DESC:FIELD OF INVENTION

The present invention relates to one pot process for the preparation of Oseltamivir phosphate (I).

Formula I

BACKGROUND OF THE INVENTION

Oseltamivir phosphate (I) is chemically known 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.

US 5763483 disclosed carbocyclic compounds and pharmaceutically acceptable salts thereof. The disclosed compounds include Oseltamivir and its salts.

US 5763483 discloses a process for the preparation of Oseltamivir (Ia) as shown in scheme-I below:

The main disadvantages of the above process are involves multiple number of steps for the preparation of Oseltamivir (Ia) which increase the time cycle of the reaction and making the process more expensive and decrease in the yields. The intermediates involved for the synthesis of Oseltamivir (Ia) need to be isolated at various steps and further purification is required to get the desired purity of the final product. The use of multiple steps results in a lower yield of final product.

US 7122684 discloses a process for the preparation of Oseltamivir phosphate (I) as shown in scheme-II below:

The main disadvantages of the above process are involves multiple number of steps for the preparation of Oseltamivir phosphate (I) which increase the time cycle of the reaction and making the process more expensive and decrease in the yields. The intermediates involved for the synthesis of Oseltamivir phosphate (I) need to be isolated at various steps and further purification is required to get the desired purity of the final product.

US 5859284 discloses a process for the preparation of Oseltamivir phosphate (I) as shown in scheme-III below:

The main disadvantages of the above process are involves multiple number of steps for the preparation of Oseltamivir phosphate (I) which increase the time cycle of the reaction and making the process more expensive and decrease in the yields. The intermediates involved for the synthesis of Oseltamivir phosphate (I) need to be isolated at various steps and further purification is required to get the desired purity of the final product.

Different methods for the preparation of Oseltamivir or its pharmaceutically acceptable salts were disclosed in Journal of organic chemistry vol. 63, issue 13, pages 4545-4550, 1998; Journal of American chemical society, vol-1165, issue-4, pages 681-690, 1997; US 5952375 and WO 1999/44185.

All the above said prior-art processes involves multiple number of steps for the preparation of Oseltamivir phosphate (I) which increase the time cycle of the reaction and making the process more expensive and decrease in the yields.

In view of the foregoing, there is an unmet need to develop an improved process for the preparation of Oseltamivir phosphate (I), which is simple, reduces the number of steps and cost effective, suitable for industrial scale and provides the desired product with high yield and purity.

Hence there is a long-felt need for the development of an improved process that circumvents the above disadvantages and provides an industrially feasible and cost effective process.

The present invention is an improved one pot process for preparing Oseltamivir phosphate (I) without isolating the intermediates in each step involved in the synthesis.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide one pot process for the preparation of Oseltamivir phosphate (I) with high purity and good yield on commercial scale.

Yet another object of the present invention is to provide a process for the preparation of Oseltamivir phosphate (I) which avoids isolation of intermediates formed during the synthesis.

Yet another object of the present invention is to provide a process for the preparation of Oseltamivir phosphate (I) which is simple, economical and suitable for industrial scale-up.
SUMMARY OF THE INVENTION

According to the present invention, there is provided an improved one pot process for the preparation of Oseltamivir phosphate (I).

According to a first aspect of the present invention there is provided one pot process for the preparation of Oseltamivir phosphate (I),

Formula I

which comprises,

i. reacting (1S,5R,6S)-ethyl 5-(pentan-3-yloxy)-7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylate of formula (X);

Formula X

with sodium azide and ammonium chloride in presence of solvent to obtain (3R,4S,5R)-ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate of formula (XVI);

Formula XVI
ii. reacting (3R,4S,5R)-ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate of formula (XVI) with hydroxyl protecting compound in presence of base and solvent to obtain compound of formula (XX);

Formula XX
wherein, P is methanesulfonyl group or p-toluenesulfonyl group or benzenesulfonyl group.

iii. reacting compound of formula (XX) with triphenylphosphine in presence of carboxylic acid, base, and solvent to obtain (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate of formula (XVII);

Formula XVII
iv. reacting (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate of formula (XVII) with sodium azide and ammonium chloride in presence of solvent to obtain (3R,4R,5S)-ethyl 4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XVIII);

Formula XVIII
v. acetylation of (3R,4R,5S)-ethyl 4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XVIII) using acetylating agent in presence of base and solvent to obtain (3R,4R,5S)-ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XIX);

Formula XIX
vi. reacting (3R,4R,5S)-ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XIX) with triphenylphosphine in presence of solvent to obtain Oseltamivir free base of formula (Ia);

vii. Oseltamivir free base of formula (Ia) is converted to Oseltamivir phosphate (I),
wherein, steps (i), (ii), (iii), (iv), (v) and (vi) are carried out without isolating the compound of formulae (XVI), (XVII), (XVIII), (XIX, (XX) and (Ia).
DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, there is provided an improved one pot process for the preparation of Oseltamivir phosphate (I), as depicted below in scheme-IV.

