WO2011021223A2 - Novel salts of ethyl (3r, 4s, 5r)-4,5-imino-3-(l-ethylpropoxy)-1- cvclohexene-1-carboxylate and its use - Google Patents

Novel salts of ethyl (3r, 4s, 5r)-4,5-imino-3-(l-ethylpropoxy)-1- cvclohexene-1-carboxylate and its use Download PDF

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WO2011021223A2
WO2011021223A2 PCT/IN2010/000545 IN2010000545W WO2011021223A2 WO 2011021223 A2 WO2011021223 A2 WO 2011021223A2 IN 2010000545 W IN2010000545 W IN 2010000545W WO 2011021223 A2 WO2011021223 A2 WO 2011021223A2
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ethyl
compound
carboxylate
acid
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WO2011021223A3 (en
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Manne Satyanarayana Reddy
Srinivasan Thirumalai Rajan
Karamala Rama Subba Reddy
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Msn Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid
    • C07C53/10—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C07C55/07—Salts thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/26—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to novel salts of ethyl (3R,4S,5R)-4,5-imino- 3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate and an improved process for their preparation.
  • Ethyl(3R,4S,5R)-4,5-imino-3-( 1 -ethylpropoxy)- 1 -cyclohexene- 1 - carboxylate is a key intermediate in the synthesis of oseltamivir phosphate.
  • Oseltamivir phosphate is chemically known as (3R,4R,5S)-4-(acetylamino)-5-amino-3-(l- ethylpropoxy)-l -cyclohexene- 1-carboxylic acid ethyl ester phosphate and is represented by the structural formula- Ia
  • Formula- 1 a Formula- 11 Oseltamivir and in particular its phosphate salt, is a potent inhibitor of neuraminidase and is currently the best drug among the currently available anti-influenza treatments due to its good bioavailability and tolerance. It acts to minimize the effects of flu by inhibiting the protein neuraminidase that lives on the flu virus cells.
  • Oseltamivir developed by Gilead Sciences, and it is currently marketed by Hoffman La Roche under the brand name Tamiflu.
  • Ethyl (3R,4S,5R)-4,5-imino-3 -( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate compound of formula- 10 having the following structural formula is a key intermediate compound in the synthesis of Oseltamivir phosphate.
  • the said intermediate compound of formula- 10 is not isolated and is obtained as an oil/residue and used to proceed further.
  • the purity of the intermediate compound of formula- 10 obtained as per the prior art is not satisfactory.
  • As the said intermediate is an oily residue, it is not possible to purify the intermediate and there is no specific process disclosed for its purification.
  • oseltamivir is obtained by the reduction of (3R,4R,5S)- ethyl-4-acetamido-5-azido-3-(pentan-3yl-oxy)cyclohex-l-ene carboxylate compound of formula- 13 having the following structure
  • the first aspect of the present invention is to provide novel salts of ethyl
  • the second aspect of the present invention is to provide a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene-1 -carboxylate, compounds of general formula-11, which comprises of treating the crude ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate compound of formula- 10 with a suitable acid in a suitable solvent to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene- 1 -carboxylate.
  • the third aspect of the present invention is to provide a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene-1 -carboxylate compounds of formula- 11, which comprises of reacting ethyl- (3R,4S,5R)-5-azido-4-hydroxy-3-(l -ethylpropoxy)cyclohex- 1 -ene carboxylate compound of formula-9 with triphenyl phosphine in a suitable solvent, followed by treatment with a suitable acid, to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate.
  • the fourth aspect of the present invention is to provide a crystalline oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula- 1 Ia. Further the present invention also provides a process for the preparation of crystalline oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)- 1 -cyclohexene -1 -carboxylate compound of formula- 1 Ia and its use.
  • the fifth aspect of the present invention is to provide a process for the preparation of oseltamivir compound of formula- 1 , which comprises of reducing ethyl (3R,4R,5 S)
  • the sixth aspect of the present invention is to provide a process for the preparation of oseltamivir compound of formula- 1, which comprises of reducing ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)cyclohex-l-ene-l-carboxylate compound of formula- 13 in presence of cobalt ion, a ligand and a reducing agent in a suitable solvent to provide the oseltamivir compound of formula- 1.
  • the seventh aspect of the present invention is to provide an improved process for the preparation of oseltamivir and its pharmaceutically acceptable salts compound of formula- 1.
  • the present invention relates to novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l-cyclohexene-l -carboxylate, compounds of formula-11, which is a key intermediate in the preparation of oseltamivir phosphate compound of formula-la. I £ H 3 PO 4
  • alcoholic solvent is selected from methanol, ethanol, isopropanol, n-propanol, butanol and the like;
  • esteer solvents refers to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like;
  • hydrocarbon solvents refers to toluene, xylene, cyclohexane, hexane, heptane and the like;
  • chloro solvents refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like;
  • polar aprortic solvents refers to dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and the like;
  • nitrile solvents refers to acetonitrile
  • the first aspect of the present invention provides novel salts of ethyl (3R,4S,5R)-
  • Acid is a acid which is capable of forming acid addition salt with ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate, compound of formula- 10 also known as "aziridine intermediate".
  • the acid is selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrohalic acid such hydrochloric acid, hydrobromic acid and the like.
  • the free base of the compound of formula- 11 i.e., ethyl (3R,4S,5R)-4,5-imin ⁇ -3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula- 10 is not isolated and obtained as an oil with a purity of approximately 60-65%.
  • the second aspect of the present invention provides a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate, compounds of general formula-11,
  • Formula- 10 with a suitable acid selected from the acids defined above, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitrile solvents or mixtures thereof to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3 -( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate.
  • a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitrile solvents or mixtures thereof to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3 -( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate.
  • the third aspect of the present invention provides a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate, compounds of general formula- 11,
  • triphenyl phosphine in a suitable solvent selected from polar aprotic solvents or nitrile solvents, followed by treatment with a suitable acid selected from the above defined acids, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitrile solvent solvent or mixtures thereof, to provide the corresponding acid addition salt of ethyl (3R,4S,5R)-4,5-imino-3- ( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate.
  • the fourth aspect of the present invention provides a novel oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate, compound of formula- 1 Ia having the following structure.
  • novel oxalate salt compound of formula-l la of the present invention is characterized by its DSC which shows two endothermic peaks at 78° C and 141° C.
  • the novel oxalate salt of the present invention is used to prepare highly pure ethyl
  • the present invention provides a process for the preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula-l la, which comprises of treating the crude ethyl (3R,4S,5R)-4,5- imino-3 -( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate compound of formula- 10 - .
  • oxalic acid in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitrile solvents or mixtures thereof, to provide the oxalic acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l -cyclohexene- 1 -carboxylate compound of formula- 1 Ia.
  • a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitrile solvents or mixtures thereof
  • a process for the preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate compound of formula- 1 Ia comprises of treating the crude ethyl (3R,4S,5R)- 4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l -carboxylate compound of formula-10 with oxalic acid in a suitable ester solvent preferably ethyl acetate to provide the oxalic acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate compound of formula- 1 Ia.
  • the fifth aspect of the present invention provides a process for the preparation of oseltamivir
  • a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitrile solvents of mixtures thereof to provide the oseltamivir compound of formula- 1.
  • a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitrile solvents of mixtures thereof.
  • dihydro impurity which is having the following structural formula
  • the said impurity is observed at the RRT of 0.85.
  • the prior art processes carried out number of purifications at the final stages.
  • the usage of Zinc dust and ammonium chloride for the said reduction avoids the formation of dihydro impurity and hence the number of purifications are not necessary at final steps making the present process highly advantageous over the prior art.
  • a process for the preparation of oseltamivir compound of formula- 1 comprises of reducing ethyl (3R,4R,5S)-4-acetamido- 5-azido-3-(l -ethyl propoxy)cyclohex-l-ene-l-carboxylate, compound of formula- 13 in presence of zinc dust and ammonium chloride in a suitable alcoholic solvent preferably isopropyl alcohol and water, followed by isolating the oseltamivir compound of formula- 1 from a suitable chloro solvent preferably methylene chloride.
