A METHOD OF PRODUCTION OF (-)-(S)-3- [1-(DIMETHYLAMINO)ETHYL] PHENYL-N-ETHYL-N-METHYLCARBAMATE - Patent EP1556338 1. A method of production of (-)-(S)-3-[1-(dimethylamino)ethyl]phenyl-N-ethyl-N-methylcarbamate, i.e. rivastigmine of formula II as a substance that induces selective inhibition of acetylcholinesterase activity in the brain. This quality along with good tolerance by the human organism, an option to serve in the form of tablets (oral efficiency) and a long-term effect predestines rivastigmine for treatment of disorders associated with the cholinergic system disorder- especially of Alzheimer's disease. 49.6 g of racemic compound (IX) are dissolved in 100 ml of methanol and a solution of 75.8 g of (+)-O,O'-ditoluyltartaric acid in 200 ml of methanol is added to the solution. 150 ml of water are added stepwise to the clear solution, which is being mixed. The solution becomes turbid and starts to crystallize under cold conditions. 81.3 g of the desired salt in the form of white crystals with m.p. = 145-147 °C are obtained. The mentioned amount of the first fraction of crystals is recrystallized from a mixture of 200 ml of methanol and 100 ml of water. The second fraction of crystals (49.6 g, m.p.= 155-156°C) is obtained which is again recrystallized from the mixture (methanol : water (2:1), 200 ml). 39.0 g of the third fraction is obtained with m.p.=159-162 °C. It is recrystallized from 150 ml of the mentioned mixture of solvents and the fourth final fraction of crystals is isolated (33.0 g, m.p.= 156-7 °C), which is 26.9% of the theoretical yield, [?] , argon) to a solution of 75.5 g of dimethylamine in 1.5 1 of ethanol cooled to 10 °C in a water-ice bath, which is placed in a 6-liter three-neck flask fitted with a KPG stirrer, inlet and outlet of the inert and a thermometer, and, finally, 148.4 g of 3-methoxyacetophenone (VI) are added (5 minutes). The addition of isopropoxide is slightly exothermic.