In an embodiment of the invention, (1S,5R,6S)-ethyl 5-(pentan-3-yloxy)-7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylate (X) is reacted with sodium azide and ammonium chloride in presence of solvent to obtain (3R,4S,5R)-ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate (XVI).

The above reaction is carried out in the presence solvent system include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about 0°C to reflux temperature of the solvent used. Preferably, the reaction is carried out at a temperature in the range of from about 20°C to about 85°C.

The reaction is carried out for about 5 hour to about 12 hours, more preferably for about 7 hours to about 12 hours, most preferably for about 7 hour to about 10 hours.

The compound (3R,4S,5R)-Ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate (XVI) obtained by the process of the present invention is then reacted with hydroxyl protecting compound in presence of base and solvent to obtain compound (XX).

Hydroxyl protecting compound used in the above reaction selected from but not restricted to methanesulfonyl chloride (MSA), p-toluenesulfonyl chloride (p-TSA), benzenesulfonyl chloride or the like.

The base used in above reaction includes an organic and inorganic bases. Organic base is selected from but not restricted to triethylamine, pyridine, monomethyl amine, dimethyl amine, trimethyl amine, ethyl amine, diethyl amine, diisopropyl ethyl amine, DBU, DABCo, 2,6-Lutidine or mixtures thereof and inorganic base selected from but not restricted to alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate or alkaline or alkaline earth metal bicarbonate or mixtures thereof.

The solvent system used in above reaction include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about 0° C to about 40°C. Preferably, the reaction is carried out at a temperature in the range of from about 5°C to about 35°C.

The reaction is carried out for about 30 minutes to about 3 hours, preferably for about 45 minutes to about 2 hour.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.

The compound (XX) obtained by the process of the present invention is then reacted with triphenyl phosphine in presence of carboxylic acid, solvent followed by acid-base treatment to obtain (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo [4.1.0]hept-3-ene-3-carboxylate (XVII).

The carboxylic acid used in above reaction include but not restricted to an aliphatic carboxylic acid, having from 2 to 8 carbon atoms, such as acetic acid, oxalic acid, propionic acid, malonic acid, butyric acid, succinic acid, maleic acid, fumaric acid, valeric acid, glutaric acid, caproic acid, adipic acid, heptanoic acid, and caprylic acid.

The solvent system used in above reaction include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The acid used in above reaction include but is not restricted to HCl, HBr, HI, H2SO4, HNO3 or H3PO4.

The base used in above reaction includes an organic and inorganic bases. Organic base is selected from but not restricted to triethylamine, pyridine, monomethyl amine, dimethyl amine, trimethyl amine, ethyl amine, diethyl amine, diisopropyl ethyl amine, DBU, DABCo, 2,6-Lutidine or mixtures thereof and inorganic base selected from but not restricted to ammonia, alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate or alkaline or alkaline earth metal bicarbonate or mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about -70°C to reflux temperature of the solvent used. Preferably, the reaction is carried out at a temperature in the range of from about 0°C to about 90°C.

The reaction is carried out for about 5 hours to about 15 hours, preferably for about 9 hours to about 11 hours.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.

The compound (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate (XVII) obtained by the process of the present invention is then reacted with sodium azide and ammonium chloride in presence of solvent to obtain (3R,4R,5S)-ethyl 4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (XVIII).

The solvent system used in above reaction include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. Amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; hydrocarbons include, but are not limited to toluene, hexane, cyclohexane, xylene and the like; alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.
The reaction is typically carried out at a temperature in the range of from about 0°C to 90°C. Preferably, the reaction is carried out at a temperature in the range of from about 20°C to about 85°C.

The reaction is carried out for about 3 hours to about 8 hours, preferably for about 3 hours to about 6 hours.

Acetylation of the compound (3R,4R,5S)-ethyl 4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (XVIII) obtained by the process of the present invention in presence of base, solvent followed by washing with inorganic acid to obtain (3R,4R,5S)-ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (XIX).

Acetylating agent used in above reaction include but not restricted to acetic anhydride or acetyl chloride or acetic acid with a coupling agent such as DCC or HOBt.

