The present invention relates to an improved process for preparation of 2-amino-5-protected-amino-3-hydroxy-1,6-diphenylhexane of Formula III or an acid addition salt thereof, which is a useful intermediate for preparing compounds with antiviral activity. The present invention further provides a process for preparation of lopinavir and ritonavir, which are HIV protease inhibitors using the compound of Formula III.
Lopinavir of Formula I is chemically [1S-[1R*,(R*),3R*,4R*]]-N-[4-[[(2,6-dimethyl-
phenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-
methylethyl)-2-oxo-1(2H)-pyrimidineacetamide.
(FORMULA REMOVED)

Ritonavir of Formula II is chemically, [5S-(5R*,8R*,10R*,11R*)]-10-Hydroxy-2-methyl-5-
(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis (phenylmethyl)-
2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester.
(FORMULA REMOVED)

Lopinavir and Ritonavir are indicated in combination with other anti-retroviral agents for the treatment of HIV-infection.
Compound of Formula III or an acid addition salt thereof wherein R1,f R2 are hydrogen and R3 is an amino protecting group is useful intermediate for preparing compounds with antiviral activity such as lopinavir and ritonavir.
(FORMULA REMOVED)

US 5,914,332 provides a process for preparation of succinic acid salt of compound of Formula III wherein R1 and R2 are hydrogen and R3 is f-butyloxy carbonyl in four steps starting from (2S)-5-amino-2-(N,N-dibenzylamino)-3-oxo-1,6-diphenylhex-4-ene. The steps involve reduction of keto functionality and double bond, protection of the 2-amino group with butyloxycarbonyl group, debenzylation of the 5-dibenzylamino group and finally forming an acid addition salt with succinic acid. After every step however, the intermediates are isolated. The intermediate of Formula III as its succinate salt is further converted to lopinavir.
WO 94/14436 provides a process for the preparation of compound of Formula III wherein R1 and R2 are hydrogen and R3 is tert-butyloxycarbonyl which is similar to that exemplified in US '332 Patent except that it provides free base of compound of. Formula
WO 95/11224 also provides a process for preparation of succinic acid salt of compound of Formula III wherein R1 and R2 are hydrogen and R3 is tert-butyloxycarbonyl which is similar to that exemplified in US '332 Patent.
The present inventors have developed a process for preparation of 2-amino-5-protected-amino-3-hydroxy-1,6-diphenylhexane of Formula III, or an acid addition salt thereof, characterized by the fact that, the whole reaction sequence is carried out in-situ. The present process avoids time consuming isolation of intermediates after every step resulting in improved yield without affecting the purity and quality of the product.
A first aspect of the present invention provides a process for preparation of a compound of Formula III
(FORMULA REMOVED)

Formula
wherein R1 R2 are hydrogen and R3 is an acid labile amino protecting group; or an acid addition salt thereof which comprises of: a) reducing a compound of Formula IV
(FORMULA REMOVED)

Formula IV wherein R1, R2 are non-acid labile amino protecting groups and R3 is hydrogen in presence of sodium borohydride, methanesulphonic acid and triethanolamine to obtain a compound of Formula V
(FORMULA REMOVED)

Formula V wherein RT, R2 are non-acid labile amino protecting groups,
b) reacting compound of Formula V with acid labile amino protecting reagent to yield a compound of Formula VI
(FORMULA REMOVED)

Formula VI wherein R1 R2 are non-acid labile amino protecting groups and R3 is acid labile amino protecting group,
deprotecting the compound of Formula VI to obtain a compound of Formula III,
optionally converting the compound of Formula III to its acid addition salt, wherein the process is characterized by the fact that, the entire reaction sequence is carried out in-situ.
Compound of Formula IV wherein R1, R2 are non-acid labile amino protecting groups and R3 is hydrogen, is reduced in presence of sodium borohydride, methanesulphonic acid and triethanolamine. The temperature of the reaction mass is maintained between -10 to 30°C during reduction. After completion of the reaction, the organic layer is separated, washed and the solvent is evaporated under reduced pressure to get a residue as an oily mass which is used in the next step without any further purification.
The residue obtained is reacted with an acid labile amino protecting reagent. The resulting mixture is stirred at room temperature and the organic layer is separated, washed and then concentrated under reduced pressure to get a residue as oil which is used directly in the subsequent step.
The 'acid labile amino protecting reagent', used is known to a person of ordinary skills in art through several literature references.
The non-acid labile amino protecting groups of the residue obtained in the previous step are deprotected by reacting with a hydrogenating catalyst at room temperature. The mixture is stirred under reflux and the catalyst is filtered off. The residue is taken up in methylene chloride and washed with alkali solution. The organic layer is concentrated to provide a residue. Isopropanol is added to the residue and stirred to get a clear solution. To the above stirred solution, acid is added at 10-30°C. The mixture is slowly heated to 35-60°C to dissolve all the acid and then stirred at about 65-70°C for 0.5-2 hours and then at about 20-40°C for next 10-15 hours. The solid acid addition salt of compound of Formula III is filtered, washed and dried.
The 'hydrogenating catalyst' used are known to a person of ordinary skills in art through several literature references. Few examples of catalyst include palladium on carbon, palladium chloride, rhodium on carbon, platinum oxide, platinum black, ruthenium and the like.
The 'acid addition salt' is selected from the group comprising of but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, formate, acetate, oxalate, maleate, succinate, citrate, tartrate, glutamate, fumarate, adipate, camphoryl, malonate, glutarate, mandelate, nicotinate, glycinate, valinate, p-toluenesulphonate and the like.
The compound of Formula III or an acid addition salt thereof obtained by the process as described in the first aspect is found to be optically pure.
A second aspect of the present invention provides a process for preparation of Lopinavir, which comprises of:
(FORMULA REMOVED)