  • the sixth aspect of the present invention provides a process for the preparation of oseltamivir compound of formula-1, which comprises of reducing ethyl (3R,4R,5S)-4- acetamido-5-azido-3-(l-ethylpropoxy) cyclohex-1-ene-l-carboxylate, compound of formula- 13
  • the cobalt ion is selected from the group consisting of cobaltous chloride, cobaltous diacetate and cobaltic chloride; and the ligand is selected from the group consisting of dimethylglyoxime, 2,2'-bipyridyl and 1,10-phenathroline;
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, tetra alkyl ammonium borohydride and zinc borohydride in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof; to provide the oseltamivir compound of formula-1.
  • process for the preparation of oseltamivir compound of formula-1 comprises of reducing ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l- ethylpropoxy) cyclohexy-l-ene-l-carboxylate, compound of formula- 13 in presence of cobalt ion, a ligand and a reducing agent to provide the oseltamivir compound of formula-1; wherein the cobalt ion is cobaltous chloride, the ligand is dimethylglyoxime and the reducing agent is sodium borohydride in methanol to provide the oseltamivir compound of formula- 1.
  • the present invention also provides novel salts of alkyl (3R,4S,5R)-4,5-imino-3- (1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate having the following structural formula
  • R is an Ci-C 4 alkyl
  • Acid is a acid group which is capable of forming acid addition salt with alkyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate, also known as "aziridine intermediate".
  • the acid is selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrohalic acid such as hydrochloric acid, hydrobromic acid and the like.
  • the seventh aspect of the present invention provides an improved process for the preparation of oseltamivir phosphate compound of formula- Ia, which comprises of the following steps,
  • the term highly pure/high pure refers to the purity of the compound more than 99.50% by HPLC, preferably more than 99.85% by HPLC.
  • Ethyl(3R,4R,5S)-4-acetamido-5-azido-3-( 1 -ethylpropoxy)cyclohex- 1 -ene- 1 - carboxylate compound of formula- 13 and ethyl (3R,4S,5R)-5-azido-4-hydroxy-3-(l- ethylpropoxy) cyclohex-1 -ene- 1 -carboxylate, compound of formula-9 can be readily prepared as per the process disclosed in US 5952375 or by the process known in the art.
  • Oseltamivir phosphate prepared by the present invention can be further micronized or milled to get the desired particle size. Analysis of particle size distribution of oseltamivir phosphate was carried out using Malvern Mastersizer 2000.
  • Triphenylphosphine (7.9 grams) was added to a mixture of (3R,4S,5R)-ethyl-5- azido-4-hydroxy-3-(pentan-3-yloxy)cyclohex-l-ene carboxylate (10 grams) in acetonitrile (25 ml) at 25-30°C. The reaction mixture was heated to reflux temperature and stirred up to the completion of the reaction. The solvent was distilled off under reduced pressure to get the title product as a oily residue.
  • Example-l Preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate, compound of formula-lla:
  • Triphenylphosphine (79 grams) was added to a mixture of (3R,4S,5R)-ethyl-5- azido-4-hydroxy-3-(pentan-3-yloxy)cyclohex-l-ene carboxylate compound of formula-9- (100 grams) in acetonitrile (250 ml) at 25-3O 0 C.
  • the reaction mixture was heated to reflux temperature and stirred up to the completion of the reaction.
  • the solvent was distilled off under reduced pressure, cooled and cyclohexane was added to the residue then distilled off.
  • Ethyl acetate 200 ml was added to the residue and stirred for 10 minutes at 25-30°C.
  • Oxalic acid (44.5 grams) was added to the reaction mixture, stirred for 30 minutes at 25-3O 0 C.
  • the reaction mixture was cooled to 0-5 0 C and stirred.
  • the solid was filtered, washed and dried to get the title compound
  • Zinc (77 grams) and aqueous ammonium chloride(77.4 grams in 250 ml of water) was added to a solution of ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethyIpropoxy) cyclohex-l-ene-1- caxboxylate compound of formula-13 (100 grams) in isopropyl alcohol (500 ml) at 18-20°C and stirred for an hour. The reaction mixture was quenched with aqueous ammonia and methylene chloride was added to it, stirred and filtered.
  • Cobaltous chloride (1 gram) was added to a mixture of ethyl (3R,4R,5S) -4-acetamido-5 -azido-3 -( 1 -ethylpropoxy)cyclohex- 1 -ene- 1 -carboxy late (10 grams), methanol (20 ml), water (100 ml) and methanol (20 ml) at 25-30 0 C and stirred for 15 minutes.
  • Aqueous sodiumborohydride (1.5 grams in 10 ml of aqueous sodium hydroxide) was added to the reaction mixture and stirred up to completion of the reaction.
  • Methylene chloride (75 ml) was added to the reaction mixture and stirred then filtered through the hyflow.
  • the organic and aqueous layers were separated and extracted aqueous layer with methylene chloride.
  • the aqueous layer was washed with water and drying with sodium sulphate.
  • the solvent from the organic layer co-distilled with acetone under reduced pressure.
  • the obtained residue is purified with column chromatography using hexane and ethyl acetate as an eluent.
  • the reaction mixture was partially distilled off and 2,2-dimethoxy propane (47.7 grams) was added to it at 40-45 0 C then stirred for 2 hours.
  • the solvent was distilled off completely under reduced pressure at below 45°C and the obtained residue was cooled to 25-35°C.
  • Ethyl acetate 750 ml was added and cooled to 0-10 0 C.
  • Methane sulphonyl chloride (76 grams) followed by triethylamine(116 grams) was added slowly to the reaction mixture and stirred for 45 minutes at 10-15 0 C.
  • the undissolved material from the reaction mixture was filtered off, washed with ethyl acetate and the filtrate was distilled off under reduced pressure at below 35°C.
  • Methanol 300 ml was added to the residue, cooled to -25 to -35°C and stirred for 3 hours. The solid obtained was filtered off, washed with chilled methanol and then dried to get the title compound.
  • Example-5 Preparation of ethyl (3R,4R,5R)-3-(l -ethyl propoxy)-4-hydroxy-5- methane sulfonyloxy-cyclohex-l-ene-l-carboxylate compound of formula-7:
  • reaction mixture was cooled to -30 to -35°C and trimethylsilane (54.3 grams) followed by titanium tetra chloride (88.92 grams) in methylene chloride (80 ml) was added slowly at -30 to 35°C for 3 hours. Quenched the reaction mixture with cooled water and raised the temperature to 20-30°C. Organic layer was separated and washed with sodium bicarbonate solution followed by water. Distilled off the solvent from organic layer under reduce pressure at below 50°C. Ethyl acetate (75 ml) was added to the residue and cooled to 25-35°C. Ether (800 ml) was added to the reaction mixture and cooled to -20 to -30°C then stirred for an hour. The solid obtained was filtered, washed with chilled ether and then dried to get the title compound.
  • Example-6 Preparation of ethyl (3R,4S,5S)-4,5-epoxy-3-(l-ethyl-propoxy)-l- cyclohex-l-ene-l-carboxylate compound of formula-8:
  • Example-7 Preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula-lla:
  • Toluene layer was washed with sodium chloride solution then distilled off the toluene completely under reduced pressure at below 50°C.
  • the obtained residue was cooled to 25-30°C and acetonitirle(275 ml), triphenyl phosphine (87 grams) was added then heated to reflux temperature.
  • the reaction mixture was stirred at reflux for 9 hours then cooled to 50 0 C and then distilled off the solvent under reduced pressure at below 50 0 C.
  • Ether 165 ml was added to the residue, stirred for 30 mins and cooled to 0-5°C and stirred for an hour. Filtered the solid and washed with ether.