The base used in above reaction includes an organic and inorganic bases. Organic base is selected from but not restricted to triethylamine, pyridine, monomethyl amine, dimethyl amine, trimethyl amine, ethyl amine, diethyl amine, diisopropyl ethyl amine, DBU, DABCo, 2,6-Lutidine or mixtures thereof and inorganic base selected from but not restricted to alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate or alkaline or alkaline earth metal bicarbonate or mixtures thereof.

The solvent system used in above reaction include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. Hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about 0° C to about 40°C. Preferably, the reaction is carried out at a temperature in the range of from about 5°C to about 35°C.

The reaction is carried out for about 30 minutes to about 3 hours, preferably for about 45 minutes to about 2 hour.

The inorganic acid used in above reaction include but is not restricted to HCl, HBr, HI, H2SO4, HNO3 or H3PO4.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.

The compound (3R,4R,5S)-ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-ene carboxylate (XIX) obtained by the process of the present invention is then reacted with triphenylphosphine in presence of solvent to obtain Oseltamivir free base (I).

The solvent system used in above reaction include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about 15° C to about 70°C. Preferably, the reaction is carried out at a temperature in the range of from about 25°C to about 55°C.

The reaction is carried out for about 10 hours to about 15 hours, preferably for about 11 to about 12 hours.

The compound Oseltamivir free base (Ia) obtained by the process of the present invention is then reacted with phosphoric acid in presence of solvent to obtain Oseltamivir phosphate (I).

The solvent system used in above reaction include but is not limited to ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like; alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like and mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about -70° C to about 70°C. Preferably, the reaction is carried out at a temperature in the range of from about 0°C to about 55°C.

Purification of Oseltamivir phosphate (I) is carried out in presence of alcohol solvent include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like followed by washing with ketonic solvent include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and hydrocarbon solvent include, but are not limited to hexane, cyclohexane, heptane or the like.

In another embodiment of the present invention is to provide a process for the preparation of (1S,5R,6S)-ethyl 5-(pentan-3-yloxy)-7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylate of formula (X), as depicted below in scheme-V.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be constructed to limit the scope of the invention.

Examples:

Example-1: Shikimic acid to hydroxy ketal
In a 500 mL round bottom flask fitted with thermopocket, mechanical stirrer, condenser with nitrogen supply was added 300 ml ethanol, 100 g of Shikimic acid (0.574 mol) and 15 g of benzene sulfonic acid (0.095 mol) were stirred for 15 min and heated to reflux for 6-8 hrs. After completion of reaction, reaction mass was cooled to 25-35°C and added 30 g of triethylorthoformate (0.202 mol). Heated the reaction mixture to 78-80°C and maintained for 7 hrs. Attained the reaction mass to ambient temperature and added 160 g of triethylorthoformate (1.08 mol), 2 g of Benzene sulfonic acid (0.0127 mol) followed by 67 g of 3-Pentanone (0.778 mol). Stirred the reaction mass for 3 hrs at 25-35°C. After completion of reaction, reaction mass pH was adjusted to 7.5-8.5 with triethylamine and distilled-out the solvent under vacuum at below 45°C. Cooled the residue to ambient temperature and charged 500 mL of MDC and 200 mL of purified water and mixture was stirred for 15 min and the layers were separated. Organic layer was charged with 200 mL of saturated sodium bicarbonate solution and mixture was stirred for 15 min and the layers were separated. Finally, organic layer was charged with 200 mL of 10% sodium chloride solution, stirred for 15 min and separated. The organic layer was dried over anhydrous sodium sulfate.

Example-2: Mesylation of hydroxyl ketal
In a 1000 mL round bottom flask fitted with mechanical stirrer and under nitrogen atmosphere was charged the above hydroxyl ketal mass and solution was cooled to 0-10°C. 116 mL of triethylamine (0.832 mol) was charged to the above mass and slowly added 68 mL of methane sulfonyl chloride (0.878 mol) at 0-10°C and stirred the reaction mass for 2 hrs. After completion of reaction, 300 mL of purified water was charged and mixture was stirred for 15 min and the layers were separated. Organic layer was charged with 160 mL of saturated sodium bicarbonate solution and mixture was stirred for 15 min and the layers were separated. 200 mL of 10% sodium chloride solution was charged into organic layer, stirred for 15 min and separated. Finally, 200 mL of purified water was charged into organic layer, stirred for 15 min and separated. The organic layer was dried over anhydrous sodium sulfate.

