FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 3-[(l-dimethylaniino)ethyl]phenol of Formula I

which is an useful intermediate in the preparation of (S)-N-ethyl-3-[l-dimethylamino)ethyl]-N-methylphenylcarbamate of Formula II

BACKGROUND OF THE INVENTION
(S)-N-ethyl-3-[(l-dimethylamino)ethyl]-N-methylphenylcarbamate is generically known as Rivastigmine. Rivastigmine as its hydrogen-(2R,3R)-tartratewhich is generically known as Rivastigmine tartrate is marketed under the trade name EXELON. Rivastigmine tartrate is an AChE inhibitor and is useful for treating Alzheimer's Disease is demonstrated by the results of 2 randomized, double-blind, placebo-controlled clinical investigations in patients with Alzheimer's Disease.
Rivastigmine as a racemic compound is first disclosed in US 4,948,807 and as an (S)-enantiomer in US 5,602,176.

In view of the importance of Rivastigmine as a AChE inhibitor, several synthetic methods have been reported in the literature to prepare Rivastigmine, which are as summarized below:
A number of different routes for preparation of Rivastigmine are known including those described in US 5,602,176 A, US 2006-0122417 Al, US 2006-0293518 Al, WO 2005/061446 A2, WO 2006/048720 Al, WO 2006/068386 Al, WO 2007/014973 A2.
US 4,948,807 discloses a process to prepare racemic Rivastigmine, which is as shown below:

US 5,602,176 discloses a process to prepare Rivastigmine hydrogen tartrate, which is as shown below:


Journal of Chemical Society, 1929, 609-617 discloses a process to prepare 3-[(l-dimethylamino)ethyl]phenol, which is as shown below:

Tetrahedron Letters, 32(49), 1991, 7175-78 disclosed a process to prepare 3-[(l-dimethylamino)ethyl]phenol, which comprises enantioselective reduction of 3-

hydroxyacetophenone using diborane in presence of a chiral ligand to obtaina chiral hydroxy compound. The hydroxy group is then converted into dimethylamino group.
The above mentioned processes for the synthesis of the intermediate 3-[(l-dimethylamino)ethyl]phenol are not amenable to practice on a commercial scale owing to the number of steps and hazards involving diborane.
Huadong Shifan Daxue Xuebao Ziran Keyueban, (2001), (1), 61-65 discloses a process to prepare 3-[(l-dimethylamino)ethyl]phenol, which comprises reacting 3-hydroxyacetophenone with hydroxylamine and the reaction product is hydrogenated using Raney Nickel. The amino compound thus obtained is then dimethylated using formic acid and formaldehyde.
OBJECTIVE
The objective of the present invention is to provide a process for preparing 3-[l-dimethylamino)ethyl]phenol, with high yields and acceptable purity.
Yet another objective of the present invention is to provide a process for preparing 3-[ 1 -dimethylamino)ethyl]phenol, which is simple, industrially applicable and commercially feasible.
Yet another objective of the present invention is to convert 3-[l-dimethylamino)ethyl]phenol in to Rivastigmine and its pharmacologically acceptable salts.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing 3-[l-dimethylamino)ethyl]phenol of Formula I,

which comprises,
i) treating 3-hydroxyacetophenone with monomethylamine in the presence of a hydrogenation catalyst and hydrogen to give the monomethylaminoethylphenol of Formula III

ii) methylating the compound of Formula III to give compound of Formula 1.
In another embodiment of the present invention the 3-[l-dimethylamino)ethyl]phenol of Formula I is further converted to Rivastigmine or its pharmacologically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for preparing 3-[(l-dimethylamino)ethyI]phenol of Formula I, by aminating 3-hydroxyacetophenone with monomethylamine in the presence of hydrogenation catalyst and hydrogen to give monomethylaminoethylphenol of Formula III. The hydrogenation catalyst is selected from Pd/C, Raney Ni. The reaction is carried out using methanol as a solvent.

