DESC:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Oseltamivir phosphate or Tamiflu. The present invention relates to an improved process for the synthesis of Oseltamivir phosphate starting from (1S,5R,6S)-ethyl-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate without using tri-phenyl Phosphine so as to avoid formation of unwanted side products.

BACKGROUND OF THE INVENTION

Till date Influenza continues to be a serious health concern with the possibility of being pandemic anytime. Increased mutation rates in influenza virus have hampered the development of antiviral drugs and design and development of new drugs is targeted towards the molecular mechanisms that are specific to the proliferation or the metabolic procedure of the virus. The mechanism of infection involves the protein neuraminidase (NA), essential to viral replication. NA is responsible for the glycosidic cleavage of sialic acid from a glycoprotein of a host cell in a process that liberates the virion from the infected cell. The NA protein active site appears to be conserved in many strains of the influenza A and B virus. Therefore, an efficient inhibitor of the NA protein serves as a broad-spectrum anti- influenza drug. One such efficient NA inhibitor is Oseltamivir that is used for the prevention and treatment of influenza caused by influenza A and B viruses. Oseltamivir is a neuraminidase inhibitor, a competitive inhibitor of the neuraminidase enzyme of influenza virus. Oseltamivir exhibits anti-viral activity through prevention of the release and dispersal of progeny virions within the mucosal secretions and thereby reduce viral infectivity. Oseltamivir phosphate is an oral anti-viral drug approved for the treatment of acute, uncomplicated influenza in patients 2 weeks of age and older whose flu symptoms have not lasted more than two days. Oseltamivir phosphate is a white crystalline solid with the chemical name (3R,4R,5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C16H28N2O4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt. The structural formula is as follows:

Formula I
Oseltamivir although does not have a complex structure, practical synthesis of the same on a large scale poses serious challenges and has remained a field of extensive research for the medicinal chemist. There have been many efforts for the modification of the processes of Oseltamivir synthesis. Among the various derivatives of Oseltamivir, phosphate salts exhibit an efficient NA binding potential. The procedure of synthesis of Oseltamivir commonly involves shikimic acid as raw material which becomes difficult to obtain and in turn limits the production capacity for the drug failing to meet the extensive demand. Other methods related to the process of synthesis of Oseltamivir have also been reported by different groups of researchers based on alteration of the reactants used in the process. Additionally, most of the processes despite being useful in pilot scale, but pose the problem of industrialization in terms of yield and purity of the product.

CN103833570B discloses a synthesis method of oseltamivir. The synthesis method of oseltamivir comprises the following steps: starting from a compound 1,3-butadiene-3-amyl ether and compound 3-nitro-ethyl acrylate, carrying out Diels-Alder reaction, then reacting at room temperature in acetonitrile in the presence of a copper catalyst and PhI-NNs to prepare an aziridine compound in a one-pot method, wherein the mole ratio of the 1,3-butadiene-3-amyl ether to 3-nitro-ethyl acrylate to the copper catalyst is 1.1: 1: 0.025-0.1; and finally synthesizing the oseltamivir for preventing bird flu through the aziridine ring opening, nitryl and p-nitrobenzene sulfonyl removal, acetylation and hydrogenation.

JP2012006921A discloses use of a specified compound of an optically active cyclic epoxy ester as a starting raw material, and reaction via cyclohexenyl azide and cyclic diamide-alcohol follows. The patent application provides a high yield and practical chemical synthesis method capable of obtaining an anti-influenza virus drug having high optical purity from a readily available raw material compound.

WO 2009/137916 A1 relates to processes for the preparation of oseltamivir and the H3PO4 salt of oseltamivir, Tamiflu®. The application further relates to novel intermediate compounds and to pharmaceutical compositions containing said compounds. The application further relates to a method of using the novel intermediates to treat or prevent influenza.

Although a large number of methods are available for the synthesis of the antiviral drug, Oseltamivir phosohate, most of the conventional methods exhibit poor yield during large scale production of the drug. Further, even if some of the processes exhibit improved yield, the processes suffers the problem of executing multiple steps for arriving at the product and the usage of the harmful chemical tri-phenyl phosphine as one of the reagents that might result in the formation of undesired of side products. This necessitates for an advanced process of synthesis of Oseltamivir phosphate whereby the yield of the desired is improved even upon using the process on industrial scale such that the process produces pure drug showing effective antiviral.

