889443-69-0

Upstream product

• 50-00-0 formaldehyd 
• 50919-07-8 (S)-1-(3-methoxyphenyl)ethylamine 
• 64-18-6 formic acid 
• 198756-81-9 S-(-)-1-(3-methoxyphenyl)ethylamine mandalate 
• 118761-92-5 N-methyl-[1-(3'-methoxylphenyl)ethylidene]amine 
• 23308-82-9 (R)-(+)-1-(3-methoxyphenyl)-1-ethanol 
• 124-40-3 dimethyl amine 
• 586-37-8 1-(3-Methoxyphenyl)ethanone 
• 127-19-5 N,N-dimethyl acetamide 
• 121-71-1 3-Hydroxyacetophenone 
• 89691-63-4 1-(3-methoxy)-phenylethanol 
• 218900-56-2 (S)-[1-(3-methoxyphenyl)ethyl]carbamic acid tert-butyl ester 
• 50919-07-8 1-(3-methoxy-phenyl)-ethylamine 

Downstream Products

• 1053241-02-3 (S)-N,N-dimethyl-1-[3-methoxy-2-(trimethylsilyl)phenyl]ethylamine 
• 1053241-01-2 (S)-N,N-dimethyl-1-[2-(diphenylphosphanyl)-3-methoxyphenyl]ethylamine 
• 7650-79-5 isobutyldiphenylphosphine 
• 139306-10-8 (S)-3-(1-dimethylaminoethyl)phenol 
• 123441-03-2 rivastigmin 
• 123441-03-2 rivastigmine tartrate 
• 1416982-01-8 (S)-1-methoxy-3-(1-p-tolylethyl)benzene 
• 1352656-45-1 (S, E)-1-methoxy-3-(4-phenylbut-3-en-2-yl)benzene 
• 1416982-25-6 (S)-1-(3-methoxyphenyl)-N,N,N-trimethylethanaminium trifluoromethanesulfonate 

Relevant academic research and scientific papers

Biaryl diphosphine ligands and their ruthenium complexes: Preparation and use for catalytic hydrogenation of ketones

Procedures for the preparation of the nucleophilic diphosphine ligands (R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((R)-Ph-Garphos, 2a) and (S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((S)-Ph-Garphos, 2b) were described. The ligands were used to prepare the ruthenium(II) Ph-Garphos complexes, chloro(p-cymene)(R)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Ph-Garphos]Cl (3)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Ph-Garphos]Cl (4)). In the presence of the chiral diamine co-ligands (1R,2R)-1,2-diphenylethane-1,2-diamine (R,R-DPEN) and (1S,2S)-1,2-diphenylethane-1,2-diamine (S,S-DPEN), complexes 3 and 4 were found to be catalyst precursors for the enantioselective reduction of aryl ketones under mild conditions (room temperature and 3–4 atm of H2). The chiral alcohols were isolated in moderate to good yields and with enantioselectivities of up to 93percent. The ruthenium complexes chloro(p-cymene)(R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Xyl-Garphos]Cl (5)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Xyl-Garphos]Cl (6)) were also prepared and used as catalyst precursors for the hydrogenation of aryl ketones in the presence of (R,R)-DPEN and (S,S)-DPEN. Significant improvements in the enantioselectivities of the alcohols (up to 98percent ee.) were afforded. A combination of 6 and (S,S)-DPEN afforded (R)-1-(3-methoxyphenyl)ethanol in 89percent yield and with 95percent ee which was shown to be a suitable precursor for the preparation of (S)-rivastigmine.

SYNTHESIS OF NOVEL INTERMEDIATE(S) FOR PREPARING RIVASTIGMINE

The present invention relates to novel intermediate(s), which are useful for the preparation of Rivastigmine compound of formula (I) and its pharmaceutically acceptable salts. The present invention further relates to the processes for the preparation of such novel intermediate(s) and preparation of Rivastigmine using such novel intermediate(s).

Iridium-catalyzed diastereoselective amination of alcohols with chiral: Tert-butanesulfinamide by the use of a borrowing hydrogen methodology

An iridium-catalyzed diastereoselective amination of alcohols with chiral tert-butanesulfinamide was developed under basic conditions, affording the optically active secondary sulfinamides in high yields and diastereoselectivities. The removal of the sulfinyl group from sulfonamides allowed a facile access to a wide range of α-chiral primary amines. This synthetic strategy was further applied in the synthesis of the marketed pharmaceuticals (S)-rivastigmine and NPS R-568.

Group-assisted Purification (GAP) Chemistry/Technology in synthesizing the chiral intermediate of rivastigmine and its ?-Alkyl benzylamine analogues

Introduction of (S)-configuration is the key step in the synthesis of the anti-dementia drug Rivastigmine. Twenty-one alkylation products were obtained through simple washing with hexane/ethyl acetate (v/v: 10/1) in good yields (>85%) and high diastereoselectivity (up to >99:1 dr). Moreover, the chiral auxiliary could be easily dissociated and readily regenerated. That is, the synthesis was proved to follow group-assisted purification (GAP) chemistry/technology. In addition, the chiral amine produced by this asymmetric alkylation reaction was effectively used in the synthesis of Rivastigmine.

Disulfonimide-Catalyzed Asymmetric Reduction of N-Alkyl Imines

A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc2O has been developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross-coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline. A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc2O was developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method was successfully applied to the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline.

PROCESSES FOR PREPARING RIVASTIGMINE, SALTS AND INTERMEDIATES THEREOF

Processes for preparing Rivastigmine, salts and intermediates thereof are disclosed. More specifically, a process for preparing S-(-)-3-[(l -dimethylamino)ethyl]-phenol is provided.

An improved process for the production of rivastigmine tartrate, a cholinesterase inhibitor

An improved and scalable process for the production of rivastigmine tartrate is reported. The improved process provides rivastigmine tartrate at considerably lower cost and allows the omission of hazardous chemicals. The overall yield is increased from 4.66% (reported process) to 17% with the improved process.

Chemoenzymatic synthesis of rivastigmine based on lipase-catalyzed processes

(Chemical Equation Presented) A straightforward chemoenzymatic synthesis of enantiomerically pure rivastigmine has been efficiently carried out under mild reaction conditions, with Candida antarctica lipase B responsible for the stereoselective acetylation of the corresponding (R)-alcohol or amine. An exhaustive enzymatic study has been developed exploring the possibilities of carry out enzyme recycling, scaling up the enzymatic process and development of a dynamic kinetic resolution procedure for the production of adequate enantiomerically pure precursors of rivastigmine. Total chemoenzymatic synthesis of this pharmaceutical has been performed in good overall yield from commercially available 3-methoxyacetophenone.

A process for the preparation of rivastigmine or a salt thereof

There are provided processes for making rivastigmine. In one embodiment, the process includes reacting S-(-)-[1-(3-hydroxyphenyl)ethyl]dimethylamine with N-ethyl-N-methyl carbamoyl chloride in the presence of an organic base to obtain a free base of rivastigmine.

PREPARATION OF RIVASTIGMINE AND ITS SALTS

There are provided processes for making rivastigmine. In one embodiment, the process includes reacting S-(?)-[1-(3-hydroxyphenyl)ethyl]dimethylamine with N-ethyl-N-methyl carbamoyl chloride in the presence of an organic base to obtain a free base of rivastigmine.