FIELD OF INVENTION:

The present invention relates to a process for the preparation of rivastigmine tartrate and its intermediates thereof. More specifically, it relates to preparation of S-(-)-l-[(3-methoxy phenyl)ethyl]dimethyl amine, which is an important intermediate for the preparation of rivastigmine and its salts.

BACKGROUND OF THE INVENTION:

Rivastigmine tartrate is chemically known as (S)-N-Ethyl-N-methyl-3-[l-(dimethylamino) ethyl]-phenyl carbamate hydrogen-(2R,3R)-tartrate (hereinafter referred to as "Rivastigmine tartrate") and has structural Formula I

Rivastigmine tartrate is administered for the inhibition of reversible cholinesterase and is marketed under the brand name EXELON® as capsules.

US patent No. 4,948,807 describes the compound of N-ethyl, N-methyl-3-[l-(dimethylamino)ethyl]phenyl carbamate and its pharmacologically acceptable salts along with a pharmaceutical composition useful for treating anti-cholinesterase activity in humans.

US patent No. 5,602,176 describes (S)-N-ethyl-N-methyl-3-[(l-dimethylaamino)ethyl]phenyl carbamate in free base or acid addition salt form as useful for its anti-cholinesterase activity. It also describes process for preparation involving resolution of N-ethyl, N-methyl-3-[l-(dimethylamino)ethyl]phenyl carbamate in presence of (+)-di-para-toluoyl tartaric acid ((+)-DPTTA). The yield of the resolution process is very low.

Resolution in the final stage of synthesis has technological disadvantage as at least 50% of the racemic compound (herein (R)-enantiomer of rivastigmine) represents as useless waste. This waste is much bigger since optical resolution never separates enantiomers quantitatively. The wastage results into higher cost, making the process not suitable for commercial manufacturing. In general, the losses at advanced intermediate stage are more cost consuming than those in the initial steps. This process also creates the necessity of using the expensive and carcinogenic N-ethyl-N-methylcarbamoyl chloride in excess amount.

International Application Publication No WO 04/ 037771 discloses preparation of rivastigmine by resoluting 3-[(l-dimethylamino)ethyl]-phenol with S-(+)-camphor-10-sulfonic acid in presence of ethylacetate to obtain an optically pure S-(-)3-[(l-dimethylamino) ethyl]-phenol and converting the same to rivastigmine. The main drawback of this process is the low yield (25-31%) obtained during the resolution of 3-[l-(dimethylamino)ethyl]phenol to get optically pure compound. This process is very lengthy as it involves more number of purification steps which consumes more solvent. Resolution with S-(+)-camphor-10- sulfonic acid is of high cost, difficult for recovery and does not suit for commercial manufacturing.

US 2008/0255383 Al discloses preparation of rivastigmine by resolution of l-(3-methoxyphenyl)ethylamine with L-(+)-mandelic acid in isopropyl alcohol, reacting the mandelate salt of l-(3-methoxylphenyl)ethylamine with formaldehyde and formic acid to get S-(-)-(l-(3-methoxyphenyl)ethyl) dimethyl amine and converting the same to rivastigmine. This process involves use of high volume of alcohol solvent making the process not viable for commercial manufacturing.
It has been found that there is a need to develop an improved process for the preparation of rivastigmine, which involves a less expensive simple resolution in earlier stages of reaction and less number of purification steps to obtain a very good yield of (S)-rivastigmine with retaining high analytic purity.

SUMMARY OF THE INVENTION:

The present invention relates a process for the preparation of rivastigmine tartrate and its intermediates.

In one aspect, present invention provides a process for the preparation of S-(-)-l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula II, which is an important intermediate for the preparation of rivastigmine and its salts.

The reaction comprises resolution of l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula III in the presence of 0,0'-di-p-toluoyl-(2R,3R)-tartaric acid (DPTTA).

In another aspect of the present invention provides a process for the preparation of rivastigmine tartrate, which comprising the steps of:

a) resolution of the compound of Formula II to give compound of Formula II;
b) O-dealkylation of compound of Formula III;
c) condensation of the compound obtained in step b) with carbamoylhalide of Formula IV; and
d) addition of tartaric acid in the presence of solvent to give rivastigmine tartrate.

BRIEF DESCRIPTION OF THE DRAWINGS:

Fig. 1 is a schematic representation of a process for preparing rivastigmine.

DETAILED DESCRIPTION:

The present invention relates to a process for the preparation of rivastigmine and intermediates thereof.
In one aspect, the present invention provides a process for the preparation of S-(-)-l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula II, which is an important intermediate for the preparation of rivastigmine and its salts.

The process comprises the reaction of l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula III with a 0,0'-di-p-toluoyl-(2R,3R)-tartaric acid (DPTTA) to give S-(-)-l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula II.

The above reaction is carried out in the presence of a solvent selected from acetone, isopropyl alcohol, ethanol in ethyl acetate, dioxane and mixtures thereof.

DPTTA used in the above reaction can be recovered for further use and it is very cheaper than other resolving agents like camphor sulfonic acid, which cannot be recovered.
The R-Form of the compound of Formula II also can be recemized to avoid yield loss.