OBJECTIVES OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of Oseltamivir phosphate.

Another objective of the present invention is to provide an improved process for the synthesis of Oseltamivir phosphate without using Triphenyl Phosphine so as to avoid formation of side products.

A preferred object of the present invention is to provide an improved process for the synthesis of Oseltamivir phosphate with less impurities and high yield.

Yet another objective of the present invention is to provide a process with less reaction time.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of Oseltamivir phosphate or Tamiflu starting from (1S,5R,6S)-ethyl-5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate. The reagents employed in the process do not include tri-phenyl Phosphine and consequently formation of unwanted side products is avoided.

Thus, the present invention provides a process for production of Oseltamivir phosphate, wherein the process comprises the steps of:
(i) base catalyzed epoxide ring opening of a compound of Formula II in presence of sodium azide and a solvent to obtain a compound of Formula III;
Formula II, Formula III

(ii) separating the compound of Formula III in dichloromethane layer and reacting with methanesulfonyl chloride in presence of an organic base to obtain a compound of Formula IV followed by reduction with a reducing agent in an alkaline medium to obtain a compound of Formula V;
Formula IV, Formula V

(iii) cyclizing the amine group of the compound of formula V in presence of toluene and an organic base to obtain a compound of Formula VI having an aziridine ring followed by reaction with sodium azide in presence of phosphoric acid to obtain a compound of Formula VII having an azido linkage;
Formula VI, Formula VII;

(iv) oxidizing the compound of Formula VII with acetic anhydride in presence of ethyl acetate and hexanes to obtain a compound of Formula VIII;
Formula VIII;

(v) reducing the compound of Formula VIII with a reducing agent and treating along with a phosphorous containing compound to obtain the Oseltamivir phosphate.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: STAGE-I: Preparation of (3R,4R,5S)-ethyl 4-acetamido-5-azido-3-(pentan-3-yloxy) cyclohex-1-enecarboxylate / OSL-I
Figure 2: STAGE-II: Preparation of Oseltamivir Phosphate / OSL-II

DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Oseltamivir phosphate or Tamiflu. The present invention advantageously provides an improved process with less number of impurities and higher yield. The present invention relates to an improved process for the synthesis of Oseltamivir phosphate without using tri-phenyl Phosphine so as to avoid formation of unwanted side products.

The present invention provides a process for production of Oseltamivir phosphate, wherein the process comprises the steps of (Figures 1 and 2):
(i) base catalyzed epoxide ring opening of a compound of Formula II in presence of sodium azide and a solvent to obtain a compound of Formula III;
Formula II, Formula III

(ii) separating the compound of Formula III in dichloromethane layer and reacting with methanesulfonyl chloride in presence of an organic base to obtain a compound of Formula IV followed by reduction with a reducing agent in an alkaline medium to obtain a compound of Formula V;
Formula IV, Formula V

(iii) cyclizing the amine group of the compound of formula V in presence of toluene and an organic base to obtain a compound of Formula VI having an aziridine ring followed by reaction with sodium azide in presence of phosphoric acid to obtain a compound of Formula VII having an azido linkage;
Formula VI, Formula VII;

(iv) oxidizing the compound of Formula VII with acetic anhydride in presence of ethyl acetate and hexanes to obtain a compound of Formula VIII;
Formula VIII;

(v) reducing the compound of Formula VIII with a reducing agent and treating along with a phosphorous containing compound to obtain the Oseltamivir phosphate.

The inorganic compounds used in the process of preparation of Oseltamivir phosphate include sodium azide and/or ammonium chloride, triphenylphosphine (TPP), NaBH4, LiAlH4, Pt, Pd, or any combination/mixture thereof. After the reaction is completed, the reaction mass is subjected to usual work-up procedures such as washings, extractions etc.

In an embodiment, the reducing agent used in steps (ii) and (v) in the process of preparation of Oseltamivir phosphate is zinc dust.

