FORM 2
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 LOPINAVIR INTERMEDIATE
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:

FILED OF THE INVENTION:
The present invention relates to process for preparation of lopinavir intennediate,(2S3S,5S)-2-Amino-3-hydroxy-5-[2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane (S)-Pyroglutamic acid salt (II).
BACKGROUND OF THE INVENTION:
Lopinavir (I) is a protease inhibitor, used in combination with ritonavirfor the treatment of HIV infection. It is chemically known as ((2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(l-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane.

Compound of formula II, chemically known as(2S,3S,5S)-2-Amino-3-hydroxy-5-[2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-l,6-diphenylhexane(S)-Pyroglutamic acid salt, is an intermediate in the preparation of lopinavir (I).

Process for the preparation of lopinavirand its intermediate isdescribed in the patents US 5,914,332, US6,472,529, US 6,372,905 and publications Stoner et al; Organic Process Research & Development 1999, 3, 145-148; Stoner et al, Organic Process Research & Development, 2000, 4, 264-269. Preparation of lopinavir described in these documents involves preparation

of pyroglutamic acid salt (II) by N-debenzylation of compound (III) with Pd/C, ammonium formate in methanol to get compound of formula (IV) followed by treatment with L-pyroglutamic acid.

The use of ammonium formate in N-debenzylation of compound (III) leads to the formation of formic acid as a by-product which affectson yield of compound (II) which in turn affects yield of lopinavir (I).
SUMMARY OF THE INVENTION:
The present invention provides aprocess for the preparation of compound of formula(II) comprising:

a) N-debenzylation of compound of formula (III)in the presence of transition metal catalyst on activated carbonand formic acid salt in alcoholic solvent to get compound of formula (IV),


b) treating the reaction mixture of step (a) with aqueous inorganic base and
c) reaction of compound of formula (IV) with L-pyroglutamic acid.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of compound of formula (II) comprising:

a) N-debenzylation of compound of formula (III) in the presence of transition metal catalyst on activated carbonand formic acid salt in alcoholic solvent to get compound of formula (IV),

b) treating the reaction mixture of step (a) with aqueous inorganic base and
c) reaction of compound of formula (IV) with L-pyroglutamic acid.
In step (a) compound of formula (III) is subjected to N-debenzylation to get compound of formula (IV) in an autoclave in the presence of transition metal catalyst on activated carbonand formic acid salt in alcoholic solvent. Step (a) can also be carried out without using autoclave.

The transition metal catalyst is selected fromnickel, raney nickel, palladium, platinum, cobalt, rhodium and the like, preferably palladium. The formic acid salt is selected from ammonium formate, sodium formate and the like.
Alcoholic solvent used for N-debenzylation is selected from aliphatic alcohol comprisingmethanol, ethanol, 2-propanol and the like, preferably methanol. N-debenzylation reactionis carried out in the temperature range of30-65 °C, preferably 50-55 °C.
In step (b) the reaction mixture, after N-debenzylation, is treated with aqueous solution of inorganic base selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like, preferably sodium bicarbonate.
In step (c) compound of formula (IV) is treated with L-pyroglutamic acid in organic solvents selected from dioxane, dimethylsufoxide, ethylacetate, dimethylformamide and the mixture thereof, preferably dioxane-dimethylsulfoxide mixture.
Compound of formula (IV) can also betreated withother organic carboxylic acid such as succinic acid or fumaric acid and the like to obtain corresponding salt of compound (IV).
The compound of formula (II) can be isolated by methods known in the literature such as filtration, concentration and evaporation etc.
Process of the present invention provides compound of formula (II) in 40% yield from 2S-(l-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid. When the process of the present invention is carried out without performing step (b) then the compound of formula (II) is obtained in 28% yield which is fairly

