INTERMEDIATE

FIELD OF THE INVENTION The present invention provides a commercially viable process for preparing saquinavir and pharmaceutically acceptable acid addition salts thereof using novel intermediate.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,196,438 disclosed benzyloxycarbonyl- and 2- quinolylcarbonyl- amino acid derivatives and pharmaceutically acceptable acid addition salts thereof. These compounds are antiviral agents. Among them saquinavir, chemically (2S)-N'-[(1S,2R)-3-[(3S,4aS,8aS)-3-[[(1 ,1-dimethylethyl) amino]carbonyl]octahydro-2(1 H)-isoquinolinyl]-2-hydroxy-1-(phenylmethyl) propyl]-2-[(2-quinolinylcarbonyl)amino]butanediamide is a selective HIV protease inhibitor and can be used as medicaments for the treatment of prophylaxis of viral infections in mammals, humans or non-humans. Saquinavir is represented by the following structure:

Processes for the preparations of saquinavir and related compounds were disclosed in U.S. Patent No. 5,196,438. According to U.S. Patent No.

5,196,438, saquinavir is prepared by reacting N-(2-quinoIylcabonyI)-L- asparagine with 2-[3(S)-aminθτ2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-dec a hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in tetrahydrofuran in presence of 3-hydroxy-1 ,2,3-benzotriazin-4(3H)-one and dicyclohexylcarbodiimide to give saquinavir.

This process involves the direct condensation of N-(2-quinolylcabonyl)-L- asparagine and 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-deca hydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, which requires longer time to

complete the reaction and the yield obtained is not satisfactory and purity is very low.

The present invention is an improved, commercially viable process solving the aforesaid problem associated with process described in the prior art.

One object of the present invention is to provide a novel process for preparing saquinavir and pharmaceutically acceptable acid addition salts of saquinavir; in high purity and in high yield using a novel intermediate. DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novel process for preparing saquinavir of formula I:

or a pharmaceutically acceptable salt thereof: which comprises: a) reacting N ^? -(2-quinolinylcarbonyI)-L-asparagine of formula

with pivaloyl chloride of formula III

in presence of an organic base to give mixed anhydride of formula IV:

b) reacting the mixed anhydride of formula IV with [3S,4aS,8aS]-2-(3(S)-amino- 2(f?J-hydroxy-4-phenylbutyI)-N-(1 , 1 -dimethylethyl)decahydro-3-isoquinoline carboxamide of formula V:

to give saquinavir of formula I and optionally converting saquinavir formed into a pharmaceutically acceptable acid addition salts of saquinavir.

Mixed anhydride of the formula IV is novel and forms part of the invention. Preferable organic base used in step-(a) is selected from the group consisting of triethyl amine, trimethyl amine, tributyl amine and n-butyl amine. More preferable base is triethyl amine.

The reaction in step (a) is carried out at about 0 - 30 ⁰ C, more preferably at about 0 - 10 ⁰ C and still more preferably at about 0 - 5 ⁰ C. Preferably the reaction in step (a) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane and cyclohexane; and a mixture thereof. More preferable solvent is methylene chloride or n-heptane. Preferably the reaction in step (b) is carried out in a solvent selected from chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride and chloroform; hydrocarbon solvents such as n-hexane, n-heptane

and cyclohexane; and a mixture thereof. More preferable solvent is methylene chloride or n-heptane.

Preferable pharmaceutically acceptable acid addition salts are selected from salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, maleic acid, fumaric acid and tartaric acid. More preferable pharmaceutically acceptable acid addition salt is methanesulfonic acid.

The invention will now be further described by the following example, which is illustrative rather than limiting.

Example Step-I:

N ² -(2-QuinoIinylcarbonyl)-L-asparagine (44.7 gm) is suspended in methylene chloride (500 ml) at 25 - 35 ⁰ C under N ₂ atmosphere, the suspension is cooled to 0 - 5 ⁰ C and then triethylamine (15.1 gm) is slowly added for 15 minutes. Then the contents are stirred for 10 minutes at 0 - 5 ⁰ C to form a clear solution. To the solution 3,5-lutidine (2.5 gm) is added, immediately pivaloyl chloride (17.2 gm) is added as fast as possible under vigorous stirring and then stirred for 2 minutes at 0 - 5 ⁰ C to obtain pivaloyl N ² -(2-quinolinylcarbonyl)-L- asparaginate as dark red colour residual mass (it is an exothermic addition so, the temperature of the mass should be maintain at 0 - 5 ⁰ C).

Step-ll: [3S,4aS,8aS]-2-(3S-amino-2F?-hydroxy-4~phenylbutyl)-N-(1 , 1 -dimethyl ethyl)decahydro-3-isoquinoline carboxamide (50 gm) is added to the pivaloyl N ² - (2-quinolinylcarbonyl)-L-asparaginate (obtained in step-l) under vigorous stirring and then stirred for 15 minutes to form a almost dark red colour clear solution. Water (200 ml) is.added to the solution, stirred for 10 minutes and separated the layers. The pH of the organic layer is adjusted to 7.8 - 8.2 with 10% aqueous sodium bicarbonate solution (500 ml) and stirred for 30 minutes. The organic layer is further washed with 10% aqueous sodium bicarbonate solution, stirred for 30 minutes, washed with water (250 ml) and then separated the layers. The resulting organic layer is concentrated at 35 - 45 ⁰ C under reduced pressure until

completely distilled off the solvent. Methanol (100 ml) is added to the mass distilled off the solvent at 35 - 45 ⁰ C under reduced pressure to obtain an oily residue.

To the residue methanol (210 ml) is added, heated to 40 - 45 ⁰ C, carbon eno anticromos (5.0 gm) is added and stirred for 15 minutes at 40 - 45 ⁰ C. The carbon is filtered through hi-flo and washed with hot methanol (70 ml). Then the filtrate is cooled to 20 - 25 ⁰ C, methane sulfonic acid (12 gm) is added drop wise for 15 minutes and stirred for 12 hours at 20 - 25 ⁰ C. The precipitated product is filtered, washed two times with methanol (each time 50 ml) and dried at 35 - 45 ⁰ C under reduced pressure to give 75 gm of saquinavir mesylate crude (HPLC purity: 98.0%).

The crude saquinavir mesylate is purified by acid/base treatment to give 60 gm of 99.5% pure saquinavir mesylate.