In an embodiment, the solvent in step (i) is selected from the group consisting of methylene chloride, ethylene dichloride and chloroform, methanol, ethanol, isopropyl alcohol, aromatic hydrocarbon or a combination thereof. Preferably, the organic solvent is methylene chloride and isopropyl alcohol.

In an embodiment, the organic base in steps (ii) and (iii) is an organic amine base selected from the group consisting of triethyl amine, trimethyl amine, tributyl amine, n-butyl amine or a combination thereof. More preferable organic amine base is triethyl amine.

In an embodiment, in step (ii) of the above disclosed process, the alkaline medium is isopropyl alcohol in toluene.

In an embodiment, the reaction processes of the present invention are carried out over temperature ranging between 0-75°C. Further, the reaction in steps (i) and (iii) are preferably performed at a temperature ranging from 70-75°C.

In another embodiment, other organic compounds of the present invention are dimethyl sulfoxide, dimethyl formamide, dioxane or any mixture thereof.

In an embodiment, the phosphorous containing compound is selected from organic phosphates and weak acids, preferably ortho phosphoric acid.

In another embodiment, the pharmaceutical dosage forms as and when used in influenza.

Some illustrative non-limiting examples of the present invention are described below.

EXAMPLE

STAGE-I: Preparation of (3R,4R,5S)-ethyl-4-acetamido-5-azido-3-(pentan-3-yloxy) cyclohex-1-enecarboxylate / OSL-I
A mixture of (1S,5R,6S)-ethyl 5-(pentan-3-yloxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate (10.0 kg), sodium azide (2.8 kg), ammonium chloride (2.3 kg), water (3.0 Lt) and ethanol (17.5 Lt) was heated to 70-75 °C and stirred for 14 hours. The reaction mixture was cooled to 25-30°C, aqueous sodium bicarbonate solution (400 grams in 30.0 Lt of water) and dichloromethane (20.0 Lt) was added and stirred for 15 min. Organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane (10.0 Lt). Dichloromethane layer was washed with sodium chloride solution. The obtained solution was cooled to 10-15 °C and triethylamine (7.5 kg), methanesulfonyl chloride (4.6 kg) was added then temperature rose to room temperature. The reaction mixture was stirred at room temperature for 2 hours. Water (50.0 Lt) was added to the reaction mass, stirred for 10 min. Aqueous and organic layer was separated. The solvent from the dichloromethane layer was distilled off completely under reduced pressure. To the obtained residue was added isopropyl alcohol (30.0 Lt) and zinc dust (10.0 kg) followed by aqueous ammonium chloride (7.6 kg in 20.0 Lt of water) at 18-20°C and stirred for an hour. The reaction mixture was quenched with water (20.0 Lt) and toluene (20.0 Lt) was added to it, stirred for 10 min. The aq. and organic layers separated, extracted the aqueous layer with toluene (10.0 Lt) and washed the organic layer with water (20.0 Lt). Triethylamine (12.5 kg) was added to the organic layer and the reaction mixture was heated to 70-75°C and stirred up to completion of the reaction, then cooled to room temperature. The undissolved material from the reaction mixture was filtered off, washed with toluene (5.0 Lt) and the filtrate was distilled off under reduced pressure at below 55°C. Sodium azide (2.0 kg), phosphoric acid (4.0 kg) and DMSO (50.0 Lt) was added to the residue and heated to 35-40°C and stirred for 4 hrs. The reaction mixture was cooled to 25-30°C and aq. sodium bicarbonate, dichloromethane (7.5 Lt) was added and stirred for 15 min. Organic and aq. layer were separated and extracted the aq. layer with dichloromethane (10.0 Lt). Washed the organic layer with water then triethylamine (6.25 kg) and acetic anhydride (5.0 kg) was added to the reaction mixture and stirred for 60 min at 20-25°C. Quenched the reaction mixture with water, stirred for 15 min 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 (6.5 Lt) was added to the residue and heated to 40-45 °C, hexanes was added to the reaction mixture and stirred for 30 min. The reaction mixture was initially cooled to 25-35°C then 0-5°C and stirred for 2.5 hours. Filtered the solid and washed with mixture of hexanes and ethyl acetate then dried it to get the title compound. Yield: 8.0 kg.

