).
  • R is a compound of the formula (3) (ethyl carbamate 3- [1-(dimethylamino)ethyl]phenyl ester) Preparation
  • the compound of the formula (1) ((S) - N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]carbamic acid benzene is a compound represented by the formula (2) wherein R is an ethyl group.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne une méthode de préparation de rivastigmine et de ses intermédiaires. L'invention décrit une méthode de préparation du composé de formule (1) consistant à faire réagir le composé de formule (2) avec CH3X ou CH3CH2X en présence d'une base, dans laquelle X est un groupe partant approprié ; R est méthyle ou éthyle ; quand R est méthyle, on fait réagir le composé de formule (2) avec CH3CH2X ; quand R est éthyle, on fait réagir le composé de formule (2) avec CH3X. La méthode de préparation selon l'invention n'utilise pas de chlorure d'éthylméthylcarbamoyle.
PCT/CN2007/001248 2007-04-16 2007-04-16 Méthode de préparation de rivastigmine et de ses intermédiaires WO2008124969A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN2007800525506A CN101707952B (zh) 2007-04-16 2007-04-16 一种制备利伐斯的明的方法及其中间体
PCT/CN2007/001248 WO2008124969A1 (fr) 2007-04-16 2007-04-16 Méthode de préparation de rivastigmine et de ses intermédiaires

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2007/001248 WO2008124969A1 (fr) 2007-04-16 2007-04-16 Méthode de préparation de rivastigmine et de ses intermédiaires

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WO2008124969A1 true WO2008124969A1 (fr) 2008-10-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786441A (zh) * 2011-05-18 2012-11-21 浙江海正药业股份有限公司 利凡斯的明的制备方法、其中间体以及中间体的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103420941B (zh) * 2013-08-26 2015-09-23 浙江大学 2-甲氧基苯基-二甲胺基甲酸酯衍生物及制备和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193926A2 (fr) * 1985-03-05 1986-09-10 Proterra Ag Phényl carbamates
GB2203040A (en) * 1987-03-04 1988-10-12 Sandoz Ltd Phenyl carbamates
WO2003101917A2 (fr) * 2002-05-31 2003-12-11 Sun Pharmaceutical Industries Limited Procede de preparation de phenylcarbamates
WO2005061446A2 (fr) * 2003-12-24 2005-07-07 Generics [Uk] Limited Nouveaux procedes pour preparer des phenylcarbamates d'aminoalkyle
WO2007025481A1 (fr) * 2005-09-02 2007-03-08 Shanghai Aobo Bio-Pharmaceutical Technology Co., Ltd Procede de preparation de carbamate (s)-n-ethyl-n-methyl-s-[1(dimethylamino) ethyl]-phenyle et de son tartrate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0193926A2 (fr) * 1985-03-05 1986-09-10 Proterra Ag Phényl carbamates
GB2203040A (en) * 1987-03-04 1988-10-12 Sandoz Ltd Phenyl carbamates
WO2003101917A2 (fr) * 2002-05-31 2003-12-11 Sun Pharmaceutical Industries Limited Procede de preparation de phenylcarbamates
WO2005061446A2 (fr) * 2003-12-24 2005-07-07 Generics [Uk] Limited Nouveaux procedes pour preparer des phenylcarbamates d'aminoalkyle
WO2007025481A1 (fr) * 2005-09-02 2007-03-08 Shanghai Aobo Bio-Pharmaceutical Technology Co., Ltd Procede de preparation de carbamate (s)-n-ethyl-n-methyl-s-[1(dimethylamino) ethyl]-phenyle et de son tartrate

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786441A (zh) * 2011-05-18 2012-11-21 浙江海正药业股份有限公司 利凡斯的明的制备方法、其中间体以及中间体的制备方法

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CN101707952A (zh) 2010-05-12

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