  • Example-8 Preparation of ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l- ethylpropoxy)cyclohex-l-ene-l-carboxylate compound of formula-13:
  • Oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate 100 grams was added to a cooled water (500 ml) at 0-5 0 C then basified with aqueous ammonia solution. The reaction mixture temperature was raised to 25-3O 0 C and methylene chloride (300 ml) was added and stirred for 15 mins. Organic layer was separated and extracted the aqueous layer with methylene chloride. Organic layer was dried over sodium sulphate and distilled off the solvent completely under reduced pressure at below 45°C.
  • Ether(651 ml) was added to the reaction mixture at 25-30 0 C, cooled to 0-5 0 C and stirred for 2 hours.
  • the solid obtained was dissolved in ethylacetate (133 ml) by heated to 40-45 0 C and the reaction mixture was subjected to carbon treatment then filtered through hyflow.
  • the f ⁇ lterate was heated to 45-50 0 C, ether (440 ml) was added to the filtrate and stirred for 30 minutes.
  • the reaction mixture was initially cooled to 25-35°C then to 0-5 0 C and stirred for 2.5 hours. Filtered the solid, washed with mixture of ether and ethyl acetate then dried it to get the title compound.
  • Zinc (90.84 grams) and aqueous ammonium chloride(61.64 grams in 300 ml of water) was added to a solution of ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethylpropoxy) cyclohex -1-ene-l-carboxylate (100 grams) in isopropyl alcohol (500 ml) at 18-20 0 C and stirred for an hour. Cooled to 5-15°C and ammonium hydroxide (100 ml) was added and stirred for an hour. Methylene chloride (150 ml) was added to the reaction mixture and stirred for 15 mins then filtered through hyflow.

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Abstract

The present invention relates to novel salts of ethyl (3R,4S,5R)- 4,5-imino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate and its use in the preparation of (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethyl propoxy)-1-cyclohexene-1-carboxylic acid ethyl ester and its pharmaceutically acceptable salts.

Description

Novel salts of ethyl (3R, 4S, 5R)-4.,5-imino-3-(l-ethylpropoxy)-l- cyclohexene-l-carboxylate and its use
Related Application:
This application claims the benefit of priority of our Indian patent application number 1974/CHE/2009 filed on 19/08/2009 which is incorporated herein by reference. Field of the Invention :
The present invention relates to novel salts of ethyl (3R,4S,5R)-4,5-imino- 3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate and an improved process for their preparation. Ethyl(3R,4S,5R)-4,5-imino-3-( 1 -ethylpropoxy)- 1 -cyclohexene- 1 - carboxylate is a key intermediate in the synthesis of oseltamivir phosphate. Oseltamivir phosphate is chemically known as (3R,4R,5S)-4-(acetylamino)-5-amino-3-(l- ethylpropoxy)-l -cyclohexene- 1-carboxylic acid ethyl ester phosphate and is represented by the structural formula- Ia
Figure imgf000002_0001
Formula- 1 a Formula- 11 Oseltamivir and in particular its phosphate salt, is a potent inhibitor of neuraminidase and is currently the best drug among the currently available anti-influenza treatments due to its good bioavailability and tolerance. It acts to minimize the effects of flu by inhibiting the protein neuraminidase that lives on the flu virus cells. Oseltamivir developed by Gilead Sciences, and it is currently marketed by Hoffman La Roche under the brand name Tamiflu.
Background of the Invention:
There are various number of synthetic processes for the preparation of
Oseltamivir and its pharmaceutically acceptable salts which have been disclosed in the literature, for example US 5763483, US 5952375, Journal of Organic Chemistry 63, 13, 1998; Journal of American Chemical Society 115, 4, 1997, 681; Organic Process Research & Development, 1999, 3, 266-274.
Ethyl (3R,4S,5R)-4,5-imino-3 -( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate compound of formula- 10 having the following structural formula is a key intermediate compound in the synthesis of Oseltamivir phosphate.
Figure imgf000003_0001
Formula- 10
As per the prior art processes, the said intermediate compound of formula- 10 is not isolated and is obtained as an oil/residue and used to proceed further. The purity of the intermediate compound of formula- 10 obtained as per the prior art is not satisfactory. As the said intermediate is an oily residue, it is not possible to purify the intermediate and there is no specific process disclosed for its purification. In any synthetic process of Active Pharmaceutical Ingredients, it is important to obtain each intermediate product with high purity, to ensure that the process provides final Active Pharmaceutical Ingredient with high purity and greater yields and conforms to ICH specifications. It should also avoid the number of purifications in final stages. Hence there is a need in the art to isolate and purify the intermediate compounds especially the intermediate compound of formula- 10, a key intermediate in the synthesis of important drug like oseltamivir, which may provide substantial advantage both economically as well as quality wise.
In prior art processes, oseltamivir is obtained by the reduction of (3R,4R,5S)- ethyl-4-acetamido-5-azido-3-(pentan-3yl-oxy)cyclohex-l-ene carboxylate compound of formula- 13 having the following structure
Figure imgf000003_0002
Formula- 13 The reported process involves the usage of hydrogen gas in presence of catalyst like Palladium on Carbon or Lindlar's catalyst. The usage of Lindlar's catalyst in the prior art process led to high level of impurity formation resulting in low yields. The present invention provides a process for the reduction of compound of formula- 13 with high purity and high yields, which proves to be highly advantageous to get the final product with high quality and yields making the process more economical.
Brief Description of the Invention:
The first aspect of the present invention is to provide novel salts of ethyl
(3R,4S,5R)-4,5-imino-3-(l -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate, compounds of general formula- 11.
The second aspect of the present invention is to provide a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene-1 -carboxylate, compounds of general formula-11, which comprises of treating the crude ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate compound of formula- 10 with a suitable acid in a suitable solvent to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene- 1 -carboxylate.
The third aspect of the present invention is to provide a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene-1 -carboxylate compounds of formula- 11, which comprises of reacting ethyl- (3R,4S,5R)-5-azido-4-hydroxy-3-(l -ethylpropoxy)cyclohex- 1 -ene carboxylate compound of formula-9 with triphenyl phosphine in a suitable solvent, followed by treatment with a suitable acid, to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate. The fourth aspect of the present invention is to provide a crystalline oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula- 1 Ia. Further the present invention also provides a process for the preparation of crystalline oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)- 1 -cyclohexene -1 -carboxylate compound of formula- 1 Ia and its use. The fifth aspect of the present invention is to provide a process for the preparation of oseltamivir compound of formula- 1 , which comprises of reducing ethyl (3R,4R,5 S)
-4-acetamido-5 -azido-3 -( 1 -ethylpropoxy)cyclohex- 1 -ene- 1 -carboxylate compound of formula- 13 in presence of zinc and ammonium chloride in a suitable solvent to provide the oseltamivir compound of formula- 1.
The sixth aspect of the present invention is to provide a process for the preparation of oseltamivir compound of formula- 1, which comprises of reducing ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethylpropoxy)cyclohex-l-ene-l-carboxylate compound of formula- 13 in presence of cobalt ion, a ligand and a reducing agent in a suitable solvent to provide the oseltamivir compound of formula- 1.
The seventh aspect of the present invention is to provide an improved process for the preparation of oseltamivir and its pharmaceutically acceptable salts compound of formula- 1.
Advantages of the Present Invention:
• Provides novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene-1 -carboxylate, compounds of general formula- 11 having high purity. - • Provides novel oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene-1 -carboxylate compound of formula- 1 Ia.
• Provides an improved process for the reduction of compound of formula-13, providing product with high purity and greater yield.
• Provides an improved process for the preparation of oseltamivir phosphate.
• Provides eco-friendly, efficient and commercially viable process for the preparation of oseltamivir phosphate and its intermediates.
Detailed Description of the Invention:
The present invention relates to novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l-cyclohexene-l -carboxylate, compounds of formula-11, which is a key intermediate in the preparation of oseltamivir phosphate compound of formula-la. I £ H3PO4
Formula- Ia
As used here in the term "alcoholic solvent" is selected from methanol, ethanol, isopropanol, n-propanol, butanol and the like; the term "ester solvents" refers to ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; the term "hydrocarbon solvents" refers to toluene, xylene, cyclohexane, hexane, heptane and the like; the term "chloro solvents" refers to methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; polar aprortic solvents refers to dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and the like; the term "nitrile solvents" refers to acetonitrile and the like; the term "polar solvent" refers to water and the like.
