This application claims priority to Indian patent application No. IN 3788/CHE/2011 filed on November 3,2011, the contents of which are incorporated by reference in their entirety.

FIELED OF THE INVENTION

The present invention relates to an improved process for the preparation of Oseltamivir phosphate form A or its intermediates thereof.

BACKGROUND OF THE INVENTION

Oseltamivir phosphate, structurally represented by formula 1, is chemically known as (3R, 4R, 5 S)-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 virus neuraminidase.

U.S. Patent 5,763,483 disclosed carboxyclic 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 F

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;

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 phosphate which is economical and industrially viable avoiding the use of harzardous/poisnous chemicals or formation of such compounds during the synthesis.

OBJECT AND SUMMARY OF THE INVENTION:

The main object of the present invention relates to a process for the preparation of Oseltamivir phosphate or its intermediates thereof.

The present invention further relates to a process for the preparation of pure crystalline form A of Oseltamivir phosphate by using amino azide of formula OSP-IV and Acetamido azide of formula OSP V.

Yet another object of the present invention relates to a process for the preparation of crystalline form A of Oseltamivir phosphate having less impurities and high purity comprising the steps of;

a) converting N-acetyl aziridine compound of formula OSP-III to amino azide of formula OSP-IV

N-acetyl Aziridine, OSP-III Amino azide, OSP -IV

b) acetylating amino azide of formula OSP-IV to acetamido azide of formula OSP-V

c) converting acetamido azide of formula OSP -V to Oseltamivir phosphate of formula -OSP -VI

d) optionally seeding and purifying Oseltamivir phosphate.

DETAILED DESCRIPTION OF THE INVENTION:

The main embodiment of the present invention relates to a process for the preparation of Oseltamivir phosphate or its intermediates thereof.

Yet another embodiment of the present invention relates to a process for the preparation of crystalline form A of Oseltamivir phosphate having less impurities and high purity comprising the steps of;

a) converting N-acetyl aziridine [OSP- III] to amino azide [OSP- IV];

b) acetylating amino azide[OSP-IV] to acetamido azide [OSP-V] Amino azide, OSP -IV Acetamido azide, OSP V

According to present invention, dissolving ethyl (5R, 6R, lR)-7-acetyl-5-(l- ethylpropoxy)-7-aza-bicyclo[4.1.0]hept-3-ene-3-carboxylate [N-acetyl Aziridine] in an organic solvent 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; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; 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 and dioxane or a mixture of thereof and adding suitable azide reagent such as sodium azide in presence of ammonium chloride followed by hydrolysis produces amino azide which is then acetylated on the amino group by treating with acetic anhydride and sodium acetate in presence of a suitable solvent selected from esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate to obtain ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate (Acetamido azide, OSP-V).

c) reducing acetamido azide[OSP-V];

According to present invention, dissolving acetamido azide in an organic solvent selected from ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone and treating with suitable reducing agent such as triphenyl phosphine obtains Oseltamivir. d) converting osteltamivir into phosphate salt and optionally seeding the salt material to obtain pure Oseltamivir phosphate in its crystalline form;

Oseltamivir Phosphate, OSP-VI pure Oseltamivir Phosphate According to present invention, dissolving Oseltamivir in an organic solvent 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 or a mixture thereof and treating with orthophosphoric acid followed by seeding with seed crystals of Oseltamivir phosphate form A obtains crystalline form A of Oseltamivir phosphate which is again optionally purified using organic solvent such as alcohol selected from methanol, ethanol, isopropylalcohol or these solvents in combination with water.

