Yield:105601-14-7 58%

Reaction Conditions:

Stage #1: N-ethyl-N-methylcarbamoyl chloride;(+/-)-3-<1-(Dimethylamino)ethyl>phenolwith sodium hydroxide in water;acetonitrile at 0 - 20; pH=11; for 24 h;O-carbamoylation;
Stage #2: with hydrogenchloride in diethyl ether;water at 20; for 1 h;

Steps:

1

[80] α-m-Hydroxyphenylethyldimethylamine (Formula 2, 50.0 g, 0.3 mol) was suspended in acetonitrile (250 ml), and then N-ethyl-N-methylcarbamoyl chloride (58.3 g, 0.48 mol) was added thereto. The reaction solution was cooled to 0°C. To the cooled solution was added sodium hydroxide (14.4 g, 0.36 mol). The resulting mixture was gradually allowed to rise to room temperature, and stirred at this temperature for 24 hours. The completion of the reaction was confirmed by HPLC. Thereafter, the reaction mixture was filtered to remove salts, and the obtained filtrate was concentrated. 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. Di-O, O'4-p-toluoyl tartaric acid monohydrate (DTTA, 26.5 g, 69 mmol) and a solution of methanol/water (2/1) (180 ml) were added to the concentrate, dissolved under heating, and gradually allowed to cool to room temperature to obtain a precipitate. 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) EPO and dichloromethane (30 ml). The suspension was stirred for 30 minutes, followed by phase separation. The obtained organic layer was concentrated, and water and ether were added to the concentrate to separate layers. The obtained ether layer was dried over K CO , and concentrated. To the concentrate were added acetone (5 ml) and L- tartaric acid (1.1 g, 7.4 mmol, 1 eq.). The resulting mixture was refluxed for one hour, cooled to 0°C, and filtered to obtain a solid. The solid was washed, and dried to afford (S)-rivastigmine tartrate salt (2.5 Ig, 99.7% ee, 85% (from the rivastigmine DTTA salt), 13% (from the α-m-hydroxyphenylethyldimethylamine).

References:

WO2006/68386,2006,A1 Location in patent:Page/Page column 8