FIELD OF INVENTION

The present invention relates to a novel process for the preparation of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)-amino-l,6-
diphenyl hexane, also known as Lopinavir.

BACKGROUND OF THE INVENTION

Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective and recently approved HIV protease inhibitor is (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)-amino-l,6-diphenylhexane, also known as Lopinavir of formula I.

Lopinavir is known to have ability of inhibiting HIV protease and the HIV infection. Lopinavir is particularly effective for the inhibition of HIV protease and for the inhibition of HIV infection when co administered with Ritonavir. US 5,914,332 patent discloses a process for the preparation of lopinavir by condensing N-[(lS,2S,4S)-4-amino-2-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide and (2R)-3-methyl-2-(2-oxotetrahydropyrimidin-l(2//)-yl)butanoic acid in presence of 1-hydroxybenzotriazole (HOBt) and a diimide like dicyclohexylcarbodiimide (DCC). The drawback of this process is the use of HOBt which is hazardous, needed in equimolar ratio and the reaction is time taking. Therefore, there is a need to provide a process for preparing lopinavir which avoids the use of HOBt.

The present inventors has developed a cost effective process for lopinavir whose yield is high, reaction time is short and which obviates the use of 1-hydroxybenzotriazole (HOBt).

SUMMARY OF THE INVENTION
Accordingly, the principal aspect of the present invention is to provide a process for the preparation of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l- tetrahydropyrimid-2-onyl)-3-methylbutanoyl)-amino-l,6-diphenylhexane of formula I comprising condensing N-[(lS,2S,4S)-4-amino-2-hydroxy-5-phenyl-l- (phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide of formula II and (2R)-3-methyl-2-(2-oxotetrahydropyrimidin-l(2H)-yl)butanoicacid of formula III in presence of 4-Dimethyl amino pyridine, dicyclohexylcarbodiimide (DCC) and in absence of 1-hydroxybenzotriazole (HOBt).
The present invention is illustrated by the below reaction scheme:

Detail Description of the Invention

Accordingly in an embodiment of the invention, the condensation of N- [(1S,2S,4S)-4-amino-2-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide of formula II with (2R)-3-methyl-2-(2-oxotetrahydropyrimidin-l(2H)-yl)butanoicacid of formula III is carried out in presence of solvent selected from the group comprising methyl acetate, ethyl acetate, methylene dichloride, ethylene dichloride, diethyl ether etc. preferably methylene dichloride to obtain (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)-amino-l,6-diphenylhexane of formula I. The reaction is carried out at temperature in the range of about 0 to 30°C, preferably at 25- to30 °C.

In another embodiment of the invention, the condensation of iV-[(lS,2S,4S)-4-amino-2-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide of formula II with (2R)-3-methyl-2-(2-oxotetrahydropyrimidin-l(2#)-yl)butanoicacid of formula III is done in presence of 4-Dimethyl amino pyridine (DMAP).

In another embodiment, the process of the present invention provides below key advantages which will be acknowledged and highly appreciated by a person skilled in the art:

1. The process of the condensation of N-[(lS,2S,4S)-4-amino-2-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide with (2R)-3-methyl-2-(2-oxotetrahydropyrimidin-l(2H )-yl)butanoicacid to obtain (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)-amino-l,6-diphenylhexane is very fast in presence of DMAP.

2. Since DMAP is highly soluble in water it can be removed easily during isolation process and can be recovered from the aq. layer. Even a trace of HOBt present in the final API may lead to solubility issue.

3. The impurity formation due to the reaction of HOBt with Lopinavir is avoided.

4. The costly & explosive HOBt is replaced with cheaper and non-explosive DMAP.

The present invention can be illustrated by the following example, which is not to limit the scope of invention.

Example 1: Preparation of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyl)-3-methyIbutanoyl)-amino-l,6-diphenylhexane (Lopinavir):

Nr-[(lS,2S,4S)-4-amino-2-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide (l0g) and 2.0 volume of methylene dichloride (MDC) were charged into a RBF. Stirred for 15 min. to get clear solution. Charged (2R)-3-methyl-2-(2-oxotetrahydropyrimidin-l(2H)-yl)butanoicacid (3.58g) and 2.73g of 4-Dimethyl amino pyridine. Added dicyclohexylcarbodiimide (DCC) in 3 volume of MDC over 30 min. Stirred the reaction mass at 25-30°C for 5-6 hrs. After the reaction, the white solid is filtered (the by-product). The filtrate was washed with 10% citric acid solution followed by 5% sodium bicarbonate solution. The organic layer was concentrated under vacuum at 30-35°C. The white solid was stirred with 2 volume heptane filtered. The material was dried at 35-40°C for 8 hours to get (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)-amino-l,6-diphenylhexane (Lopinavir).
Yield: 90% Purity: 99.8 %

We claim:

1. A process for the preparation of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2-(l-tetrahydropyrimid-2-onyI)-3-methylbutanoyl)-amino-l,6-diphenylhexane of formula I comprising condensing JV-[(lS,2S,4S)-4-amino-2-hydroxy-5-phenyl-l-(phenylmethyl)pentyl]-2-(2,6-dimethylphenoxy)acetamide of formula II and (2R)-3-methyl-2-(2-oxotetrahydropyrimidin-l(2//)-yl)butanoicacid of formula III in presence of 4-DimethyI amino pyridine, dicyclohexylcarbodiimide (DCC) and in absence of l-hydroxybenzotriazole (HOBt).

2. A process according to claim 1 wherein, the condensation is carried out in presence of a solvent selected from the group comprising methyl acetate, ethyl acetate, methylene dichloride, ethylene dichloride and diethyl ether.

3. A process according to claim 1 wherein, the condensation is carried out in presence of methylene dichloride.