(S)-3-[(1-Dimethylamino) ethyl]phenyl-N-ethyl-N-methyl-carbamate (rivastigmine) of Formula I or its pharmaceutically acceptable salts is known to possess cholinesterase inhibitor activity and is used in the treatment of Alzheimer's disease.

U.S. Pat. No. 4,948,807 discloses a method for the preparation of phenyl carbamate compounds by reacting α-m-hydroxyphenylisopropyldimethylamine or α-m-hydroxyphenylethyl dimethylamine with appropriate isocyanate or carbamoyl halides. The process using isocyanates involves the use of benzene as a solvent. Isocyanates such as lower alkyl isocyanates are hazardous to handle due to their toxic and non-volatile nature.
The other reported alternative is the use of carbamoyl halides along with reactive base like sodium hydride to prepare carbamate. However, the use of sodium hydride on commercial scale is hazardous and difficult to handle due to its pyrophoric and reactive nature.
U.S. Pat. No. 5,602,176 discloses resolution of the racemic rivastigmine by forming the diastereoisomeric salts with di-O,O′-p-toluoyl-D-tartaric acid and their separation by repeated crystallization. The (S)-enantiomer of rivastigmine is obtained by treating the salt with sodium hydroxide solution. Since the resolution is performed in the last step, about 50% of the racemic mixture (containing R-enantiomer) is wasted which results in low yield, thus making the process industrially less viable.
WO 2004037771 discloses the resolution of 3-[1-(dimethylamino)ethyl]phenol followed by reaction of its S-enantiomer with carbamoyl halide using strong base like sodium hydride. The main drawback of this process is the low yield (25-31%) obtained during the resolution of 3-[1-(dimethylamino)ethyl]phenol to get optically pure compound. Furthermore, the use of reactive base like sodium hydride on industrial scale is not only hazardous but also operationally difficult due to its pyrophoric and reactive nature.
WO 2006048720 discloses the resolution of 3-[1-(dimethylamino)ethyl]phenol using D-(+)-10-camphor sulphonic acid to obtain diastereomeric salt with a yield of only 25-30%.
EP 1939172 discloses another alternative method for producing rivastigmine comprising reacting (S)-3-[1-(methylamino)ethyl]phenol with carbamoyl halide to form an intermediate, which is subjected to reductive amination reaction or methylation reaction by reacting with methyl halide to obtain rivastigmine. The (S)-3-[1-(methylamino)ethyl]phenol is obtained by the resolution of racemic 3-[1-(methylamino)ethyl]phenol or dealkylation of (S)-1-(3-methoxyphenyl)ethylmethylamine. The diastereomeric salts of racemic 1-(3-methoxyphenyl)ethylmethylamine are formed by reacting with D-(−)-tartaric acid and finally releasing the S-enantiomer by treating with sodium hydroxide solution. This process requires additional crystallizations steps to obtain tartrate salt with a yield of 27% only. Further, the process employs carcinogenic and toxic methyl iodide. Titanium isopropoxide, sodium hydride, hydrobromic acid and sodium cyanoborohydride used in various stages of synthesis as disclosed in various examples are expensive and make the process highly economically unfavorable. Moreover, carbamate formation involves the use of sodium hydride that requires special handling during work-up.
The processes disclosed in the prior art involves use of hazardous chemicals like isocyanate, low yield in the resolution step and use of expensive chemicals like titanium isopropoxide, sodium hydride, hydrobromic acid and sodium cyanoborohydride, thereby making the process unsuitable for commercial scale production.
Thus there exists a need for a safe, economically viable and efficient industrial process for producing rivastigmine and its pharmaceutically acceptable salt, which is free from above mentioned drawbacks. In addition the process provides high yield and high purity in environmentally friendly condition.