Yet another embodiment of the present invention relates to a process for the preparation of Oseltamivir phosphate comprising the steps of

a) dissolving ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l- cyclohexene-1 -carboxylate (Acetamido azide, OSP-V) in an organic solvent

b) adding a base

c) adding a reducing agent

d) adding ethanolic solution of orhophosphoric acid and

e) isolating Oseltamivir phosphate

According to the present invention, dissolving ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate (Acetamido azide, OSP-V) in an organic solvent 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, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate or a mixture thereof.Adding a base selected from organic base such as triethylamine, stir the reaction mass, adding reducing agent such as triphenyl phosphine obtains Oseltamivir. Adding ethanolic solution of ortho phosphoric acid obtains Oseltamivir phosphate.

Yet another embodiment of the present invention relates to a process for the preparation of Oseltamivir phosphate comprising the steps of:

a) dissolving ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l- cyclohexene-1-carboxylate in a keto solvent

b) adding a reducing agent

c) adding ethanolic solution of ortho phosphoric acid

d) optionally seeding the material; and

e) isolating Oseltamivir phosphate.

According to the present invention,dissolving ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate (acetamido azide, OSP-V) in a ketone such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate or a mixture thereof. Stir the reaction mass, adding reducing agent such as triphenyl phosphine obtains Oseltamivir.

Adding ethanolic solution of ortho phosphoric acid obtains Oseltamivir phosphate, optionally seeding with form A, thus isolating crystalline form A of Oseltamivir phosphate.

Yet another embodiment of the present invention relates to process for preparation of crystalline Form A of Oseltamivir phosphate free of N-acetyl impurity of formula (N), structurally represent as below:

According to present invention, reducing the acetamido azide intermediate by using triphenyl phosphine in the presence of ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanone restricts the acetyl migration compare with other solvents mixtures such as THF-water, acetonitrile-water, ethylacetate-water and isopropyl acetate-water.

Thus ketone solvents play a significant role in this step by restricting the migration of acyl group.

Yet another embodiment of the present invention relates to crystalline form A of Oseltamivir phosphate having overall impurities less than 0.1 %.

In yet another embodiment of the present invention relates to crystalline form A of

Oseltamivir phosphate having overall impurities less than 0.07 %.

Yet another embodiment of the present invention relates to crystalline form A of
Oseltamivir phosphate having purity 99.8 %. (by HPLC)

In yet another embodiment of the present invention relates to crystalline form A of Oseltamivir phosphate having purity more than 99.9 %.

Yet another embodiment of the present invention pure crystalline form A of Oseltamivir phosphate having water of hydration less than 0.5 %.

EXAMPLES:

Example -1: Preparation of ethyl (3R, 4S, 5R)-5 (4)-azido-3-(l-ethylpropoxy)-4(5)-hydroxy-cyclohexene-1-carboxylate (Hydroxy azides, OSP-I).

Ethyl (3R, 4S, 5S)-4, 5-epoxy-3-(l-ethylpropoxy)-cyclohex-l-ene-l-carboxylate (epoxide, 200 g) was taken in ethanol, stirred the reaction mass, added sodium azide and ammonium chloride at 27±5°C, slowly heated the reaction mass to 75°C. Maintained the reaction mass up to completion of reaction, cooled the reaction mass to at 20-25 °C and filtered and washed the residue with pre-cooled ethanol.

Concentrated the clear filtrate under reduced pressure at 40-45°C, cooled the reaction mass to 20-25 °C and added DM water. Added cyclohexane to the reaction mass, separated both layers and washed the organic layer with sodium chloride.

The organic layer is dried over anhydrous sodium sulfate and concentrated to obtain Ethyl (3R, 4S, 5R)-5 (4)-azido-3-( 1 -ethylpropoxy)-4(5)- hydroxy-cyclohexene-1 -carboxylate(OSP-1).

Example -2: Preparation of acetyl aziridine (OSP-III) To acetonitrile [pre-checked with water content] was added triphenyl phosphine under nitrogen atmosphere at 27±5°C and heated the reaction mass to reflux. Taken OSP-1 in acetonitrile and added to the above solution followed by maintenance till the completion of the reaction.