Example-3: Reduction of mesylated hydroxyl ketal
In a 1000 mL round bottom flask fitted with mechanical stirrer and under nitrogen atmosphere was charged the above mesylated mass cooled to -32 to -40°C. Charged 68 g of triethylsilane (0.585 mol) followed by slow addition of 109.5 g of titanium tetrachloride diluted in 100 mL of MDC in about 6-8 hrs. The mixture was stirred for 2 hrs and after completion of reaction, reaction mass was quenched with 380 mL of purified water, stirred for 15 min and layers were separated. Organic layer was charged with 300 mL of 10% sodium chloride solution and mixture was stirred for 15 min and the layers were separated. Finally, 300 mL of saturated sodium bicarbonate solution was charged into organic layer, stirred for 15 min and layers were separated. The organic layer was dried over anhydrous sodium sulfate. Distilled-out MDC under vacuum at below 45°C and striped-off the residue with 100 mL of diisopropyl ether (DIPE). The pale yellow colored oily residue was obtained and up on standing at ambient temperature, bottom thick layer was separated and added 350 mL of DIPE at 25-35°C. Cooled the reaction mixture to -20°C and material was precipitated-out. Filtered the material and washed with 50 mL of pre-chilled DIPE. Unloaded and dried the material under vacuum at 40-45°C for 4 hrs. Dry weight of the product is 140 g
Example-4: Preparation of (1S,5R,6S)-Ethyl 5-(pentan-3-yloxy)-7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylate (X)
In a 2000 mL round bottom flask equipped with a mechanical stirrer was charged 140 g of compound of example 3 followed by 400 mL of ethanol, 700 mL of purified water and 56 g of sodium bicarbonate (0.667 mol) were added at ambient temperature. The reaction mixture was heated to 60-65°C and maintained for 2 hrs. After completion of reaction, reaction mass was cooled 0-5°C and maintained for 2 hrs. Filtered the material and washed with 100 mL of purified water. The product was recrystallized in mixture of purified water (500 mL) and ethanol (100 mL) at 40-45°C for 30 min. The pure epoxide product was dried as a white to off-white fluffy solid.
Dry wt.: 90 g
Example-5: Preparation of (3R,4S,5R)-Ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate (XVI)
In a 1000 mL round bottom flask equipped with a mechanical stirrer was charged with 300 mL of isopropanol, 100 g of compound (X) (0.393 mol) at 25-35°C followed by slowly charged 51.3 g of sodium azide (0.789 mol), 43 g of ammonium chloride (0.804 mol) and 50 mL of purified water. Reaction mixture was heated to reflux and maintained for 7 hrs at 75-85°C. After completion of reaction, reaction mass was cooled to 25-35°C and charged 300 mL of purified water followed by extraction of reaction mass into 300 mL of toluene and layers were separated. Aqueous layer was extracted with 200 mL of toluene and separated. Organic layers were combined and washed with 200 mL of purified water and separated. Organic layer is dried over anhydrous sodium sulfate. Distilled-out the solvent under vacuum at below 50°C to get wine red oily residue and proceeded to next stage.
Example-6: Preparation of (3R,4S,5R)-ethyl 4-methanesulfonyloxy-5-azido-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate (XXa)
In a 1000 mL round bottom flask equipped with a mechanical stirrer, under nitrogen atmosphere was charged 300 mL of toluene, (3R,4S,5R)-ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate (XVI) followed by 66 mL of triethylamine (0.474 mol). The mixture was cooled to 5-10°C and slowly added 54.8 g of methane sulfonyl chloride (0.478 mol). Stirred the reaction mass for 1 hr at 10-15°C. After completion of reaction, 300 mL of purified water was charged, stirred and layers were separated. Aqueous layer was extracted with 100 mL of toluene. The combined organic layer was washed with 200 mL of purified water. Distilled-out the solvent under vacuum at below 50°C to get dark brown oily mass and proceeded to next stage.
Example-7: Preparation of (1R,5R,6R)-Ethyl-5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate (XVII)
In a 1000 mL round bottom flask equipped with a mechanical stirrer, under nitrogen atmosphere was charged 300 mL of isopropyl alcohol, 3 mL of acetic acid and 87 g of triphenyl phosphine (0.331 mol) followed by compound (XXa). Reaction mass was heated to 80°C and maintained for 9 hrs. After completion of reaction, reaction mass was cooled to below 50°C and distilled-out the solvent under vacuum and cooled the reaction mass to 30°C. Charged 500 mL of purified water and cooled to 0°C. Reaction mass pH was adjusted to 1.0 with aqueous HCl (40 mL Conc. HCl dissolves in 120 mL of purified water) followed by charged 300 mL of toluene, stirred for 15 min and filtered the reaction mass through hyflo supercel bed. Washed the bed with 100 mL of purified water. Filtrate was cooled to 0°C, stirred for 15 min and separated-out the organic layer. Aqueous layer was washed with 300 mL of toluene followed by adjusted the pH of the aqueous layer to 8.0-9.0 with aq. Ammonia (38 mL diluted in 120 mL of purified water). Stirred the reaction mass for 15 min and extracted the mass with 300 mL of toluene at 0°C. Distilled-out toluene under vacuum at below 50°C to get the light reddish oily syrup and proceeded to next step.