Methylating monomethylaminoethylphenol of Formula III to give 3-[(l-dimethylamino)ethyl]phenol of Formula I by using a methylating agent selected from a mixture of formic acid and formaldehyde or methyl halide in presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, lithium hydroxide, potassium carbonate.
The process to prepare rivastigmine and its pharmacologically acceptable salts thereof,comprises reacting 3-[(l-dimethylamino)ethyl]phenol of Formula I with ethylmethylcarbamoyl halide in presence of a base to give racemic rivastigmine. A wide variety of bases can be used in the reaction. Typical examples of such bases include without any limitation, metal alkoxide (e.g. sodium ethoxide, sodium methoxide, potassium tert-butoxide and alike); metal hydroxides (e.g sodium hydroxide, potassium hydroxide); organic amines (e.g triethylamine, 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU); l,5-diazabicyclo[2.2.0] non-5-ene (DBN); l,4-diazabicyclo[2.2.2] octane (DABCO), tert-butylamine etc.) and alike. The instant process may be conducted in presence or absence of solvent. The solvent is preferably inert during the reaction. Resolving the racemic Rivastigmine is done with a chiral resolving agent to give a single enantiomer of Rivastigmine in a solvent. The solvent is selected, such that individual salts have different solubilitities in the selected solvent or a solvent mixture. Rivastigmine is treated with an acid or a base to yield pharmacologically acceptable salts thereof.
The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE 1
PREPARATION OF 3-[(l-MONOMETHYLAMINO)ETHYL]PHENOL
A mixture of 3-hydroxyacetophenone (300 g), 20% monomethylamine in methanol
(3.0 L) was hydrogenated over Raney nickel (300 g) at 80° C and 10 Kg/Cm^ in an autoclave. After 12-14 hr Raney nickel was filtered off and the filtrate was concentrated to half the volume. The resulting product was isolated by filtration. Yield: 203 g
EXAMPLE 2
PREPARATION OF 3-[(l-DIMETHYLAMINO)ETHYL]PHENOL
3-[(l-Monomethylamino)ethyl]phenol (100 g) was added to a mixture of 85% formic acid (91.39 g) and 35% formaldehyde solution (85.14 g). The reaction mixture was refluxed for 2 h and cooled to room temperature. Water (100 ml) was added to the reaction mass. Thereafter, pH of the aqueous solution was adjusted to 8.8 using 40% aqueous sodium hydroxide solution and the precipitated product was filtered and dried to constant weight. Yield: 71 g
EXAMPLE 3
PREPARATION OF RACEMIC RIVASTIGMINE
A mixture of aminophenol (50 g), potassium tert-butoxide (35.7g),
ethylmethylcarbamoyl chloride (40.5 g) were stirred in tetrahydrofuran (500 ml) at ambient temperature for 24 hours. The reaction mass was poured into water (1200 ml) and acidified to pH 2. The aqueous layer was washed with toluene and basified to pH 11 and extracted with diisopropyl ether (3 X 300 ml). Combined extracts were

washed with water and concentrated under reduced pressure to give rivastigmine base as a thick yellowish brown oily material Yield: 68 g
EXAMPLE 4
PREPARATION OF RIVASTIGMINE
Racemic Rivastigmine was treated with di-p-toluoyl-D-tartaric acid (105 g) in methanol and water (2:1,. 680 ml) at reflux for 3 hr. It was cooled to S^^C and stirred for 2 hr. Crystalline solid thus obtained was filtered and dried. White solid was re-crystallized from methanol and water to get pure di-p-toluoyl-Z)-tartrate of Rivastigmine. Di-p-toluoyl-/)-tartrate of Rivastigmine (12.0 g) was suspended in water and basified to pH 10.5 with NaOH solution and the product was extracted into diisopropyl ether (3 x 50 ml). Combined diisopropyl ether extracts were washed with water, dried over sodium sulphate and concentrated under reduced pressure to obtain Rivastigmine as a colourless thick oily mass. Yield: 4 g
EXAMPLE 5:
PREPARATION OF RIVASTIGMINE HYDROGEN TARTRATE
The mixture of Rivastigmine (4.0 g), tartaric acid (2.28 g) and methanol (10 ml) was refluxed for 1 hr. The contents were cooled to 10 °C and stirred for 2 hr and acetone

(20 ml) was added and continued under stirring for 2 hr. at 3-5°C and filtered, dried under vaccum at 60° C to get Rivastigmine hydrogen tartrate. Yield: 2.5 g.

WE CLAIM
1) An improved process for preparing 3-[(l-dimethylaniino)ethyl]phenol of Formula
I

which comprises,
i) treating 3-hydroxyacetophenone with monomethylamine in the presence of a hydrogenation catalyst and hydrogen to give the monomethylaminoethylphenol of Formula III; and

ii) methylating the compound of Formula III to give compound of Formula I.
2) The process according to claim 1, hydrogenation catalyst is selected from Pd/C, RaneyNi.
3) The process according to claim 1, wherein the step (i) is carried out using methanol as a solvent.
4) The process according to claim 1, the methylation is carried out using a methylating agent.

5) The process according to claim 4, the methylating agent is selected from_formic acid and formaldehyde or methyl halide in presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, lithium hydroxide, potassium carbonate.
6) The 3-[(l-dimethylamino)ethyl]phenol of Formula I is further converted to Rivastigmine or its pharmacologically acceptable salts thereof.