As used here in the term "crude" refers to the compound obtained directly after the reaction or the compound before purification.
The first aspect of the present invention provides novel salts of ethyl (3R,4S,5R)-
4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate represented by the following general formula- 11 ,
Figure imgf000006_0001
Formula- 11
wherein "Acid" is a acid which is capable of forming acid addition salt with ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate, compound of formula- 10 also known as "aziridine intermediate". The acid is selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrohalic acid such hydrochloric acid, hydrobromic acid and the like.
As per the prior art the free base of the compound of formula- 11 i.e., ethyl (3R,4S,5R)-4,5-iminό-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula- 10 is not isolated and obtained as an oil with a purity of approximately 60-65%.
When this crude with a purity of 60-65% is used to proceed further into subsequent stages, it will lead to decrease in yield and purity of the consecutive stages and will require a number of purifications to get the desired purity at the final stage.
The novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-
1-carboxylate, compounds of general formula- 11 of the present invention are having high purity of greater than 98%. The same have been utilized in the process for the preparation of the oseltamivir or its pharmaceutically acceptable salts providing high yields and purity, at the same time avoiding the numerous recrystallizations in final and intermediate stages to get the desired purity set by ICH.
The second aspect of the present invention provides a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate, compounds of general formula-11,
Figure imgf000007_0001
Formula-11
Where in acid is as defined as above,
which comprises of treating the crude ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l- cyclohexene- 1 -carboxylate, compound of formula- 10
Figure imgf000007_0002
Formula- 10 with a suitable acid selected from the acids defined above, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitrile solvents or mixtures thereof to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3 -( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate.
The third aspect of the present invention provides a process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate, compounds of general formula- 11,
Figure imgf000008_0001
Formula- 11
which comprises of reacting ethyl (3R,4S,5R)-5-azido-4-hydroxy-3-(l-ethylpropoxy) cyclohex- 1 -ene- 1 -carboxylate compound of formula-9,
Figure imgf000008_0002
Formula-9
with triphenyl phosphine, in a suitable solvent selected from polar aprotic solvents or nitrile solvents, followed by treatment with a suitable acid selected from the above defined acids, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitrile solvent solvent or mixtures thereof, to provide the corresponding acid addition salt of ethyl (3R,4S,5R)-4,5-imino-3- ( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate.
The fourth aspect of the present invention provides a novel oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate, compound of formula- 1 Ia having the following structure.
Figure imgf000009_0001
Formula-l la
The novel oxalate salt compound of formula-l la of the present invention is characterized by its DSC which shows two endothermic peaks at 78° C and 141° C. The novel oxalate salt of the present invention is used to prepare highly pure ethyl
(3R,4S,5R)-4,5-imino-3-(l -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate compound of formula- 10 and high pure oseltamivir phosphate compound of formula- Ia.
Further the present invention provides a process for the preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula-l la, which comprises of treating the crude ethyl (3R,4S,5R)-4,5- imino-3 -( 1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate compound of formula- 10 - .
Figure imgf000009_0002
Formula- 10
with oxalic acid in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitrile solvents or mixtures thereof, to provide the oxalic acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l -cyclohexene- 1 -carboxylate compound of formula- 1 Ia. In a preferred embodiment of the present invention, a process for the preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate compound of formula- 1 Ia, comprises of treating the crude ethyl (3R,4S,5R)- 4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l -carboxylate compound of formula-10 with oxalic acid in a suitable ester solvent preferably ethyl acetate to provide the oxalic acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate compound of formula- 1 Ia. The fifth aspect of the present invention provides a process for the preparation of oseltamivir compound of formula- 1,
Figure imgf000010_0001
Formula- 1
which comprises of reducing ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethyl propoxy)cyclohex-l-ene carboxylate, compound of formula- 13
Figure imgf000010_0002
Formula- 13
in presence of zinc dust and ammonium chloride in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitrile solvents of mixtures thereof to provide the oseltamivir compound of formula- 1. Optionally converting the oseltamivir compound formula- 1 into its pharmaceutically acceptable salts, especially phosphate salt of formula- Ia by conventional methods.
In the prior art processes, reduction involves the usage of hydrogen gas in presence of Lindlar's catalyst. The usage of Lϊndlar's catalyst led to the formation of impurity, herein designated as "dihydro impurity" which is having the following structural formula
Figure imgf000010_0003
Dihydro Impurity at the level of more than 30% along with the oseltamivir. The said impurity is observed at the RRT of 0.85. In order to remove this impurity the prior art processes carried out number of purifications at the final stages. The usage of Zinc dust and ammonium chloride for the said reduction avoids the formation of dihydro impurity and hence the number of purifications are not necessary at final steps making the present process highly advantageous over the prior art.
In a preferred embodiment of the above aspect, a process for the preparation of oseltamivir compound of formula- 1 comprises of reducing ethyl (3R,4R,5S)-4-acetamido- 5-azido-3-(l -ethyl propoxy)cyclohex-l-ene-l-carboxylate, compound of formula- 13 in presence of zinc dust and ammonium chloride in a suitable alcoholic solvent preferably isopropyl alcohol and water, followed by isolating the oseltamivir compound of formula- 1 from a suitable chloro solvent preferably methylene chloride. The sixth aspect of the present invention provides a process for the preparation of oseltamivir compound of formula-1, which comprises of reducing ethyl (3R,4R,5S)-4- acetamido-5-azido-3-(l-ethylpropoxy) cyclohex-1-ene-l-carboxylate, compound of formula- 13
Figure imgf000011_0001
, Formula- 13
in the presence of cobalt ion, a ligand and a reducing agent;
wherein the cobalt ion is selected from the group consisting of cobaltous chloride, cobaltous diacetate and cobaltic chloride; and the ligand is selected from the group consisting of dimethylglyoxime, 2,2'-bipyridyl and 1,10-phenathroline; the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, tetra alkyl ammonium borohydride and zinc borohydride in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof; to provide the oseltamivir compound of formula-1. In a preferred embodiment, process for the preparation of oseltamivir compound of formula-1 comprises of reducing ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l- ethylpropoxy) cyclohexy-l-ene-l-carboxylate, compound of formula- 13 in presence of cobalt ion, a ligand and a reducing agent to provide the oseltamivir compound of formula-1; wherein the cobalt ion is cobaltous chloride, the ligand is dimethylglyoxime and the reducing agent is sodium borohydride in methanol to provide the oseltamivir compound of formula- 1.