Example-8: Preparation of (3R,4R,5S)-Ethyl 4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (XVIII)
In a 1000 mL round bottom flask equipped with a mechanical stirrer under nitrogen atmosphere was charged 250 mL of N,N-Dimethylformamide (DMF), 34 g of sodium azide (0.522 mol) followed by compound (XVII). Stirred the reaction mass for 10 min followed by addition of 28 g of ammonium chloride (0.523 mol) at 25-35°C. Reaction mass was heated to 80°C and maintained for 5 hrs. After completion of reaction, reaction mass was cooled to 15°C. Slowly added 300 mL of purified water and 300 mL of toluene. Allowed to attain the temperature to 25-35°C, stirred and separated the organic layer. Extracted the aqueous layer with 100 mL of toluene and combined the organic layers. Dried the organic layer over anhydrous sodium sulfate.
Example-9: Preparation of (3R,4R,5S)-Ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (XIX)
In a 1000 mL round bottom flask equipped with a mechanical stirrer under nitrogen atmosphere was charged compound (XVIII) and 68 mL of triethylamine (0.489 mol). Reaction mass was cooled to 5°C and slowly added 44 g of acetic anhydride (0.431 mol) in 1 hr. Reaction mass was stirred for 1 h. After completion of the reaction, reaction mass was allowed to ambient temperature and charged 300 mL of purified water. Reaction mass was stirred for 15 min and layers were separated. Organic layer was washed with dilute HCl (12.7 mL diluted in 87 mL of purified water) followed by distillation of the mass till the residual volume comes to 200 mL under vacuum at below 50°C. 150 mL of isopropyl alcohol was charged and distilled-out under vacuum at below 50°C. The oily residue is proceeded to next stage.
Example-10: Preparation of Oseltamivir (Ia)
600 mL of Isopropyl alcohol was added to compound (XIX) obtained in example-9 followed by charged 85 g of triphenyl phosphine (0.323 mol) and 50 mL of purified water at 25-35°C. Reaction mass was heated to 55°C and maintained for 12 hrs. After completion of the reaction, solvent was distilled under vacuum at below 50°C and added 100 mL of acetone and strip-off. After complete strip-off, semi solid brown colored material was observed and was dissolved 450 mL of acetone. Reaction mass was heated and stirred at below 55°C till clear solution observed. Filtered the reaction mass through whatman paper and collected the clear solution.
Example-11: Preparation of crude Oseltamivir Phosphate (I)
Oseltamivir (Ia) in acetone obtained in example-10 was transferred to 2000 mL round bottom flask equipped with a mechanical stirrer and nitrogen atmosphere at 25-35°C. Reaction mass was heated to 50°C followed by slowly added a mixture of o-Phosphoric acid (0.30 mol) in acetone (34 g of o-Phosphoric acid (min. 85%) dissolves in 600 mL of acetone) at 50°C over a period of 3 hrs. The pH of the reaction mass was maintained at 4.0-5.0 and stirred for 20 mins. Cooled the reaction mass to 0°C and stirred for 2 hrs. Filtered the product under nitrogen atmosphere and washed with 100 mL of acetone. Suck dried the material and unloaded. 400 mL of acetone was added to wet material at 25-35°C and stirred for 30 mins. Filtered the material and washed with 300 mL of acetone followed by 200 mL of heptane. Dried the material under vacuum at 50°C for 6 hrs.
Dry weight of the product is 80 g from compound (X).
Example-12: Preparation of pure Oseltamivir Phosphate (I)
In a 1000 mL round bottom flask equipped with a mechanical stirrer and nitrogen atmosphere was charged 500 mL of ethanol and 80 g Oseltamivir phosphate crude at 25-35°C. Stirred the suspension for 15 min and heated to 50°C. Slowly added purified water till the mass becomes clear solution. Filtered the reaction mass through micron filter and collected the clear filtrate into the 1000 mL round bottom flask fitted with mechanical stirrer under nitrogen atmosphere. Cooled the reaction mass gradually up to 0°C. A white colored material was crashed-out from the reaction and mass was maintained for 2 hrs at 0°C. Filtered the material under nitrogen atmosphere and washed with 300 mL of acetone followed by 200 mL of heptane. Dried the material under vacuum. Dry weight of the pure Oseltamivir phosphate is 60 g with purity NLT 99.5%. ,CLAIMS:WE CLAIM:
1. One pot process for the preparation of Oseltamivir phosphate (I),