The compound of Formula III is prepared according to well-known process as shown below:

In another aspect of the present invention provides a process for the preparation of rivastigmine using the intermediate compound of Formulall. The process comprises:

a) resolution of compound of Formula III to give S-Form of Formula II;
b) O-dealkylation of compound of Formula II;
c) addition of carbamoylhalide of Formula IV to give rivastigmine base; and
d) addition of L-tartaric acid to give rivastigmine tartrate.


wherein resolution is carried out using DPTTA in the presence of a solvent selected from acetone, acetone, isopropyl alcohol, ethanol in ethyl acetate, dioxane and mixtures thereof. O-dealkylation is carried out in the presence of HBr. In step d) rivastigmine tartrate is prepared in the presence of an organic solvent selected from MIBK, MEK and water, preferably acetone.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES:
Example 1: Process for the preparation of S-(-)-l-[(3-methoxy phenvDethyl]dimethyl amine of Formula II:
Charge 2L of acetone into RB flask at 25-30°C and charge 100 gr of l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula III. Stir for 15min and add DPTTA (0,0'-di-p-toluoyl-(2R,3R)-tartaric acid) at 25-30°C. Stir for 2hat 25-30°. Filter and wash the reaction mass with 100 ml of acetone. Dry the solid at 50-55°C for 10 h.

Purification of DPTTA salt of Formula II:
Charge 1L of methanol into 2L RB flask at 25-30°C and charge DPTTA salt of compound of Formula II. Rise the temperature to 65-68°C and stir for 1 h. Cool the temperature to 25-30°C and stir for 1 h. Filter and wash the reaction mass with 100 ml of methanol. Dry the solid at 50-55°C for 10 h.
Preparation of compound of Formula II:

Charge 650 ml of ethyl acetate and 325 ml of water in 2 L RB flask at 25-30°C. Charge the purified DPTTA salt obtained in the above step and adjust the pH to 9-9.5 with 10% NaOH solution at 20-25°C. Stir the reaction mass for 30 min. Settle and separate the layers and extract the aqueous layer with 325 ml of ethyl acetate. Combine organic layer and wash with 325 ml of water. Dry the organic layer with sodium sulfate at 25-30°C. Distill the organic layer under vacuum up to get residue at 50-55°C.

Yield-25-35% Chiral purity - > 99.7%.

Example 2: Preparation of Rivastigmine tartrate of Formula I:

a) Preparation of S-(-)3-[l-dimethvlamino1ethyl-phenol:
Charge 550 ml of 48% aq. HBr in 3L RB flask and charge 100 gr of compound of Formula II obtained in the process according to the example 1 at 25-30°C. Rise the temperature to 100-110°C and stir for 10-12 h. Cool the reaction mass to room temperature and charge 1L of water. Adjust the pH to 8.5-9.0 with 40% NaOH solution at 10-15°C. Extract with ethyl acetate(lx500 ml and 1x350 ml). Combine organic layer and wash with water. Distill the organic layer under vacuum up to get residue at 40-45°C and cool to room temperature. Charge 800 ml of n-heptane and stir for 1 h. Filter and wash the reaction mass with 100 ml of heptane. Dry the solid at 50-55°C for 10 h.
Yield-80-85%

b) Preparation of Rivastigmine base:
Charge 650 ml of THF in 1L RB flask and charge 24.3 gr of 60% NaH under Nitrogen atmosphere. Charge 100 gr of the compound obtained according the above process (step a) and cool to 10-15°C under Nitrogen atmosphere. Add 76.8 gr of N-ethyl-N-methyl carbamoyl chloride of Formula IV drop wise for 30 min. Rise the reaction temperature to 25-30°C and stir for 2 h. Distill the mixture completely under vacuum at 40-45 °C and cool to room temperature. Charge 430 ml of IN NaOH solution at 25-30°C. Charge 1075 ml of ethyl acetate and stir for 30 min. Settle and separate layers and extract aqueous layer with ethyl acetate (2x1075 ml). Combine the organic layer and wash with water and distill the solvent under vacuum up to get residue.

Yield-85-90%

c) Preparation of Rivastigmine tartrate of Formula I:
Charge 3.5 L of acetone into 5L RB flask and charge 100 gr of rivastigmine base obtained according the process of step (b). Add 60 gr of L-(+)-tartaric acid at 25-30°C. Rise the temperature to 55-58°C and stir for 1 h. Filetr the mass through hiflo bed under hot condition. Distill 50% of filtrate (acetone) at 50-55°C and cool to room temperature. Stir for 1 h and add 0.005 gr of seeding material to reaction mass and stir for 2 h. Filter and wash the reaction mass with 100 ml of acetone. Dry the solid at 50-55°C for 10 h.
Yield-90-95%

We claim,

1. A process for the preparation of S-(-)-l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula II, which is an intermediate for the preparation of rivastigmine and its salts.

which comprises resolution of l-[(3-methoxy phenyl)ethyl]dimethyl amine of Formula III

2. A process according the claim 1, wherein the resolution is carried in the presence of DPTTA (0,0'-di-p-toluoyl-(2R,3R)-tartaricacid).

3. A process for the preparation of rivastigmine tartrate, which comprises:

a) resolution of compound of Formula III to give S-Form of Formula II;
b) O-dealkylation of compound of Formula II;
c) addition of carbamoylhalide of Formula IV to give rivastigmine base; and
d) addition of L-tartaric acid to give rivastigmine tartrate.

4. A process according to claim 3, resolution is carried out in the presence of DPTTA.

5. A process according to claim 1 and 3, resolution is carried out in the presence of an organic solvent selected from acetone, isopropyl alcohol, ethanol in ethyl acetate, dioxane and mixtures thereof.

6. A process according to claim 3, O-dealkylation is carried out in the presence of HBr.

7. A process according to claim 3, step d) rivastigmine tartrate is prepared in the presence of an organic solvent selected from MIBK, MEK and water, preferably acetone.