This application claims priority to Indian patent application numbered 1525/CHE/2011 filed on May 03, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF INVENTION:

The present invention relates to an improved process for the preparation of Oseltamivir phosphate.
The present invention further relates to an improved and commercially viable process for the
preparation of amino azide of formula B, an intermediate in the preparation of Oseltamivir
phosphate, prepared from N- Acetyl Aziridine of formula A.

BACKGROUND OF THE INVENTION:

Oseltamivir phosphate, structurally represented by formula 1, is chemically know as (3R, 4R, 5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). It is an orally administered active inhibitor of influenza vims 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 pharmaceutically 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. 6204398 disclosed a process for preparing Oseltamivir or its salts as shown
below

U.S. Patent No. 7122684 discloses a process for preparing Oseltamivir or its salts by using below Scheme;

U.S. Patent No. 7687658 discloses a process for preparing Oseltamivir or its salts by using below Scheme;

U.S. publication No.20080009639 discloses a process for preparing Oseltamivir or its salts by using below Schemes;

TBCI (Z.OSttq), quantitative
Scheme 3

Wherein, R" is a leaving group selected from mesyloxy, trifloxy or tosyloxy R'" is a leaving group the same as defined above for R", or a protecting group most preferably selected from silyloxy groups. Most preferably, R"' is tosyloxy.

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 Oseltamivir phosphate.

In one aspect, the present invention relates to an improved process for the preparation of Oseltamivr phosphate comprising the steps of converting N-acetyl aziridine of formula A to give amino compound of formula B; Acetylating compound of formula B to give compound of formula C; reducing the compound of formula C by using tributylphosphine in the presence of aqueous organic solvent to obtain Oseltamivir free base; and optionally converting oseltamivir into its pharmaceutical^ acceptable salts.
Another object of the present invention relates to an improved process for the preparation of Aminoazide of formula B, an intermediate in the preparation of Oseltamivir phosphate;

by using an N-Acetyl Aziridine intermediate of formula A

Yet another object of the present invention relates to an improved process for the preparation of N- Acetyl Aziridine of formula A, a precursor of amino azide.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Oseltamivr phaosphate by using N- acetyl aziridine of formula A and amino azide of formula B, One embodiment of the present invention relates to an improved process for the preparation of Oseltamivir phosphate comprising the steps of;

i) converting N-acetyl aziridine of formula A to amino azide of formula B using an azide
in presence of an acid or acidic salt,

ii) Acetylating compound of formula B to give compound of formula C using suitable acetylating agent in the presence of organic solvent,

iii) reducing the compound of formula C using a phosphine in the presence of an aqueous organic solvent to obtain Oseltamivir free base; and

iv) Optionally converting oseltamivir into pharmaceutically acceptable salts

According to the present invention, N-acetyl aziridine is reacted with sodium azide in the presence of ammonium chloride, triethylamine hydrochloride, sulfuric acid or ammonium sulphate etc. preferebely ammonium chloride or ammonium sulphate most preferebly ammonium chloride and organic solvent such as alcohols selected form methanol, ethanol, isopropyl alcohol or nitriles such as acetonitrile, ether e.g. tetrahydrofuran, dioxane etc.to give compound of formula B. Compound of formula B is then reacted with suitable acetylating reagents such as acetic anhydride or acetyl chloride in the presence of inorganic or organic bases such as sodium acetate, triethyl amine, diisopropyl ethyl amine, potassium acetate and solvent selected from hydrocarbon such as toluene, cyclohexane, chlorinated solvents such as dichloromethane, chloroform and ether solvents such as diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran and dioxane to obtain compound of formula C. Reducing compound of formula C with suitable reducing agents such as trialkylylphosphine e.g. tributyl phosphine, trioctyl phosphine or triaryl phosphine such as triphenyl phosphine or tritolyl phosphine to obtain oseltamivir base. The Oseltamivir base is converted into its pharmaceutically acceptable salts preferably a phosphate salt by using orthophosphoric acid to obtain Oseltamivir Phosphate.

Yet another embodiment of the present invention, isolated Oseltamivir base having HPLC purity
more 99.5%.

Yet another embodiment of the present invention, Oseltamivir phosphate having HPLC purity
more 99.5%.

