An improved preparing process for rivastigmine

WU Jiaquan; ZHOU Ping; LIU Yang; JIE Chuanming; CAO Huanyan; PENG Tao; LI Xiaohong; ZHANG Haijun

doi:10.11665/j.issn.1000-5048.20150406

Journal of China Pharmaceutical University > 2015 > 46(4): 421-425. > DOI: 10.11665/j.issn.1000-5048.20150406

WU Jiaquan, ZHOU Ping, LIU Yang, JIE Chuanming, CAO Huanyan, PENG Tao, LI Xiaohong, ZHANG Haijun. An improved preparing process for rivastigmine[J]. Journal of China Pharmaceutical University, 2015, 46(4): 421-425. DOI: 10.11665/j.issn.1000-5048.20150406

Citation:

PDF (1036 KB)

An improved preparing process for rivastigmine

More Information

Graphical Abstract

Abstract

Abstract

An improved manufacturing process for rivastigmine( 1 )was developed by performing the condensation reaction of m-hydroxyacetophenone( 4 )with N-ethyl-N-methyl carbamoyl chloride, then Corey-Bakshi-Shibata(CBS)chiral reduction to(R)-3-(1-hydroxyethyl)phenyl ethyl(methyl)carbamate( 2 )and then mesylation with methanesulfonyl chloride and nucleophilic substitution with dimethylamine, respectively. To be successful, a crucial reductive process in the conversion of ketone( 3 )to chiralalcohol( 2 )had to be correctly understood and optimized via orthogonal experiment. The whole improved process was convenient for operation and purification, with completion of the synthesis of rivastigmine and an overall yield of 88%.
- rivastigmine,
- asymmetric synthesis,
- CBS reduction,
- process improvement

FullText(HTML)

References (19)

References

[1]	Emre M,Aarsland D,Albanese A,et al.Rivastigmine for dementia associated with Parkinson′s disease[J].N EngJ Med,2004,351(24):2509-2518.
[2]	Marta WR,Michael C,Zeev T.Phenyl carbamates.US,4948807[P].1989-03-08[1990-08-14] .
[3]	Albert E.Phenyl carbamates.US,5602176[P].1995-06-06[1997-02-11] .
[4]	Stepankova H,Hajicek J,Simek SA.Method of production of(-)-(S)-3-[1-(dimethylamino)ethyl] phenyl-N-ethyl-N-methylcarbamate.WO,2004037771[P].2003-10-21[2004-05-06] .
[5]	Zhang Y,Cai ZQ,Sun TM,et al.New synthetic route of rivastigmine[J].Chin J Med Chem(中国药物化学杂志),2010,20(2):102-105.
[6]	Boezio AA,Pytkowicz J,Côté A,et al.Asymmetric,catalytic synthesis of α-chiral amines using a novel bis(phosphine)monoxide chiral ligand[J].J Am Chem Soc,2003,125(47):14260-14261.
[7]	Veera RA,Laxminarasimhulu G,Pramod KD.A simple and highly efficient enantioselective synthesis of(S)-rivastigmine[J].Int J Org Chem,2011,1(2):26-32.
[8]	Rao R,Shewalkar MP,Nandipati R,et al.General strategy for large-scale synthesis of(+)-rivastigmine and(+)NPS R-568[J].Syn Commun,2012,42(4):589-598.
[9]	Hu M,Zhang FL,Xie MH.Novel convenient synthesis of rivastigmine[J].Syn Commun,2009,39(9):1527-1533.
[10]	Fieldhouse R.Process for the preparation of teriary amines attached to a secondary carbon centre.WO,2005058804[P].2004-12-08[2005-06-30] .
[11]	Guijarro D,Pablo O,Yus M.Asymmetric synthesis of chiral primary amines by transfer hydrogenation of N-(tert-butanesulfinyl)ketimines[J].J Org Chem,2010,75(15):5265-5270.
[12]	Mathes C,Foulkes M,Kesselgruber M.Process for the preparation of optically active compounds using transfer hydrogenation.WO,2010072798[P].2009-12-23[2010-07-01] .
[13]	Ma DW,Pan QB,Pan S.Process for preparing(S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenylcarbamate and tartrate thereof.WO,2007025481[P].2006-09-01[2007-03-08] .
[14]	Fuchs M,Koszelewski D,Tauber K,et al.Chemoenzymatic asymmetric total synthesis of(S)-rivastigmine using ω-transaminases[J].Chem Commun,2010,46(30):5500-5502.
[15]	Mangas-Sánchez J,Rodríguez-Mata M,Busto E,et al.Chemoenzymatic synthesis of rivastigmine based onlipase-catalyzed processes[J].J Org Chem,2009,74(15):5304-5310.
[16]	Han K,Kim C,Park J,et al.Chemoenzymatic synthesis of rivastigmine via dynamic kinetic resolution as a key step[J].J Org Chem,2010,75(9):3105-3108.
[17]	Arunkumar K,Reddy MA,Kumar TS,et al.Achiral bis-imine in combination with CoCl₂:a remarkable effect on enantioselectivity of lipase-mediated acetylation of racemic secondary alcohol[J].J Org Chem,2010,6:1174-1179.
[18]	Yan PC,Zhu GL,Xie JH.Industrial scale-up of enantioselective hydrogenation for the asymmetric synthesis of rivastigmine[J].Org Process Res Dev,2013,17(2):307-312.
[19]	Chen WM,Feng J,Sun PH.An improvement for synthesis of rivastigmine[J].Chin J New Drugs(中国新药杂志),2007,16(20):1693-1694.

Cited By

Get Citation

PDF

XML

Article views (1287) PDF downloads (1966)

Turn off MathJax

Article Contents

Abstract

References

An improved preparing process for rivastigmine

Abstract

References

Catalog

Export File

Citation

Format

Content