This application claims priority to Indian patent application No. 124/CHE/2011 filed on January 14, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF INVENTION:

The present invention relates to an improved and commercially viable process for the preparation of acetamido azide of formula X, an intermediate in the preparation of Oseltamivir, prepared from N- acetyl aziridine of formula Y.

BACKGROUND OF THE INVENTION:

Oseltamivir phosphate, structurally represented by formula 1, is chemically know as (3R, 4R, 5S)-4-acetylamino-5-amino-3(l -ethylpropoxy)-1 -cyclohexene-1 -carboxylic acid, ethyl ester, phosphate (1:1). It is an orally administered active inhibitor of influenza virus neuraminidase.

U.S. Patent 5,763,483 disclosed carbocyclic compounds and pharmaceutically acceptable salts thereof. The disclosed compounds include Oseltamivir and its salts.

Different methods for the preparation of Oseltamivir and its pharmaceutical^ acceptable salts were disclosed in U.S. Pat. No. 5,763,483, J. Org. Chem., Vol. 63, No. 13, 1998 (page: 4545-4550), J. Amer. Chem. Soc., Vol. 115, No. 4, 1997 (Page: 681-690), U.S. Pat. No. 5,952,375 and PCT Publication No. WO 99/44185.

U.S. Patent No. 6,204,398, 7,122,684, 7,687,658, disclosed a process for preparing Oseltamivir or its salts Still there is a need to have an improved process for the preparation of Oseltamivir which is economical and industrially viable avoiding the use of harzardous/poisnous chemicals or formation of such compound during the synthesis.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention relates to an improved process for the preparation of acetamido azide of formula X, an intermediate in the preparation of Oseltamivir phosphate;

by using an N-acetyl aziridine intermediate of formula Y

Another object of the present invention relates to an improved process for the preparation of N- acetyl aziridine of formula Y, a precursor of Acetamido azide.

In one aspect, the present invention relates to an improved process for the preparation of Oseltamivr phosphate comprising the steps of

i) converting N-acetyl aziridine of formula (Y) to Acetamido azide of formula

(X)




ii) reducing the acetamido azide reduction in the presence of lindler catalyst or Triphenyl phosphine/trialkyl phosphine to obtain Oseltamivir free base; and

iii) Salt formation.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of an acetamido azide of formula X, an intermediate of Oseltamivir Phosphate using N- acetyl aziridine of formula Y

In one embodiment the present invention relates to an improved process for the preparation of acetamido azide as represented in scheme below:

According to the present invention, N-acetyl aziridine is reacted with suitable azide in presence of tetraalkylammonium fluorides such as tetrabutylammonium fluoride or cesium fluoride or ammonium fluoride and suitable organic solvent to obtain acetamido azide.

In one embodiment, the azide is selected from trialkyl silyl azide preferably trimethylsilyl azide and the organic solvent is selected from hydrocarbons preferably tetrahydrofuran, acetonitrile, ethereal solvents such as diisopropyl ether, halogenated solvents such as dichloromethane, hydrocarbon solvents such as hexane or heptane.

Another embodiment of the present invention relates to an improved process for the

preparation of Oseltamivir phosphate comprising the steps of;

1. converting N-acetyl aziridine compound of formula (Y) to acetamido azide of formula (X) using terabutyl ammonium flouride and an azide compound in the presence of an organic solvent;

2. reducing the azide compound in the presence of lindler catalyst or triphenyl phosphine/trialkyl phosphine to obtain oseltamivir base; and

3. converting the Oseltamivir free base to its phosphate salt.

According to the present invention, N-acetyl aziridine is reacted with tetrabutylammonium fluoride and an azide compound preferably trimethylsilylazide in the presence of suitable organic solvent such as tetrahydrofuran to obtain to Acetamido azide. The acetamido azide is hydrogenated in presence of Lindler catalyst to obtain Oseltamivir base.

The Oseltamivir base is converted to phosphate salt using phosphoric
acid.

Yet another embodiment of the present invention relates to an improved process for the preparation of Oseltamivir phosphate as shown in scheme below;

OEt
OEt
Acetamido azide
N-Acetyl Aziridine
Aziridine
OEt
AcHN T
NH2.H3PO4

Oseltamivir phosphate

Osteltamivir phosphate prepared according to the present process have HPLC purity greater than 99.5%.

The following examples are merely shown as representative examples of the present invention but are not intended to be limiting.