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

Yet another embodiment of the present invention relates to an improved process for the preparation of amino azide as represented in scheme below:

According to the present invention, N-acetyl aziridine is reacted with suitable azide such as sodium azide, lithium azide or other organic azide in presence of suitable organic solvent such as alcohols selected form methanol, ethanol, isopropyl alcohol or nitrites such as acetonitrile, ether e.g. tetrahydrofuran, dioxane etc. to obtain amino azide.

It has been observed that the opening of un substituted aziridine results in the formation of number of related impurities mainly the dimer impurity of formula D which is very difficult to remove during the isolation of the drug substances. Also drastically decreasing the yield of the product. It should be noted that the opening of the aziridine ring requires increasing the polarity that is being achieved by introducing the acetyl substituent.

Yet another embodiment of the present invention relates to a process for the preparation of N-acetyl aziridine as represented in scheme below:

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 Ethyl (3R, 4S, 5R)-5-azido-3-(1-ethyl-propoxy)-4-hydroxy-Cyclohexene-1-carboxylate and Ethyl (3R, 4R, 5S)-4-azido-3-(1-ethyl-propoxy)-5-hydroxy-1-cyclohexene-1-carboxylate (9:1) (hydroxy azides)

To the suspension of ethyl (3R, 4S, 5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-"Icarboxylate (Epoxide) (200.0 g, 0.786 mol) in ethanol (1000 ml) was added sodium azide ( 76.68 g, 1.179 mol) and ammonium chloride (63.0 g, 1.179 mol) and stirred at 70-75 °C for 15 h. The reaction mass was cooled to room temperature and filtered the insoluble materials. The filtrate was concentrated under vacuum and partitioned between cyclohexane (400 ml) and water 600 ml). Aqueous layer was extracted with cyclohexane (200 ml). Combined cyclohexane layer was washed with water (200 ml) and dried with anhydrous sodium sulphate. Cyclohexane was concentrated under vacuum below 50 °C to afford mixture of hydroxyl azides (228.0 g, 9:1) as brown oil.

Example 2: Preparation of Ethyl (5R, 6R, 1R)-S-(1-ethyl-propoxy)-7-aza-bicyclo[4.1.0]hept-3-ene-3-carboxylate (Aziridine) and Ethyl (5R, 6R, 1R)-7-acetyl-5-(1-ethyl-propoxy)-7-aza-bicyclo[4.1.0]hept-3-ene-3-carboxylate (N-acetyl aziridine)

To the solution of triphenylphosphine (95.5 g, 0,364 mol) in acetonitrile (800 ml) was added a solution of mixture of hydroxyl azides (114.0 g, from 100.0 g epoxide, 0.393 mol,) in acetonitrile (200 ml) at reflux temperature in 1 h and stirred at the same temperature for additional 3 h. The reaction mass was cooled to room temperature and added sodium bicarbonate (49.5 g, 0.589 mol). Added acetic anhydride (52.18 g, 0.51 mol) at the same temperature in 30 min and stirred for 2 h. Reaction mass was concentrated under vacuum below 50 °C. To the resulted semi solid mass was added water (400 ml), cyclohexane (400 ml) and MTBE (100 ml) and stirred for 30 min at RT and then 2h at 0-5 °C. Filtered the precipitate (TPPO) and washed the TPPO with precooled mixture of cyclohexane and MTBE (4:1). Separated aqueous layer and extracted with MTBE (100 ml). Combined organic layer was washed with brine and dried with anhydrous sodium sulphate and concentrated under vacuum to afford N-acetyl aziridine (130.0 g) as brown oil containing traces of triphenyl phosphine oxide (TPPO) and triphenyl phosphine.

Example 3: Preparation of Ethyl (3R, 4R, 5S)-4-amino-5-azido-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxy!ate( Amino azide) and Ethyl (3R, 4R, 5S)-4-Acetamido-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate(Acetamidoazide)