Formula I

which comprises,

i. reacting (1S,5R,6S)-ethyl 5-(pentan-3-yloxy)-7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylate of formula (X);

Formula X

with sodium azide and ammonium chloride in presence of solvent to obtain (3R,4S,5R)-ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate of formula (XVI);

Formula XVI
ii. reacting (3R,4S,5R)-ethyl 5-azido-4-hydroxy-3-(pentan-3-yloxy) cyclohex-1-ene carboxylate of formula (XVI) with hydroxyl protecting compound in presence of base and solvent to obtain compound of formula (XX);

Formula XX
wherein, P is methanesulfonyl group or p-toluenesulfonyl group or benzenesulfonyl group.

iii. reacting compound of formula (XX) with triphenylphosphine in presence of carboxylic acid, base, and solvent to obtain (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate of formula (XVII);

Formula XVII
iv. reacting (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate of formula (XVII) with sodium azide and ammonium chloride in presence of solvent to obtain (3R,4R,5S)-ethyl 4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XVIII);

Formula XVIII
v. acetylation of (3R,4R,5S)-ethyl 4-amino-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XVIII) using acetylating agent in presence of base and solvent to obtain (3R,4R,5S)-ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XIX);

Formula XIX
vi. reacting (3R,4R,5S)-ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate of formula (XIX) with triphenylphosphine in presence of solvent to obtain Oseltamivir free base of formula (Ia);

vii. Oseltamivir free base of formula (Ia) is converted to Oseltamivir phosphate (I),
wherein, steps (i), (ii), (iii), (iv), (v) and (vi) are carried out without isolating the compound of formulae (XVI), (XVII), (XVIII), (XIX), (XX) and (Ia).

2. The process as claimed in claim 1, wherein hydroxyl protecting compound used in step-ii comprises methanesulfonyl chloride (MSA), p-toluenesulfonyl chloride (p-TSA), benzenesulfonyl chloride or the like.

3. The process as claimed in claim 1, wherein carboxylic acid used in step-iii comprises acetic acid, oxalic acid, propionic acid, malonic acid, butyric acid, succinic acid, maleic acid, fumaric acid, valeric acid, glutaric acid, caproic acid, adipic acid, heptanoic acid, and caprylic acid.

4. The process as claimed in claim 1, wherein acetylating agent used in step-v comprises acetic anhydride or acetyl chloride or acetic acid with a coupling agent such as DCC or HOBt.

5. The process as claimed in claim 1, wherein solvent used in step-i, step-ii, step-iii, step-iv, step-v and step-vi comprises water, methanol, ethanol, propanol, isopropanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

6. The process as claimed in claim 1, wherein base used in step-ii, step-iii and step-v comprises an organic base selected from triethylamine, pyridine, aqueous or alcoholic methyl amine, ethyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine and an inorganic base selected from ammonia, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.

7. A process for the preparation of (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate of formula (XVII);

Formula XVII

which comprises,
reacting compound of formula (XX) with triphenylphosphine in presence of carboxylic acid, base, and solvent to obtain (1R,5R,6R)-ethyl 5-(pentan-3-yloxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate of formula (XVII);

Formula XX
wherein, P is methanesulfonyl group or p-toluenesulfonyl group or benzenesulfonyl group.

8. The process as claimed in claim 7, wherein carboxylic acid comprises acetic acid, oxalic acid, propionic acid, malonic acid, butyric acid, succinic acid, maleic acid, fumaric acid, valeric acid, glutaric acid, caproic acid, adipic acid, heptanoic acid, and caprylic acid.

9. The process as claimed in claim 7, wherein base comprises ammonia, triethylamine, pyridine, methyl amine, ethyl amine, diisopropyl ethyl amine, , sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof and solvent comprises water, methanol, ethanol, propanol, isopropanol, toluene, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.