The present invention also provides novel salts of alkyl (3R,4S,5R)-4,5-imino-3- (1 -ethylpropoxy)- 1 -cyclohexene- 1 -carboxylate having the following structural formula
Figure imgf000012_0001
Where in R is an Ci-C4 alkyl,
wherein "Acid" is a acid group which is capable of forming acid addition salt with alkyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate, also known as "aziridine intermediate". The acid is selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, methanesulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrohalic acid such as hydrochloric acid, hydrobromic acid and the like. The seventh aspect of the present invention provides an improved process for the preparation of oseltamivir phosphate compound of formula- Ia, which comprises of the following steps,
a) Reacting the (3R,4S,5R)-3,4,5-trihydroxy cyclohex-1-ene carboxylic acid compound offomula-2
Figure imgf000012_0002
Formula-2 with ethanol in presence of thionyl chloride in toluene to provide the ethyl(3R,4S,5R)-3,4,5-trihydroxy cyclohex-1-ene carboxylate compound of formula-3,
Figure imgf000013_0001
Formula-3
which on in-situ treatment with 2,2-dimethoxy propane in presence of toluene sulfonic acid in ethyl acetate provides ethyl (3aR,7R,7aS)-2,2-dimethyl-7-hydroxy- 3a,6,7,7a-tetrahydro benzo[l,3]dioxole-5-carboxylate compound of formula-4,
Figure imgf000013_0002
Formula-4
which on in-situ reaction with methane sulfonylchloride in presence of triethylamine to provide the ethyl (3aR,7R,7aR)-2,2-dimethyl-7-methanesulfonyl-oxy-3a,6,7,7a- tetrahydrobenzo[l ,3]dioxole-5-carboxylate compound of formula-5,
Figure imgf000013_0003
Formula-5
treating the compound of formula-5 with 3-ρentanone in presence of trifluoromethane sulfonic acid to provide the ethyl (3aR,7R,7aR)-2,2-diethyl-7-methanesulfonyloxy- 3a,6,7,7a-tetrahydrobenzo[l ,3]-dioxole-5-carboxylate compound of formula-6,
Figure imgf000013_0004
Formula-6 which on in-situ reaction with trimethyl silane in presence of titanium tetrachloride in methylene chloride to provide the ethyl(3R,4R,5R)-3-(l-ethyl-propoxy)-4-hydroxy-5- methane sulfonyloxy-cyclohex-1-ene-l-carboxylate compound of formula-7,
Figure imgf000014_0001
Formula-7
c) treating the compound of formula-7 with sodiumbicarbonate in a mixture of isopropylalcohol and water to provide the ethyl(3R,4R,5R)-4,5-epoxy-3-(l- ethylpropoxy)-l-cyclohex-l-ene-l-carboxylate compound of formula-8,
Figure imgf000014_0002
Formula-8
d) reacting the compound of formula-8 with sodium azide in presence of ammonium chloride in isopropylalcohol to provide ethyl(3R,4S,5R)-5-azido-3-(l-ethylpropoxy)- 4-hydroxy-cyclohexene-l-carboxylate compound of formuala-9,
Figure imgf000014_0003
Formula-9
which on in-situ reaction with triphenyl phosphine, in a suitable solvent selected from polar aprotic solvent or nitrile solvent, followed by treatment with a suitable acid selected from the above defined acids, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitrile solvents or mixtures thereof, to provide the corresponding acid addition salt of ethyl (3R,4S,5R)-4,5-imino-3-(l -ethylpropoxy)- 1 -cyclohex- 1 -ene- 1 -carboxylate compound of formula- 11,
Figure imgf000015_0001
Formula- 11
wherein Acid is as defined above,
e) reacting the compound of formula- 11 with a suitable base in a suitable solvent, followed by treating with sodium azide in presence of ammonium chloride in dimethylformamide to provide the ethyl(3R,4R,5S)-4-amino-5-azido-3-(l-ethyl propoxy)-cyclohex-l-ene-l-carboxylate compound of formula- 12,
Figure imgf000015_0002
Formula- 12
which on in-situ reaction with acetic anhydride in a mixture of water and methylene chloride to provide the ethyl(3R,4R,5S)-4-acetamido-5-azido-3-(l-ethylpropoxy) cyclohex- 1 -ene- 1 -carboxylate compound of formula- 13,
Figure imgf000015_0003
Formula- 13
f) reducing the ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethyl propoxy)cyclohex-l- ene-1 -carboxylate compound of formula- 13 with zinc dust and ammonium chloride in a suitable alcoholic solvents preferably isopropyl alcohol and water, followed by isolating the oseltamivir compound of formula- 1 from a suitable chloro solvent preferably methylene chloride to provide oseltamivir, which on in-situ treatment with phosphoric acid in a suitable solvent to provide the oseltamivir phosphate compound of formula- Ia. As used herein the present invention, the term highly pure/high pure refers to the purity of the compound more than 99.50% by HPLC, preferably more than 99.85% by HPLC. Ethyl(3R,4R,5S)-4-acetamido-5-azido-3-( 1 -ethylpropoxy)cyclohex- 1 -ene- 1 - carboxylate compound of formula- 13 and ethyl (3R,4S,5R)-5-azido-4-hydroxy-3-(l- ethylpropoxy) cyclohex-1 -ene- 1 -carboxylate, compound of formula-9 can be readily prepared as per the process disclosed in US 5952375 or by the process known in the art. Oseltamivir phosphate prepared by the present invention can be further micronized or milled to get the desired particle size. Analysis of particle size distribution of oseltamivir phosphate was carried out using Malvern Mastersizer 2000.
The related substance of oseltamivir and its pharmaceutically acceptable salts as well as its intermediates were analyzed by HPLC using the following conditions:
Column: Inertsil ODS-3V, 250 X 4.6 mm, 5 μm or equivalent; wavelength: 220 nm; Temperature: 30°C; Load: 20 μl; Run time: 60 min; and using acetonitrile and water. in the ratio of 9: las a diluent and aqueous phosphoric acid as a buffer.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention Examples:
Reference Example: Preparation of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)- 1 -cyclohexene-l -carboxylate:
Triphenylphosphine (7.9 grams) was added to a mixture of (3R,4S,5R)-ethyl-5- azido-4-hydroxy-3-(pentan-3-yloxy)cyclohex-l-ene carboxylate (10 grams) in acetonitrile (25 ml) at 25-30°C. The reaction mixture was heated to reflux temperature and stirred up to the completion of the reaction. The solvent was distilled off under reduced pressure to get the title product as a oily residue.
Yield: 7 grams;
Purity by HPLC: 63.2 %
Example-l: Preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate, compound of formula-lla:
Triphenylphosphine (79 grams) was added to a mixture of (3R,4S,5R)-ethyl-5- azido-4-hydroxy-3-(pentan-3-yloxy)cyclohex-l-ene carboxylate compound of formula-9- (100 grams) in acetonitrile (250 ml) at 25-3O0C. The reaction mixture was heated to reflux temperature and stirred up to the completion of the reaction. The solvent was distilled off under reduced pressure, cooled and cyclohexane was added to the residue then distilled off. Ethyl acetate (200 ml) was added to the residue and stirred for 10 minutes at 25-30°C. Oxalic acid (44.5 grams) was added to the reaction mixture, stirred for 30 minutes at 25-3O0C. The reaction mixture was cooled to 0-50C and stirred. The solid was filtered, washed and dried to get the title compound
Yield: 85 grams
Purity by HPLC: 98.42 %; 0.52 % (27.7); 0.41% (13.6)
MR: 75-8O0C; SOR:-40 to-45°(C =1; methanol)
ExampIe-2: Preparation of oseltamivir phosphate compound of formula-la:
Zinc (77 grams) and aqueous ammonium chloride(77.4 grams in 250 ml of water) was added to a solution of ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethyIpropoxy) cyclohex-l-ene-1- caxboxylate compound of formula-13 (100 grams) in isopropyl alcohol (500 ml) at 18-20°C and stirred for an hour. The reaction mixture was quenched with aqueous ammonia and methylene chloride was added to it, stirred and filtered. The aqueous and organic layers from the filtrate separated, extracted the aqueous layer with methylene chloride and washed the organic layer with water. The solvent was distilled off under reduced pressure and the obtained residue treated with phosphoric acid in methanol and stirred. The solid formed was filtered, washed with methanol and dried to get the title compound.
Yield: 91 grams;
Purity by HPLC: 98.40%; Impurity at 0.85 RRT: Not detected
MR: 198 to 202°C; SOR: -27 to-34° (C =1.5; chloroform)
Particle Size Distribution:
Before micronization : D(0.1): 17 μm ; D(0.5): 81 μm ; D(0.9) :265 μm ; D[4,3] : 115 μm After micronization: D(0.1): 13 μm ; D(0.5): 47 μm ; D(0.9) : 115 μm ; D[4,3] : 58 μm
Example-3: Preparation of oseltamivir compound of formula-1:
Cobaltous chloride (1 gram) was added to a mixture of ethyl (3R,4R,5S) -4-acetamido-5 -azido-3 -( 1 -ethylpropoxy)cyclohex- 1 -ene- 1 -carboxy late (10 grams), methanol (20 ml), water (100 ml) and methanol (20 ml) at 25-300C and stirred for 15 minutes. Aqueous sodiumborohydride (1.5 grams in 10 ml of aqueous sodium hydroxide) was added to the reaction mixture and stirred up to completion of the reaction. Methylene chloride (75 ml) was added to the reaction mixture and stirred then filtered through the hyflow. The organic and aqueous layers were separated and extracted aqueous layer with methylene chloride. The aqueous layer was washed with water and drying with sodium sulphate. The solvent from the organic layer co-distilled with acetone under reduced pressure. The obtained residue is purified with column chromatography using hexane and ethyl acetate as an eluent.