EXAMPLES

Example 1: Preparation of mixture of Ethyl (3R, 4S, 5R)-5-azido-3-(l-ethyl- propoxy)-4-hydroxy-cyclohexene-l-carboxylate and Ethyl (3R, 4R, 5S)-4-azido-3-(l- ethyl-propoxy)-5-hydroxy-l-cyclohexene-l-carboxylate (9:1)

To the solution of Ethyl (3R, 4S, 5S)-4, 5-epoxy-3-(l- ethyl-propoxy)cyclohex-l-ene-l- carboxylate (epoxide) (50.0 g, 0.197 mol) in ethanol (250 ml) was added sodium azide (19.2 g, 0.29 mol) and ammonium chloride (15.8 g, 0.29 mol) and stirred at 78-80°C for 15 hours. The reaction mass was cooled to room temperature and ethanol was distilled under vacuum at 50°C. To the mass was added toluene and water and separated toluene layer which was washed with water, brine, dried with anhydrous sodium sulphate then concentrated under vacuum to get the said mixture of title compounds (56.0 g, 95.6 % yield, combined HPLC purity 95 %) as brown oil.

Example 2: Preparation of Ethyl (5R, 6R, lR)-5--(l-ethyl-propoxy)-7-aza- bicyclo [4.1.0] hept-3-ene-3-carboxylate (Aziridine):

To the solution of triphenylphosphine (41.89 g, 0.159 mol) in acetonitrile (400 ml) was added a solution of above mixture of products (50.0 g, 0.168 mol) in acetonitrile (100 ml) at reflux temperature in 1 hour and maintained at the same temperature for additional 3 hours. The reaction mass was cooled to room temperature and acetonitrile was distilled under vacuum completely at 45 °C. To the semi solid mass was added hexane (300 ml) and stirred at room temperature for 30 min during triphenylphosphine oxide precipitate out. Stirred at 10°C for 1 hour and filtered triphenylphosphine oxide which was washed with cold hexane. The filtrate was concentrated under vacuum at 45°C to afford aziridine (43.0 g, 100% yield, HPLC purity 81 %) as brown oil containing traces of triphenylphosphine oxide and triphenylphosphine.

Example 3: Preparation of Ethyl (5R, 6R, lR)-7-acetyl-5-(l-ethyl-propoxy)-7-aza- bicyclo[4.1.0]hept-3-ene-3-carboxylate (N-acetyl aziridine):

To the solution of above aziridine (10.0 g, 3.9 mmol) in ethyl acetate (90 ml) was added triethyl amine (11.98 g, 0.118 mol) and cooled to 0-5 °C. A mixture of acetic anhydride (8.06 g, 0.078 mol) in ethylacetate (10 ml) was added drop wise in 5-10 min at the same temperature and stirred for 45 min at 0-5 °C. A saturated solution of potassium carbonate (50 ml) was added at the same temperature in 5 min and extracted. Ethyl acetate layer was washed with brine (50 ml) and dried. The ethyl acetate was concentrated under vacuum and crude mass was purified by column chromatography to afford titled compound (6.2 g, 53 % yield) as light yellow oil.

Example 4: Preparation of Ethyl (3R, 4R, 5S)-4-Acetamido-5-azido-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate

To a solution of N-acetyl aziridine (lg, 0.33mmol) in dry tetrahydrofuran was added trimethylsilylazide (2g, 1.65mmol) and Tetrabutylammonium fluoride (lmolar solution in THF; 0.16mmol). The resulting solution was heated to reflux for 16hours. The reaction mass was cooled to room temperature, added Ethylacetate and washed with water. The organic layer was collected dried and evaporated. The crude product was crystallized in Ethylacetate-Hexane to give pure acetamido azide (yield 70%).

We Claim:

1. A process for the preparation of acetamido azide from N-acetyl aziridine using suitable base, azide and organic solvent.

2. The process according to claim 1, wherein the base is selected from tetrabutylammonium fluoride, cesium fluoride or ammonium fluoride.

3. The process according to claim 1, wherein the azide is a trialkyl silyl azide such as trimethylsilyl azide.

4. The process according to claim 1, wherein the organic solvent is selected from tetrahydrofuran, acetonitrile, dichlorimethane, hexane or diisopropyl ether.

5. A process for the preparation of ethyl-4-acetamido-5-azido-3-(l-ethylpropoxy)-l- cyclohexene-l-carboxylate from ethyl-7-acetyl-5-(l-ethyl-propoxy)-7-azabicyclo[4.1.0]- hept-3-end-3-carboxylate using trimethylsilyl azide and tetrabutylammonium fluoride in tetrahydrofuran.

6. An improved process for the preparation of Oseltamivir phosphate comprising the steps of;

A. converting N-acetyl aziridine compound of formula (Y) to Acetamido azide of formula (X)

B. hydrogenating the acetamido azide compound in presence of Lindler catalyst to obtain oseltamivir free base; and

C. converting the oseltamivir free base to its phosphaste salt.

7. Osteltamivir phosphate prepared according to claim 6 having HPLC purity greater than 99.5%.