low, moreover, HPLC purity is also slightly lesser. The process described in the prior art for preparation of compound (II) doesn't involve step (b).
Another embodiment of the present invention provides further conversion of compound of formula (II) into lopinavir. The compound (II) can be converted into lopinavir (I) by the methods known in the literature.
The present invention provides lopinavir of purity>99.4% (by HPLC) which is obtained by using the compound of formula (II) obtained by the process of present invention.
The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.
EXAMPLE 1: i. Preparation of 2S-(l-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride:
2S-(l-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid (81.56 g) was dissolved in dichloromethane (815.6 mil) and cooled to 0-5 °C. Dimethyl formamide (0.25 g) was added followed by thionyl chloride (29.71 ml) andstirred for 3-6 hours at 25-30 °C.DistilIed under vacuum to get residue. n-Heptane (375 ml) was added and removed under vacuum. The resultant solid was slurried in dimethylformamide (250 ml). ii. Preparation of (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane:
To the solution of sodium borohydride (43.12 g)in 1, 2-dimethoxyethane (243.75 ml) was added solution of methane sulfonic acid (177.5 ml) in 1,2- dimethoxyethane (81.25 ml) at 0-5 °C. Isopropyl alcohol (158.7 ml) was added to the reaction mass followed by solution of (5S)-2-amino-5-N,N-dibenzylamino-4-oxo-1,6-diphenylhex-2-ene(l 25 g) in 1,2-dimethoxyethane (206 ml). Stirred for 3 hours at room temperature.

Cooled and Methanol amine (132.5 g) was added. Solution of sodium borohydride (16.5 g) in dimethylacetamide (212.5 g) at 0-5 °C was added to the reaction mass. Stirred for one hour at 0-10°C then water (625 ml) followed by toluene (375 ml) were added. The organic layer was separated washed with brine solution (1875 ml), toluene layer was concentrated. Residue was dissolved in ethyl acetate (125 ml).
iii. Preparation of (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-[2S-(l-
tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-l,6-
diphenylhexane (III):
Solution of (2S,3S,5S)-2-N,N-diberizylamino-3-hydroxy-5-amino-l,6-
diphenylhexanein ethyl acetate obtained above in step (ii) was cooled to 0-
5 °C. Imidazole (92.5 g) was added, further cooled to -10 to -5°C. 2S-(1-
Tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride in
dimethylformamide, obtained in step (i), was added and stirred for one hour at 0-5 °C then at 25-30 °C for 16 hours. Water (312.5 ml) was added, cooled to 10-15 °C and pH adjusted to 3-3.5 using conc.HCl. Ethyl acetate (656 ml) was added and separated. The concentrated organic layer wasdiluted with methanol (875ml) and used in next step.
iv. Preparation of (2S,3S,5S)-2-amino-3-hydroxy-5-[2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-l,6-diphenylhexane (IV):
The solution of compound of formula (III) in methanol, obtained in step (iii), charged in autoclave followed by ammonium formate (63.37 g), 10% Pd/C (18.75 g) in methanol (175 ml) were added at room temperature. Heated to 50-55 °C and stirred for 3 hours. Cooled to room temperature and filtered. To the filtrate water (625 ml) was added and pH adjusted to 8.92 using 8% aqueous sodium bicarbonate (625 ml). Dichloromethane (1250 ml) was added, layers were separated and washed with water (625 ml). To the organic layer dioxane (375 ml) was added and distilled.

v. (2S,3S,5S)-2-Amino-3-hydroxy-5-[2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-l,6-diphenylhexane (S)-Pyroglutamic acid salt
(II):
To the solution of (2S,3S,5S)-2-Amino-3-hydroxy-5-[2S-(l-tetrahydro-
pyrimid-2- onyl)-3-methyl butanoyl]amino-1,6-diphenylhexane(IV) in dioxane (1250 ml), obtained in step (iv), dimethylsulfoxide (37.5 ml) andL-pyroglutamic acid (29.81 g) were added. Heated to 50- 55°C with seed of compound (II) (0.0125g) and stirred for 2 hours. Cooled to room temperature and stirred for 12 hours. Solid was filtered, washed with dioxane (625 ml) and dried.Yield: 97 g; Purity: 98.30%as measured by HPLC
EXAMPLE-2:
i. Preparation of 2S-(l-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride:
2S-(l-Tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid (32.63 g) was dissolved in dichloromethane (360 ml) and cooled to 0-5 °C. Dimethyl formamide (1 drop) was added followed by thionyl chloride (11.88 ml) and stirred for 5 hours at 25-30 °C. Distilled under vacuum to give residue. n-Heptane (300 ml) was added and removed under vacuum. The resultant solid was slurried in dimethyl formamide (100 ml).
ii. Preparation of (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-[2S-(l-
tetrahydro-pyrimid-2-onyI)-3-methyl butanoyl]amino-1,6-
diphenylhexane (III):
Solution of (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-l,6-
diphenylhexane(50 g) in ethyl acetate (50 ml) was cooled to 0-5 °C.
Imidazole (37 g) was added, further cooled to -10 to -5°C. 2S-(1-
Tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl chloride in
dimethylformamide, obtained in step (i), was added and stirred for one hour at 0-5 °C then at 25-30 °C for 16 hours. Water (125 ml) was added,