Yield: 4 grams Example-4: Preparation of ethyl (3aR,7R,7aR)-2,2-dimethyl-7-methanesulfonyl-oxy- 3a,6,7,7a-tetrahydrobenzo[l,3]dioxole-5-carboxylate compound of formula-5:
A mixture of thionyl chloride (34.19 grams) and toluene (100 ml) was added to a (-)shikimic acid (100 grams) in ethanol (200 ml) at 25-35°C over 2 hours. The reaction mixture was heated to reflux temperature and stirred upto completion of the reaction, then cooled to 40-50σC. The solvent was distilled off under reduced pressure at below 50°C and the residue cooled to 25-35°C. Ethyl acetate(680 ml), 2,2-dimethoxy propane (47.7 grams), p-toluene sulphonic acid (1 grams) was added to the residue at 25-350C then heated to 40-450C and stirred for 2 hours. The reaction mixture was partially distilled off and 2,2-dimethoxy propane (47.7 grams) was added to it at 40-450C then stirred for 2 hours. The solvent was distilled off completely under reduced pressure at below 45°C and the obtained residue was cooled to 25-35°C. Ethyl acetate (750 ml) was added and cooled to 0-100C. Methane sulphonyl chloride (76 grams) followed by triethylamine(116 grams) was added slowly to the reaction mixture and stirred for 45 minutes at 10-150C. The undissolved material from the reaction mixture was filtered off, washed with ethyl acetate and the filtrate was distilled off under reduced pressure at below 35°C. Methanol (300 ml) was added to the residue, cooled to -25 to -35°C and stirred for 3 hours. The solid obtained was filtered off, washed with chilled methanol and then dried to get the title compound.
Yield: 170 grams;
M.R: 85-1050C
Example-5: Preparation of ethyl (3R,4R,5R)-3-(l -ethyl propoxy)-4-hydroxy-5- methane sulfonyloxy-cyclohex-l-ene-l-carboxylate compound of formula-7:
A mixture of ethyl (3aR,7R,7aR)-2,2-dimethyl-7-methanesulfonyl-oxy-3a,6,7,7a- tetrahydrobenzo[l,3]dioxole-5-carboxylate (100 grams), 3-pentanone(130 grams), and trifluoromethane sulphonic acid(2.04 grams) was heated to 35-400C and stirred for an hour. Partially distilled off the reaction mixture and 3-pentanone(81.3 grams) was added and stirred for an hour at 35-4O0C. Reaction mixture was distilled off partially under reduced pressure then cooled to 25-35°C. The reaction was basified with triethyl amine (2.88 grams) and distilled off the solvent under reduced pressure at below 500C. Cyclohexane (120 ml) was added to the residue and distilled off completely. The residue was dissolved in methylene chloride (80 ml) at 25-35 °C, stirred for 15 mins and washed it with aqueous sodiumbicarbonate solution followed by water. Distilled off the organic layer completely and methylene chloride (870 ml) was added to the obtained residue at 25-30°C. The reaction mixture was cooled to -30 to -35°C and trimethylsilane (54.3 grams) followed by titanium tetra chloride (88.92 grams) in methylene chloride (80 ml) was added slowly at -30 to 35°C for 3 hours. Quenched the reaction mixture with cooled water and raised the temperature to 20-30°C. Organic layer was separated and washed with sodium bicarbonate solution followed by water. Distilled off the solvent from organic layer under reduce pressure at below 50°C. Ethyl acetate (75 ml) was added to the residue and cooled to 25-35°C. Ether (800 ml) was added to the reaction mixture and cooled to -20 to -30°C then stirred for an hour. The solid obtained was filtered, washed with chilled ether and then dried to get the title compound.
Yield: 92 grams
Example-6: Preparation of ethyl (3R,4S,5S)-4,5-epoxy-3-(l-ethyl-propoxy)-l- cyclohex-l-ene-l-carboxylate compound of formula-8:
A mixture of ethyl (3R,4R,5R)-3-(l-ethyl propoxy)-4-hydroxy- 5 -methane sulfonyloxy- cyclohex-1-ene-l-carboxylate (100 grams), aqueous sodium bicarbonate (41.2 grams in 550 ml water) and isopropylalcohol(330 ml) was heated to 50-55°C and stirred for 6 hours. The reaction mixture was distilled off partially at below 45°C, cooled to 5-100C then stirred for 1.5 hours. The solid obtained was filtered and washed with water. Ether (800 ml), water (400 ml) and sodium chloride solution (10 grams in 100 ml water) was added to the obtained wet solid, heated to 35-400C and stirred for 15 mins. Aqueous and organic layer was separated and extracted the aqueous layer with ether. The solvent from the ether layer was distilled off completely under reduced pressure. Water (IL) was. added to the obtained residue at 35-4O0C and stirred for 1.5 hours. The compound was filtered, washed with water and then dried to get the title compound.
Yield: 68 grams Example-7: Preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula-lla:
A mixture of ethyl (3R,4S,5S)-4,5-epoxy-3-(l-ethyl-propoxy)-l-cyclohex-l-ene- 1-carboxylate (100 grams), sodium azide(28 grams), ammonium chloride (23 grams), water (30 ml) and isopropyl alcohol (175 ml) was heated to 70-750C and stirred for 14 hours. The reaction mixture was cooled to 25-30°C, aqueous sodiumbicarbonate solution (4 grams in 75 ml of water) and toluene (250 ml) was added and stirred for 15 mins. Organic and aqueous layers were separated and extracted the aqueous layer with toluene. Toluene layer was washed with sodium chloride solution then distilled off the toluene completely under reduced pressure at below 50°C. The obtained residue was cooled to 25-30°C and acetonitirle(275 ml), triphenyl phosphine (87 grams) was added then heated to reflux temperature. The reaction mixture was stirred at reflux for 9 hours then cooled to 500C and then distilled off the solvent under reduced pressure at below 500C. Ether (165 ml) was added to the residue, stirred for 30 mins and cooled to 0-5°C and stirred for an hour. Filtered the solid and washed with ether. The solvent from the filtrate was distilled off completely under reduced pressure at below 500C, cooled the obtained residue to 25-350C and ethyl acetate(165 ml) was added to it. The reaction mixture was added to the solution of oxalic acid (49 grams) in ethyl acetate(55 ml) at 0-50C then stirred for an hour. Filtered the solid, washed with ethyl acetate and dried to get the title compound.