The reaction mass is cooled to 22-30°C and added sodium bicarbonate and acetic anhydride slowly. Maintained the reaction till the completion of the reaction monitored by HPLC analysis of unreacted aziridine. Removed the solvent under reduced pressure at 27-47°C. Cooled the reaction mass and added DM water, cyclohexane and ( methyl tertiary butyl ether(MTBE) at 27±5°C. The reaction mass is cooled to 2-6°C for precipitation of the byproduct triphenyl phosphine oxide. Filtered the biphasic reaction mass to remove the byproduct. Washed the filtrate with pre-cooled cyclohexane and MTBE. Separate the layers.

The aqueous layer is further extracted with MTBE and the combined organic layers are washed with sodium chloride and concentrated under reduced pressure to obtain a brown viscous oil. Cooled the concentrated oil and added ethanol. Further cooled the solution to about 0 degree centigrade and stored.

Example -3: Process for the preparation of Ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate (Acetamido azide, OSP-V) To the ethanolic solution of ethyl (5R, 6R, lR)-7-acetyl-5-(l-ethylpropoxy)-7-aza- bicyclo[4.1.0]hept-3-ene-3-carboxylate [N-acetyl aziridine (OSP-III] was added sodium azide, ammonium chloride and DM water.

Maintained the reaction mass at a temperature of about 74-78°C till the completion of the reaction. Concentrated the reaction mass under reduced pressure to remove the ethanol to certain volume. Cooled the contents and added toluene and DM water. Separated the layers. Further extracted the aqueous layer twice with toluene.

The combined organic layer was washed with water and added dilute orthopho phoric acid and DM water. Stirred the biphasic reaction mass and allowed to settle. Colledted the bottom aqueous layer containing the product. Repeated the step again to collect the product left from the biphasic layers.

The aqueous layer was washed with toluene. To the aqueous layer was added dichloromethane and allowed the contents to cool to 0 to 5 °C. Adjusted the pH of the reaction mass to 8.5 to 9.0 by adding aqueous ammonia at 0 to 15 °C. Allowed the reaction mass to settle and separated the organic layer containing the product. Repeated the extractioin step to collect the product left over in the aqueous layer.

The combined organic layers are washed with water and dried over anhydrous sodium sulphate. Cooled the reaction mass, adjusted the PH of the reaction mass with aqueous ammonia, settled the mass and separate the organic layer and re- I extract product by using dichloromethane. To this solution was added anhydrous sodium I acetate at 25±5°C and cooled the reaction mass to 0-5°C. Added acetic anhydride and I stirred the reaction mass up to completion of the reaction. Added DM water. Stirred biphasic reaction mass and separated the organic layer.

The combined organic layer is treated with sodium bicarbonate solution. The solvent is removed by distillation under reduced pressure (30-300 mm Hg) at 27-40°C. Added ethylacetate to the concentrate and distilled out completely.

The residue was dissolved in ethylacetate at 32-40°C, heated the reaction mass to 55-60°C. N-hexane was added to the reaction mass. Cooled the reaction mass, filtered and the obtained cake was further washed with N-hexane and dried under reduced pressure at 30-35°C to yield ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l- ethylpropoxy)-l- cyclohexene-l-carboxylate (acetamido azide, OSP-V).

Example -4: Preparation of Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate, phosphate (1:1) (Oseltamivir Phosphate).

Ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate (Acetamido azide, OSP-V, lOOg) was dissolved in acetone at 27±5°C. Added DM water and triphenyl phosphine to the reaction mass and raised the temperature to about 54±3°C. Maintained the reaction till the completion of the reaction. Cooled the reaction mass to 41±3°C, distilled out acetone under reduced pressure. Added dichloromethane and DM water at 27±3°C. Separated both the layers, dried the organic layer over anhydrous sodium sulphate.