cooled to 10-15 °C and pH adjusted to 3-3.5 using conc. HC1 (17.5 ml). Ethyl acetate (262.5 ml) was added and separated. The concentrated organic layer was diluted with methanol (420 ml) and used in next step.
iii. Preparation of (2S,3S,5S)-2-amino-3-hydroxy-5-[2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-l,6-diphenylhexane (IV):
The solution of compound of formula (III) in methanol, obtained from step (ii), charged in autoclave followed by ammonium formate (25.35 g), 10% Pd/C (7.5 g). Heated to 50-55 °C and stirred for 3 hours. Cooled to room temperature, filtered and the filtrate distilled under vacuum. To the residue,dioxane (650 ml) was added and heated to get clear solution and used in next step.
rv. (2S,3S,5S)-2-Amino-3-hydroxy-5-[2S-(l-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl]amino-l,6-diphenylhexane (S)-Pyroglutamic acid salt (II):
To the solution of (2S,3S,5S)-2-Amino-3-hydroxy-5-[2S-(l-tetrahydro-pyrimid-2- onyl)-3-methyl butanoyl]amino-l,6-diphenylhexane(rV) in dioxane, obtained in step (iii), L-pyroglutamic acid (11.58 g) were added. Heated to 50- 55 °C with seed of compound (II) and stirred for 2 hours. Cooled to room temperature and stirred for 18 hours. Solid was filtered, washed with dioxane (250 ml) and dried. Yield: 27.5 g; Purity: 97.81% as measured by HPLC
EXAMPLE-3:
Preparation of lopinavir (I): i. 2,6-Dimethylphenoxy acetic acid (15.12 g) was slurried in ethyl acetate (50 ml) and thionyl chloride (12 g)was added followed by dimethyl formamide (0.2g). Heated to 50-53 °C, stirred for 4 hours and cooled.

ii. To the solution of sodiumbicarbonate (40 g) in water (425 ml), ethylacetate (425 ml) were added and stirred. S-pyroglutamic acid salt (II) (50 g), obtained from example -1 step (v), was added and stirred for one hour. The reaction mass obtained in step (i) was added and stirred. Organic layer was separated, washed with water, concentrated under vacuum and stripping off with ethyl acetate (250 ml). Ethyl acetate (250 ml) and n-heptane (250 ml) were added heated to 60 °C, stirred, cooled and filtered. Washed with n-hepatne-ethyl acetatemixture (50 ml: 50 ml) and dried. Yield: 37g. Purity: 99.45%as measured by HPLC.

WE CLAIM:
1. A process for the preparation of compound of formula (II) comprising:

a) N-debenzylation of compound of formula (III) in the presence of transition metal catalyst on activated carbon and formic acid salt in alcoholic solvent to get compound of formula (IV),

b) treating the reaction mixture of step (a) with aqueous inorganic base and
c) reaction of compound of formula (IV) with L-pyroglutamic acid.

2. The process according to claim 1, wherein step (a) is optionally carried out in an autoclave.
3. The process according to claim 1, wherein the transition metal catalyst used in step (a) is selected from nickel, raney nickel, palladium, platinum, cobalt and rhodium on activated carbon.
4. The process according to claim 3, wherein the transition metal catalyst is palladium.

5. The process according to claim 1, wherein the alcoholic solvent used in step (a)is selected from aliphatic alcohol comprising methanol, ethanol, n-propanol and 2-propanol.
6. The process according to claim 5, wherein the aliphatic alcohol is methanol.
7. The process according to claim 1, wherein the formic acid salt used in step
(a) is selected from ammonium formate and sodium formate.
8. The process according to claim 1, wherein step (a) is performed at a temperature between 30°C -65°C.
9. The process according to claim 8, wherein the reaction temperature is between 50-55°C.
10. The process according to claim 1, wherein the inorganic base used in step
(b) is selected from sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, sodium hydroxide and potassium
hydroxide.
11. The process according to claim 10, wherein the inorganic base is sodium bicarbonate.
12. The process according to claim 1, wherein step (c) is carried out in an organic solvent selected from dioxane, dimethylsufoxide, ethylacetate, dimethylformamide and the mixture thereof.
13. The process according to claim 12, wherein the solvent is dioxane-dimethylsulfoxide mixture.

14. The process according to precedent claims, wherein the compound of formula (II) is further converted into lopinavir.