Yield: 90 grams
Example-8: Preparation of ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l- ethylpropoxy)cyclohex-l-ene-l-carboxylate compound of formula-13:
Oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate (100 grams) was added to a cooled water (500 ml) at 0-50C then basified with aqueous ammonia solution. The reaction mixture temperature was raised to 25-3O0C and methylene chloride (300 ml) was added and stirred for 15 mins. Organic layer was separated and extracted the aqueous layer with methylene chloride. Organic layer was dried over sodium sulphate and distilled off the solvent completely under reduced pressure at below 45°C. Sodium azide (23.5 grams), ammonium chloride (19 grams) and dimethylformamide (200 ml) was added to the residue and heated to 70-750C and stirred for 5 hours under nitrogen atmosphere. The reaction mixture was cooled to 25-300C and aqueous sodium bicarbonate solution, ether(150 ml) was added and stirred for 15 minutes. Organic and aqueous layers were separated and extracted the aqueous layer with ethers. Washed the organic layer with water and subjected the organic layer to carbon treatment. Filtered the reaction mixture through hyflow and washed with ether. The solvent from reaction mixture was distilled off completely under reduced pressure at below 45°C then cooled to 25-35°C. Methylene chloride(260 ml), water(5 ml, triethylamine(33.2 grams), acetic anhydride(28 grams) was added to the reaction mixture and stirred for 60 mins at 20-250C. Quenched the reaction mixture with water, stirred for 15 mins then separated the layers. Washed the organic layer with water and dried with sodium sulphate. The solvent from the organic layer was distilled off completely under reduced pressure at below 45°C. Ethyl acetate(130 ml) was added to the residue and heated to 40-450C, stirred for 20 mins then cooled to 25-35°C. Ether(651 ml) was added to the reaction mixture at 25-300C, cooled to 0-50C and stirred for 2 hours. The solid obtained was dissolved in ethylacetate (133 ml) by heated to 40-450C and the reaction mixture was subjected to carbon treatment then filtered through hyflow. The fϊlterate was heated to 45-500C, ether (440 ml) was added to the filtrate and stirred for 30 minutes. The reaction mixture was initially cooled to 25-35°C then to 0-50C and stirred for 2.5 hours. Filtered the solid, washed with mixture of ether and ethyl acetate then dried it to get the title compound.
Yield: 50 grams;
SOR [C=I.5% in CHCl3) -42 to -48°C Example-9: Preparation of oseltamivir phosphate compound of formula-la:
Zinc (90.84 grams) and aqueous ammonium chloride(61.64 grams in 300 ml of water) was added to a solution of ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l-ethylpropoxy) cyclohex -1-ene-l-carboxylate (100 grams) in isopropyl alcohol (500 ml) at 18-200C and stirred for an hour. Cooled to 5-15°C and ammonium hydroxide (100 ml) was added and stirred for an hour. Methylene chloride (150 ml) was added to the reaction mixture and stirred for 15 mins then filtered through hyflow. Organic and aqueous layers were separated from the filtrate. Extracted the aqueous layer with methylene chloride and washed with organic layer with water then dried with sodiumsulphite. The solvent from the organic layer was distilled off under reduced pressure and the obtained residue was cooled to 20-30°C. Dissolved the residue in acetone (648 ml) and subjected to carbon treatment. The reaction mixture was filtered through hyflow and washed with acetone. Phosphoric acid (34 grams) was slowly added to the filtrate and stirred for 45 mins. Acetone (460 ml) was added to the reaction mixture, cooled to 0-50C and stirred for 2 hours. Filtered the solid and washed with acetone. Water (50 ml) and acetone (920 ml) was added to the wet solid at 25-35°C and stirred for an hour. Phosphoric acid (2 grams) was added to the reaction mixture at 5 tolO°C and stirred for 2 hour. Filtered the solid, washed with acetone and then dried to get the title compound.
Yield: 85 grams
Purity by HPLC: 99.92%
Before micronization : D(0.1): 16 μm ; D(0.5): 74 μm ; D(0.9) :225 μm ; D[4,3] : 99 μm - After micronization: D(0.1): 9 μm ; D(0.5): 36 μm ; D(0.9) : 112 μm ; D[4,3] : 57 μm .,

Claims

We Claim:
1. Novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate, compounds represented by the following general formula- 11,
Figure imgf000024_0001
Formula- 11
where in acid is capable of forming acid addition salt with ethyl (3R,4S,5R)-4,5- imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate and is selected from oxalic acid, succinic acid, fumaric acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, methane sulfonic acid, paratoluene sulfonic acid, acetic acid, sulfuric acid, phosphoric acid and hydrohalic acid such as hydrochloric acid, hydrobromic acid and the like.
2. Process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethyl_ propoxy)-l-cyclohexene-l-carboxylate compounds of general formula-11, which comprises of treating the crude ethyl (3R,4S,5R)-4,5-imino-3-(l -ethyl propoxy)-l- cyclohexene-1-carboxylate compound of formula- 10
Figure imgf000024_0002
Formula- 10
with a suitable acid selected from the acids defined above in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof to provide the corresponding acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l -ethyl propoxy)-l-cyclohexene-l- carboxylate.
3. A process for the preparation of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l -ethyl propoxy)-l-cyclohexene-l-carboxylate, compounds of formula-11, which comprises of reacting ethyl (3R,4S,5R)-5-azido-4-hydroxy-3-(l -ethyl propoxy)cyclohex-l-ene- 1-carboxylate, compound of formula-9
Figure imgf000025_0001
Formula-9
with triphenyl phosphine in a suitable solvent selected from polar aprotic solvent or m'trile solvents, followed by treating with a suitable acid selected from the above defined acids in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof, to provide the corresponding acid addition salt of ethyl (3R,4S,5R)- 4,5-imino-3-(l -ethyl propoxy)-l-cyclohexene-l-carboxylate, compounds of general formula-11.
4. Oxalic acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethyl propoxy)-l-cyclohexene-l- carboxyϊate, compound of formula- 11a having the following structure.
Figure imgf000025_0002
Formula-l la
5. Crystalline ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate oxalate characterized by its DSC which shows two endothermic peaks at 78° C and 141° C.
i:
6. A process for the preparation of crystalline ethyl (3R,4S,5R)-4,5-imino-3-(l- ethylpropoxy)-l-cyclohexene-l-carboxylate oxalate of claim 5, comprises of treating the ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate with oxalic acid in ethyl acetate.
7. Use of novel salts of ethyl (3R,4S,5R)-4,5-imino-3-(l -ethyl propoxy)- 1 -cyclohexene- 1-carboxylate as claimed in claim 1 and oxalate salt compound of formula-l la as claimed in claim 4 or 5 for the preparation of highly pure ethyl (3R,4S,5R)-4,5-imino- 3-(l-ethylpropoxy)-l-cyclohexene-l-carboxylate compound of formula-10 or in the preparation of oseltamivir compound of formula- 1 and its pharmaceutically acceptable salts.
8. A process for the preparation of oxalate salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethyl propoxy)- 1-cyclohexene-l-carboxylate compound of formula-lla, which comprises of treating the ethyl (3R,4S,5R)-4,5-imino-3-(l-ethyl propoxy)- 1-cyclohexene-l- carboxylate, compound of formula-10
Figure imgf000026_0001
Formula-10
with oxalic acid in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof to provide the oxalic acid salt of ethyl (3R,4S,5R)-4,5-imino-3-(l- ethyl propoxy)- 1 -cyclohexene- 1 -carboxylate.
9. A process for the preparation of oseltamivir compound of formula- 1 ,
Figure imgf000026_0002
Formula- 1
which comprises of reducing ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l -ethyl propoxy)cyclohexy-l-ene-l -carboxylate compound of formula-13,
Figure imgf000027_0001
Formula- 13
in presence of zinc dust and ammonium chloride in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof to provide the oseltamivir compound of formula- 1.
10. A process for the preparation of oseltamivir compound of formula- 1, which comprises of reducing ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l -ethyl propoxy)cyclohex-l-ene-l-carboxylate, compound of formula- 13 in the presence of zinc dust and ammonium chloride in a suitable alcoholic solvents preferably isopropyl alcohol and water, followed by isolating the oseltamivir compound of formula- 1 from a suitable chloro solvent preferably methylene chloride.
11. A process for the preparation of oseltamivir compound of formula- 1, which comprises of reducing ethyl (3R,4R,5S)-4-acetamido~5-azido-3-(l-ethyl propoxy)cyclohex-l-ene-l-carboxylate compound of formula- 13
Figure imgf000027_0002
Formula- 13
in presence of cobalt ion, a ligand and a reducing agent
wherein the cobalt ion is selected from the group consisting of cobaltous chloride, cobaltous diacetate and cobaltic chloride; and the ligand is selected from the group consisting of dimethylglyoxime, 2,2'-bipyridyl and 1,10-phenathroline; the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, tetra alkyl ammonium borohydride and zinc borohydride; in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof; to provide the oseltamivir compound of formula- 1.
and optionally converting the obtained oseltamivir compound of formula- 1 into its pharmaceutically acceptable salt thereof.