The mixture of crude N-acetyl aziridine (164.0 g, from 142 g epoxide, 0.558 mol) containing traces of
TPPO and triphenyl phosphine, sodium azide (54.44 g, 0.837 mol), ammonium chloride (41.8 g, 0.782 mol), ethanol (1136 ml) and water (284 ml) was stirred at 75-80 °C for 12 h. Cool to RT and distilled the solvents below 50 °C. Added toluene (500 ml) under stirring followed by water (710 ml). Separated aqueous layer and extracted with toluene (200 ml). Discarded aqueous layer and combined toluene layer was stirred with dilute phosphoric acid (113.6 g of 85 % H3P04 in 870 ml water) for 20 min. Separated aqueous layer which was extracted with toluene (200 ml and 200 ml ) sequentially. Discarded toluene layer and to the aqueous layer was added dichloromethane (350 ml) under stirring and adjusted pH 9.0 with aqueous ammonia at 0-5 °C. Separated dichloromethane layer and aqueous layer were extracted with dichloromethane (350 ml). Combined dichloromethane was dried with anhydrous sodium sulphate. To the dichloromethane layer was added sodium acetate (34.4 g, 0.418 mol) and cooled to 0-5 °C. Added acetic anhydride (37.05 g, 0.362 mol) in 30 min at the same temperature and stirred for 2 h. Added water (300 ml) and separated DCM layer which was washed with saturated sodium bicarbonate solution (710 ml) followed by water (300 ml). DCM layer was dried with anhydrous sodium sulphate and concentrated under vacuum. Added ethyl acetate (142 ml) and co-distilled the solvents completely. To the resulting solid mass was added ethyl acetate (213 ml) followed by n-hexane (426 ml) and stirred at RT for 1h followed by 2h stirring at 0-5 °C. Filtered the solid and washed with pre cooled mixture of ethyl acetate and n-hexane (1:3). The solid was dried under vacuum for 6 h at RT to afford acetamido azide (70 g). HPLC purity 98.4 %.

Example 4: Preparation of Ethyl (3R ,4R ,5S )-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate, phosphate (1:1) (Oseltamivir Phosphate)
Procedure: To the suspension of acetamido azide (10.0 g, 0.029 mol) in a mixture ethanol (60 ml) and water (10 ml) was added tributylphosphine (8.1 ml, 0.032 mol, in 10 ml ethanol) drop wise in 30 min and further stirred for 30 min. Added 3 drops of methanesolfonic acid and distilled solvents. The reaction mass was partitioned between dichloromethane and sodium bicarbonate solution. The dichloromethane layer was washed with water (2 x 20 ml) and the dried with anhydrous sodium sulphate that was filtered through celite bed. The filtrate was concentrated under vacuum to afford crude oseltamivir free base (17.2 g). To the solution of crude oseltamivir free base (17.2 g) in ethanol (90 ml) was added phosphoric acid solution (3.4 g 85 % phosphoric acid in 10 ml ethanol) drop wide in 30 min at 48-52 °C, during addition precipitate takes place. Added acetone (50 ml) drop wise in 15 min at the same temperature. Stirred at room temperature for 3.0 h. Filtered the precipitate, washed with acetone, heptane and dried to give oseltamivir phosphate (8.4 g, 69.2 %). HPLC purity: 99.84 %.

We claim:

1. A process for the preparation of formula I comprising the steps of;

a) converting compound of formula A to Compound of formula B,

b) converting compound of formula B to Compound of formula C,

c) converting compound of formula C to Oseltamivir free base,

d) converting Oseltamivir free base to Oseltamivir phosphate salt,

2. The process according to claim 1, wherein

a) in step a) compound of formula a is treated with an azide

b) in step b) compound of formula b is treated with an acetylating agent,

c) in step c) compound of formula c is reduced with trialkylylphosphine or triaryl phosphine, and

d) converting Oseltamivir base to Oseltamivir phosphate

3. An Improved process for the preparation of Oseltamivir phosphate comprising the steps of: a. converting N-acetyl aziridine of formula A to amino azide of formula B by treating with sodium azide in presence of organic solvent,

b. acetylating compound of formula B to give compound of formula C by treating with acetic anhydride or acetyl chloride or acetic acid with a coupling agent such as DCC, HOBt in presence of organic solvent,

c. reducing the compound of formula C using tributylphosphine in the presence of an aqueous organic solvent to obtain Oseltamivir free base; and

d. converting oseltamivir free base into oseltamivir phosphate.

4. The process according to claim 3, wherein the organic solvent is selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, tertiary-butyl alcohol, cyclohexanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether; nitriles such as acetonitrile, propionitrile; or polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide, dioxane, or water or mixtures thereof.

5. Oseltamivir phosphate free of dimmer impurity of formula D

6. Oseltamivir free of dimmer impurity of formula D.

7. Oseltamivir phosphate having HPLC purity more than 99.5 %.

8. Process for the preparation of oseltamivir phosphate compirisng the steps of: