FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - An Improved Process for the preparation of pure (S)- Rivastigmine
base.
2. Applicant(s)
(a) NAME : ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention :

Field of invention:
The present invention relates to an improved process for the preparation of pure Ethylmethylcarbamic acid 3-[(lS)-l-(dimethyIamino) ethyl] phenyl ester of formula (I) or commonly known as (S) - Rivastigmine base.

Rivastigmine is prescribed for the treatment of mild to moderate Alzheimer's disease. The tartarate salt of Rivastigmine is marketed under brand name of Exelon®. Rivastigmine is in a class of medications called cholinesterase inhibitors. It improves mental function by increasing the amount of a certain natural substance in the brain. Rivastigmine increases the amounts of a chemical called acetylcholine in the brain. Acetylcholine may be involved in memory, attention, and learning.
US5602176 discloses the process for the preparation of (S)-Rivastigmine by resolving (+/-)-N-ethyl-3-[-l-(dimethylamino) ethyl]-N-methy] phenyl carbamate with (+)-di-0,0'-p-toluoyl tartaric Acid monohydrate in MeOH/H20. The salt thus formed is recrystallised in MeOH/H20 to get pure (S)-Rivastigmin DPTT salt. The S-enantiomer base is released by Partitioning between NaOH and ether.
Journal of Labelled compounds and Radiopharmaceuticals -vol. XXXIX, No.8 also discloses the process of preparation of Rivastigmin base from Rivastigmin DPTT salt using aqueous ammonia to obtain (S)-Rivastigmine.
However, during this conversion many impurities develop, which reduces the overall yield and purity and which are very difficult to remove. Thus there is a need to develop the process in which less impurity is detected and pure Rivastigmin base can be isolated

from the Rivastigmin salt. It is the surprising finding by the inventors of the present application that the process for the present application provides less amount of impurity with high yield, which makes the process commercially viable.
Summary of the invention:
The present inventors have focused on the problems associated with the prior art process and has developed an improved Process for the preparation of pure (S)- Rivastigmine base.
Therefore, in one aspect the present invention provides the improved Process for the preparation of pure (S) - Rivastigmine base from Rivastigmine tartrate.
In Yet another aspect the present invention provides the improved Process for the preparation of pure (S) - Rivastigmine base from Rivastigmine tartrate in the presence of alkali metal carbonates and water immiscible solvents
In Yet another aspect the present invention provides the improved Process for the preparation of pure (S)- Rivastigmine base from Rivastigmine tartrate in the presence of alkali metal carbonates or alkali metal hydrogen carbonates such as potassium carbonate , sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, etc. Water immiscible solvents such as carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, diethyl ether, ethyl acetate, heptane, hexane, methyl-tert-butyl ether, toluene, xylene, diisopropyl ether.
Detail description of invention:
In one embodiment the present invention provides the improved Process for the preparation of pure (S)- Rivastigmine base
In another embodiment the present invention provides the improved Process for the preparation of pure (S)- Rivastigmine base from Rivastigmine tartrate.

In Yet another embodiment the present invention provides the improved Process for the preparation of pure (S)- Rivastigmine base from Rivastigmine tartrate in the presence of alkali metal carbonates and water immiscible solvents
In Yet another embodiment the present invention provides the improved Process for the preparation of pure (S)- Rivastigmine base from Rivastigmine tartrate in the presence of alkali metal carbonates or alkali metal hydrogen carbonates such as potassium carbonate , sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, etc. Water immiscible solvents are selected from the group of carbon tetrachloride, chloroform, cyclohexane, 1,2-dichloroethane, dichloromethane, diethyl ether, ethyl acetate, heptane, hexane, methyl-tert-butyl ether, pentane, toluene, xylene, diisopropyl ether.
The impurity formed during neutralization is 3-acetylphenyl ethyl(methyl)carbamate.

Below table shows content of impurity by the treatment with various bases.

Sr.No Name of the Base Rivastigmine Related compound D impurity (By HPLC, %area)
1 Sodium hydroxide 0.093
2 Sodium bicarbonate 0.022
3 Sodium carbonate 0.011
The present invention further illustrated in detail by the below examples which are
however not limit to the scope of the invention.
Example:
l00gm of pure (S)-Rivastigmine Tartrate salt was charged in to the four necked RBF
containing 400ml water. The reaction mixture was stirred at 25-30°C for 10-15mins and
then charged 466ml toluene. The pH of the reaction mixture was adjusted to 9.0-9.5 by
using 10% sodium carbonate solution at 25-30°C under stirring. The reaction mixture is

allowed to settle and separate the toluene layer. Toluene layer was washed with water and then dried using sodium sulphate. Toluene was removed below 35°C under vacuum to obtain pure Rivastigmin base. Yield-100%, HPLC purity>99.8

We Claim:
1. A process for the preparation of (S)-Rivastigmine base from (S)-Rivastigmine Tartrate in the presence of base and water immiscible solvent.
2. The process according to claim 1, where in the base is selected from the group of alkali metal carbonate or alkali metal hydrogen carbonate such as sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, More preferably sodium carbonate.
3. The process according to claim 1, where in water immiscible solvent is selected from the group of carbon tetrachloride, chloroform, cyclohexane. 1,2-dichloroethane, dichloromethane, diethyl ether, ethyl acetate, heptane, hexane, methyl-tert-butyl ether, pentane, toluene, disiopropyl ether. More preferably toluene.
4. A process for the preparation of (S)-Rivastigmine base from (S)-Rivastigmine Tartrate in the presence of sodium carbonate and toluene.