12. An improved process for the preparation of oseltamivir phosphate compound of formula- Ia, which comprises of the following steps,
a) Reacting the (3R,4S,5R)-3,4,5-trihydroxy cyclohex-1-ene-carboxylic acid compound of fomula-2
Figure imgf000028_0001
Formula-2
with ethanol in presence of thionyl chloride in toluene to provide the ethyl(3R,4S,5R)-3,4,5-trihydroxy cyclohex-1-ene carboxylate compound of formula-3,
Figure imgf000028_0002
Formula-3
which on in-situ treatment with 2,2-dimethoxy propane in presence of toluene sulfonic acid in ethylacetate provides ethyl (3aR,7R,7aS)-2,2-dimethyl-7- hydroxy-3a,6,7,7a-tetrahydro benzo[l,3"]dioxole-5-carboxylate compound of formula-4,
Figure imgf000028_0003
Formula-4 which on in-situ reaction with methane sulfonylchloride in presence of triethylamine to provide the ethyl (3aR,7R,7aR)-2,2-dimethyl-7-methanesulfonyl- oxy-3a,6,7,7a-tetrahydrobenzo[l,3]dioxole-5-carboxylate compound of formula-5,
Figure imgf000029_0001
Formula-5
b) treating the compound of formula-5 with 3-pentanone in presence of trifluoromethane sulfonic acid to provide the ethyl (3aR,7R,7aR)-2,2-diethyl-7- methanesulfonyloxy-3a,6,7,7a-tetrahydrobenzo[l,3]-dioxole-5-carboxylate compound of formula-6,
Figure imgf000029_0002
Formula-6
which on in-situ reaction with trimethyl silane in presence of titanium tetrachloride in methylene chloride to provide the ethyl(3R,4R,5R)-3-(l-ethyl- propoxy)-4-hydroxy-5-methanesulfonyloxy-cyclohex-l-ene-l-carboxylate compound of formula-7,
Figure imgf000029_0003
Formula-7
c) treating the compound of formula-7 with sodiumbicarbonate in a mixture of isopropylalcohol and water to provide the ethyl(3R,4R,5R)-4,5-epoxy-3-(l- ethylpropoxy)- 1 -cyclohex- 1 -ene- 1 -carboxylate compound of formula-8,
Figure imgf000030_0001
b Formula-8
d) reacting the compound of formula-8 with sodium azide in presence of ammonium chloride to provide ethyl(3R,4S,5R)-5-azido-3-(l-ethylpropoxy)-4-hydroxy- cyclohexene-1-carboxylate compound of formuala-9,
Figure imgf000030_0002
which on in-situ reaction with triphenyl phosphine, in a suitable solvent selected from polar aprotic solvent or nitrile solvent, followed by treatment with a suitable acid selected from the above defined acids, in a suitable solvent selected from alcohols, ketones, esters, hydrocarbons, polaraprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof, to provide the corresponding acid addition salt of ethyl (3R,4S,5R)-4,5-imino-3-(l-ethylpropoxy)-l-cyclohexene-l- carboxylate compound of formula- 11 ,
Figure imgf000030_0003
Formula- 11
e) reacting the compound of formula- 11 with a suitable base in a suitable solvent, followed by treating with sodium azide in presence of ammonium chloride in dimethylformamide to provide the ethyl(3R,4R,5S)-4-amino-5-azido-3-(l- ethylpropoxy)-cyclohex-l-ene-l-carboxylate compound of formula-12,
Figure imgf000031_0001
Formula- 12
which on in-situ reaction with acetic anhydride in a mixture of methylene chloride and water to provide the ethyl(3R,4R,5S)-4-acetamido-5-azido-3-(l- ethylpropoxy)cyclohe- 1 -ene- 1 -carboxylate compound of formula- 13,
Figure imgf000031_0002
f) reducing the ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(l -ethyl propoxy)cyclohex- 1 -ene- 1 -carboxylate compound of formula- 13 with zinc dust and ammonium chloride in a suitable alcoholic solvents preferably isopropyl alcohol and water, followed by isolating the oseltamivir compound of formula- 1 from a suitable chloro solvent preferably methylene chloride to provide oseltamivir, which on in- situ treatment with phosphoric acid in a suitable solvent to provide the oseltamivir phosphate compound of formula- Ia.
13. A process according to claim 12, wherein the obtained oseltamivir phosphate compound of formula- Ia is having purity greater than 99.50%, preferably greater than 99.80 by HPLC.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103833570A (en) * 2014-03-19 2014-06-04 浙江师范大学 Synthesis method of oseltamivir
CN108047076A (en) * 2017-12-26 2018-05-18 杭州新博思生物医药有限公司 A kind of preparation method of Oseltamivir enantiomter
CN110194728A (en) * 2019-06-19 2019-09-03 湖南华腾制药有限公司 Oseltamivir phosphate intermediate is continuously synthesizing to method
CN110698374A (en) * 2019-07-09 2020-01-17 苏州奥普拓新材料有限公司 Synthesis of continuous oseltamivir phosphate intermediate
CN111153818A (en) * 2020-03-13 2020-05-15 遂成药业股份有限公司 Method for preparing antiviral drug Tamiflu intermediate tert-butylamine derivative I
CN114133364A (en) * 2021-11-05 2022-03-04 广东中润药物研发有限公司 Synthetic method of oseltamivir intermediate
CN115266965A (en) * 2022-07-01 2022-11-01 苏州博研医药科技有限公司 High performance liquid chromatography method for detecting specific impurities of oseltamivir phosphate key intermediate
CN115745921A (en) * 2022-10-28 2023-03-07 北京格林意锐医药科技有限责任公司 Preparation method and application of oseltamivir intermediate impurity
CN116375595A (en) * 2023-03-31 2023-07-04 重庆医药高等专科学校 Preparation method and refining method of oseltamivir phosphate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026933A1 (en) * 1995-02-27 1996-09-06 Gilead Sciences, Inc. Novel selective inhibitors of viral or bacterial neuraminidases
WO2001032617A1 (en) * 1999-11-02 2001-05-10 Sagami Chemical Research Center Process for the preparation of 7-azabicyclo[4.1.0]-hept-3-ene-3-carboxylic acid esters

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026933A1 (en) * 1995-02-27 1996-09-06 Gilead Sciences, Inc. Novel selective inhibitors of viral or bacterial neuraminidases
WO2001032617A1 (en) * 1999-11-02 2001-05-10 Sagami Chemical Research Center Process for the preparation of 7-azabicyclo[4.1.0]-hept-3-ene-3-carboxylic acid esters

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ROHLOFF J.C. ET AL: 'Practical Total Synthesis of the Anti-Influenza Drug GS-4104' J. ORG. CHEM. vol. 63, no. 13, 05 June 1998, pages 4545 - 4550 *

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CN103833570A (en) * 2014-03-19 2014-06-04 浙江师范大学 Synthesis method of oseltamivir
CN108047076A (en) * 2017-12-26 2018-05-18 杭州新博思生物医药有限公司 A kind of preparation method of Oseltamivir enantiomter
CN108047076B (en) * 2017-12-26 2020-05-08 杭州新博思生物医药有限公司 Preparation method of oseltamivir enantiomer
CN110194728B (en) * 2019-06-19 2021-04-30 湖南华腾制药有限公司 Continuous synthesis method of oseltamivir phosphate intermediate
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CN111153818A (en) * 2020-03-13 2020-05-15 遂成药业股份有限公司 Method for preparing antiviral drug Tamiflu intermediate tert-butylamine derivative I
CN111153818B (en) * 2020-03-13 2023-03-28 遂成药业股份有限公司 Method for preparing antiviral drug Tamiflu intermediate tert-butylamine derivative I
CN114133364A (en) * 2021-11-05 2022-03-04 广东中润药物研发有限公司 Synthetic method of oseltamivir intermediate
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