FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention.- PROCESS FOR PREPARATION OF
ATAZANAVIR SULFATE
2. Applicant(s)
(a) NAME : LUPIN LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : 159 CST Road, Kalina, Santacruz (East),
Mumbai-400 098, State of Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

BACKGROUND OF THE INVENTION:
Atazanavir is chemically known as (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,ll-dioxo-9-(phenylmethyI)-6-[[4-(2-pyridinyI)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester. Atazanavir sulfate (I) in combination with other antiretroviral agents is used for the treatment of HIV-1 infection.

The methods for preparation of atazanavir sulfate in the prior art documents are discussed below.
The patent US 6,087,383 discloses the process for preparation of atazanavir sulfate comprising treating atazanavir base with sulfuric acid in solvents selected from ethanol or isopropanol or acetone.
Other patents US 7,829,720 and US 7,838,678 disclose the preparation process of atazanavir sulfate involves the use of solvents selected from acetone/N-methyl pyrrolidone and ethanol/heptane.
The PCT application WO 2011/107843 discloses the use of acetonitrile, acetone, ethanol and heptane or mixtures thereof in the preparation of atazanavir sulfate.
The patent publication US 2013/0035493 discloses the preparation of atazanavir sulfate by reacting atazanavir base with sulfuric acid in solvents consisting methanol, ethanol, isopropanol, N-methyl pyrrolidone or mixture thereof then adding anti-solvents consisting methyl tertiary-butyl ester, ethyl acetate, acetonitrile, isopropyl acetate, cyclohexane and combination thereof followed by seeding then isolation of the product.

Zhongminet al, Organic Process Research and Development, 6, p-323-328, (2002) describes reaction of atazanavir base with sulphuric acid in ethanol to give atazanavir sulfate.
SUMMARY OF THE INVENTION:
The present invention provides a process for preparation of atazanavir sulfate comprises: reaction of atazanavir base with sulfuric acid in alcoholic solvent, partial removal of alcoholic solvent, addition of ketonic solvent, distillation of alcohol-ketone mixture and isolation.
DETAILED DESCRIPTION OF THE INVENTION:
An embodiment of the present invention provides a process for preparation of atazanavir sulfate comprising:
a) reaction of atazanavir base with sulphuric acid in alcohol,
b) removal of alcohol partially,
c) addition of ketone,
d) removal of alcohol-ketone mixture,
e) optionally repeating steps (c) and (d),
f) diluting the concentrated mass with ketone,
g) cooling, and
h) isolation.
Atazanavir base is dissolved in alcohol by stirring at room temperature. To the resulting solution sulphuric acid is added at room temperature.
The quantity of sulphuric acid with respect to atazanavir base is 0.9 to 1.3 mole, preferably 1 to 1.2 mole.
The quantity of alcohol with respect to atazanavir free base is 1-10 times (weight/volume), preferably 2-7 times (weight/volume).
According to the present invention the alcoholic solvent is selected from methanol, ethanol, propanol and isopropanol.

According to the present invention the ketonic solvent is selected from acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and methyl tert-butyl ketone.
Solvent is removed either by distillation or evaporation. Distillation is carried out either at normal pressure or at reduced pressure. Distillation is carried out till alcohol content of the residual mixture is below 1%. The resulting mixture is cooled initially to 20-30 °C then further cooled to 0-5 °C.
The pure atazanavir sulfate according to the present invention can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
According to the present invention the purity of atazanavir sulfate is greater than 99.9%.
Atazanavir sulfate can be dried using different techniques of drying like tray drying and rotatory drying techniques with or without application of vacuum and/or under inert condition.
The present invention is described in the following example, however it should be noted that the scope of the present invention is not limited by the example.
Example 1: Preparation of atazanavir sulfate
To a solution of atazanavir base (80 g) in methanol (400 ml) concentrated H2S04 (6.8 ml) was added at 25 °C and stirred for one hour. Methanol was distilled out under vacuum till 80-120 ml solvent was left. Acetone (160 ml) was added, stirred and acetone-methanol mixture was distilled out. Addition of acetone (160 ml) and distillation was repeated thrice. The methanol content of the resulting mixture by gas chromatography was found to be 0.99 by area percent. Then acetone (400 ml) was added and stirred for 45 minutes at 25 °C. Further cooled to 5 °C and stirred for one hour. Solid was filtered, washed with acetone (160 ml) and dried. Yield: 80 g. HPLC Purity: 99.95%

WE CLAIM:
1. A process for preparation of atazanavir sulfate comprising:
a) reaction of atazanavir base with sulphuric acid in alcohol,
b) removal of alcohol partially,
c) addition of ketone,
d) removal of alcohol-ketone mixture,
e) optionally repeating steps (c) and (d),
f) diluting the concentrated reaction mass with ketone,
g) cooling, and h) isolation.

2. The process according to claim 1, wherein the quantity of sulfuric acid with respect to atazanavir base is 0.9-1.3 mole.
3. The process according to claim 1, wherein the alcoholic solvent is selected from methanol, ethanol, propanol and isopropanol.
4. The process according to claim 3, wherein the alcoholic solvent is methanol.
5. The process according to claim 1, wherein the ketonic solvent is selected from acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and methyl tert-butyl ketone.
6. The process according to claim 5, wherein the ketonic solvent is acetone.
7. The process according to claim 1, wherein the methanol content is below 1 % in step (f).