STAGE-II: Preparation of Oseltamivir Phosphate / OSL-II
Zinc (7.28 kg) and aqueous ammonium chloride (4.96 kg in 24.0 Lt of water) was added to a solution of (3R,4R,5S)-ethyl-4-acetamido-5-azido-3-(pentan-3-yloxy)cyclohex-1-enecarboxylate (8.0 kg) in isopropyl alcohol (40.0 Lt) at 18-20 °C and stirred for an hour. Cooled to 5-15 °C and ammonium hydroxide (8.0 Lt) was added and stirred for an hour. Methylene chloride (12.0 Lt) was added to the reaction mixture and stirred for 15 min then filtered through hyflow. Organic and aqueous layer were separated from the filtrate. Extracted the aqueous layer with methyelene chloride and washed with water then dried with sodium sulphite. 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 (52.0 Lt) and subjected to carbon treatment. The reaction mixture was filtered through hyflow and washed with acetone. Phosphoric acid (2.72 kg) was slowly added to the filtrate and stirred for 45 min. Acetone (37.0 Lt) was added to the reaction mixture, cooled to 0-5 °C and stirred for 2 hours. Filtered the solid and washed with acetone. Water (4.0 Lt) and acetone (74.0 Lt) was added to the wet solid at 25-35 °C and stirred for an hour. Phosphoric acid (0.16 kg) was added to the reaction mixture to 5 -10 °C and stirred for 2 hours. Filtered the solid and washed with acetone then dried to get the title compound. Yield: 7.0 kg.

Table 1: Comparison of Oseltamivir phosphate obtained from different processes
Parameters Conventional process Present invention
% yield (wt %) 35-40% 50-55%
Purity 97.0% 99.2%

From Table 1, it can be inferred that the yield of the product synthesized based on the presently disclosed process is 50-55% that is much higher than the yield of 35-40% as obtained from the conventional processes. Moreover, the Oseltamivir phosphate thus prepared has purity of more than 99 %.
,CLAIMS:1. A process for production of oseltamivir phosphate, wherein the process comprises:
(i) base catalyzed epoxide ring opening of a compound of Formula II in presence of sodium azide and a solvent to obtain a compound of Formula III;

Formula II, Formula III

(ii) separating the compound of Formula III in dichloromethane layer and reacting with methanesulfonyl chloride in presence of an organic base to obtain a compound of Formula IV followed by reduction with a reducing agent in an alkaline medium to obtain a compound of Formula V;
Formula IV, Formula V

(iii) cyclizing the amine group of the compound of formula V in presence of toluene and an organic base to obtain a compound of Formula VI having an aziridine ring followed by reaction with sodium azide in presence of phosphoric acid to obtain a compound of Formula VII having an azido linkage;
Formula VI, Formula VII;

(iv) oxidizing the compound of Formula VII with acetic anhydride in presence of ethyl acetate and hexanes to obtain a compound of Formula VIII;
Formula VIII;

(v) reducing the compound of Formula VIII with a reducing agent and treating along with a phosphorous containing compound to obtain the Oseltamivir phosphate.

2. The process as claimed in claim 1, wherein the reducing agent in steps (ii) and (v) is zinc dust.

3. The process as claimed in claim 1, wherein the solvent in step (i) is selected from the group consisting of methylene chloride, ethylene dichloride and chloroform, methanol, ethanol, isopropyl alcohol, aromatic hydrocarbon or a combination thereof.

4. The process as claimed in claim 1, wherein the organic base in steps (ii) and (iii) is an organic amine base selected from the group consisting of triethyl amine, trimethyl amine, tributyl amine, n-butyl amine or a combination thereof.

5. The process as claimed in claim 1, wherein in step (ii) the alkaline medium is isopropyl alcohol in toluene.

6. The process as claimed in claim 1, wherein the phosphorous containing compound is phosphoric acid.

7. The process as claimed in claim 1, wherein steps (i) and (iii) are performed at a temperature ranging from 70-75°C.