Distilled dichloromethane under atmospheric pressure at 45±5°C. Cooled the reaction mass, filtered the mass, added ethanol to the oily mass at 27±5°C. Heat the reaction mass to 53±3°C, added solution of orthophosphoric acid taken in ethanol over a period of 5-10 min. Added seed material (Oseltamivir phosphate, form -A) at 53±3°C. Stirred the reaction mass at 53±3°C, cooled the reaction mass gradually over a period of 90-120min at 27±5°C. Filtered the reaction mass, washed the wet cake with acetone.

Wet cake was dissolved in ethanol and acetone, stirred the reaction mass, filtered the reaction mass and dried under reduced pressure to give pure crystalline form A of Oseltamivir phosphate. Yield: 85-100gm.

Example -5: Alternate process for Preparation of Ethyl (3R, 4R, 5S)-4-acetamido-5- amino-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate, phosphate (1:1) (Oseltamivir Phosphate)

Dissolved ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate (acetamido azide, OSP-V, 100 g) in ethyl acetate and water. Added triethylamine at 27±5 °C. Raised the temperature of the reaction mass to 57±3 °C and added triphenyl phosphine.

Maintained the reaction mass at a temperature of about 57±3 °C till the completion of the reaction and cooled the reaction mass. Distilled off ethyl acetate and added Dichloromethane and DM water. Allowed the reaction mass to settle and separated the bottom organic layer, extracted the product from the aqueous layer with dichloromethane.

The combined organic layers were concentrated under reduced pressure to obtain an oily residue. Cooled the oily residue to 27±5 °C, added ethanol and acetone and heated the reaction mass. Added ethanolic solution of orthophosphoric acid and maintained the reaction mass till the completion of the reaction. Filtered the product and washed with acetone and n-heptane to obtain the title product which is further dried under reduced pressure.

We claim:

1) A process for the preparation of Oseltamivir phosphate comprising the steps of:

a) dissolving ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l- cyclohexene-1-carboxylate in an keto solvent

b) adding a reducing agent

c) adding ethanolic solution of orthophosphoric acid

d) optionally seeding the material; and

e) isolating Oseltamivir phosphate.

2) The process according to claim 1 wherein the keto solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone and cyclohexanon.

3) The process according to claim 1 wherein the reducing agent is triphenyl phospine.

4) A process for the preparation of pure crystalline form A of Oseltamivir phosphate
comprising the steps of;

a) converting N-acetyl aziridine to amino azide ; N-acetyl Aziridine Amino azide

b) acetylating amino azide to acetamido azide Amino azide Acetamido azide

c) reducing acetamido azide in presence of a keto solvent;

d) converting Oseltamivir into phosphate salt and optionally seeding the salt material to obtain pure crystalline form A of Oseltamivir phosphate Oseltamivir Phosphate Pure Oseltamivir Phosphate

5) The process according to claim 4 wherein,

a) step a is carried in presence of sodium azide

b) step b, acetylating agent is acetic anhydride

c) step c, reducing agent is triphenyl phosphine and solvent is acetone

d) Step d, orthophosphoric acid is added in presence of ethanol and acetone mixture.

6) Pure crystalline form A of Oseltamivir phosphate having at least one of the characteristics selected from the group consisting of;

a) Purity more than 99.9 %

b) Water of hydration less than 0.5 %

c) Overall impurities less than 0.07 %.

7) Crystalline Form A of Oseltamivir phosphate free of N-acetyl impurity of formula (N)

8) A process for the preparation of Oseltamivir phosphate comprising the steps of

a) dissolving ethyl (3R, 4R, 5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)-l- cyclohexene-1-carboxylate (Acetamido azide, OSP-V) in an organic solvent

b) adding a base

c) adding a reducing agent

d) adding ethanolic solution of orho phosphoric acid ande) isolating Oseltamivir phosphate

9) The process according to claim 8 wherein,

a) step a, organic solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof

b) step b, base is triethylamine

c) step c, reducing agent is triphenyl phosphine

d) Step d, orthophosphoric acid is added in presence of ethanol and acetone mixture.