Formula IV
a) reducing a compound of Formula IV

wherein R1 R2 are non-acid labile amino protecting groups and R3 is hydrogen in presence of sodium borohydride, methanesulphonic acid and triethanolamine to obtain a compound of Formula V

Formula V wherein R1, R2 are non-acid labile amino protecting groups,
b) reacting compound of Formula V with acid labile amino protecting reagent to yield a compound of Formula VI(FORMULA REMOVED)
Formula VI wherein R1, R2 are non-acid labile amino protecting groups and R3 is acid labile amino protecting group, d) deprotecting the compound of Formula VI to obtain a compound of Formula III,
(FORMULA REMOVED)

Formula wherein R1, R2 are hydrogen and R3 is an acid labile amino protecting group,
optionally converting the compound of Formula III to its acid addition salt,
coupling the acid addition salt with compound of Formula VII
(FORMULA REMOVED)

wherein R is hydroxy or a leaving group to obtain a compound of Formula VIII,
(FORMULA REMOVED)

wherein R3 is acid labile amino protecting group,
g) deprotecting the acid labile amino protecting group in the compound of Formula VIII
to obtain compound of Formula IX,
(FORMULA REMOVED)

h) reacting compound of Formula IX with a compound of Formula X
(FORMULA REMOVED)

wherein R is hydroxy or leaving group to obtain lopinavir or salt thereof,
wherein the process is characterized by the fact that, the reaction sequence up to step
e) is carried out in-situ.
The acid addition salt obtained in the first aspect of the invention is coupled with a compound of Formula VII wherein R is hydroxy or a leaving group in the presence of an inorganic base in an inert solvent at about room temperature. The resulting mixture is stirred at room temperature to provide a white solid. Ethyl acetate is added at room temperature and stirred to complete the reaction. After separating the organic layer, aqueous layer is extracted with ethyl acetate. The combined organic layer is washed, filtered and concentrated under reduced pressure to afford an off-white solid of a compound of Formula VIII.
The 'inorganic base' is selected from the group comprising of but not limited to sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like.
The 'inert solvent' selected from the group comprising of but not limited to ethyl acetate/water or isopropyl acetate/water or toluene/water or THF/water and the like.
Compound of Formula VIII, in methylene chloride, is added trifluoroacetic acid at room temperature and stirred for about 2-5 hours. The solvent is removed under reduced pressure and water is added followed by methylene chloride. The biphasic mixture is cooled to about 10-15°C, and solid inorganic base is added. Finally the pH is adjusted to about 6-10 with a base. The organic layer is separated, washed and concentrated to provide a residue as thick oil of a compound of Formula IX.
Ethyl acetate is added in to the above residue of compound of Formula IX and stirred to get a clear solution. To the resulting solution, imidazole is added at room temperature and the mixture is cooled to about 0°C. To the cold reaction mixture, compound of Formula X in dimethyl formamide is slowly added at about 0-10°C and stirred. The
reaction mixture is warmed and stirred at room temperature for 10-15 hours. The mixture is cooled to about 10°C and quenched with aqueous mineral acid at 10-15°C. Ethyl acetate is added into the mixture and stirred at room temperature for about 20-45 minutes. The organic layer is separated, washed, and the solvent is evaporated under reduced pressure to afford a crude off-white solid, which is dissolved in ethyl acetate at 40-50°C, and then heptane is added at 50-45°C. The resulting clear solution on cooling yielded a white solid, which is filtered, washed and dried.
A third aspect of the present invention provides a process for preparation of Ritonavir, which comprises of:
a) reducing a compound of Formula IV
(FORMULA REMOVED)

wherein R1, R2 are non-acid labile amino protecting groups and R3 is hydrogen in presence of sodium borohydride, methanesulphonic acid and triethanolamine to obtain a compound of Formula V
(FORMULA REMOVED)

wherein R1 R2 are non-acid labile amino protecting groups,
b) reacting compound of Formula V with acid labile amino protecting reagent to yield a
compound of Formula VI
(FORMULA REMOVED)

Formula VI wherein R1, R2 are non-acid labile amino protecting groups and R3 is acid labile amino protecting group, d) deprotecting the compound of Formula VI to obtain a compound of Formula III,

(FORMULA REMOVED)

Formula wherein R1, R2 are hydrogen and R3 is an acid labile amino protecting group,
optionally converting the compound of Formula III to its acid addition salt,
coupling the acid addition salt with 5-(p-nitrophenyloxycarbonyloxymethyl) thiazole hydrochloride and treating the resulting residue with a mixed anhydride of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine to obtain ritonavir, wherein the process is characterized by the fact that, the reaction sequence up to step e) is carried out in-situ.
The acid addition salt obtained in the first aspect of the invention in ethyl acetate solution is mixed with 5-(p-nitrophenyloxycarbonyloxymethyl)thiazole hydrochloride and base. Water is charged to the resulting mixture and stirred at room temperature. The organic layer is separated, heated to about 50-75°C for 5-9 hours. The mixture is cooled to about 30°C and aqueous base is added. After stirred for 1-3 hours the reaction mixture is washed and to the organic layer concentrated mineral acid is added. The resultant slurry is stirred at about 50°C for 2-5 hours. The solid is filtered, washed and the wet solid is treated with ethyl acetate and dilute base. The organic layer is separated and concentrated to obtain the oil residue.
The oil residue obtained from the above step is cooled to about 0°C and combined with a mixed anhydride of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine. The resultant mixture is warmed to ambient temperature and stirred. The reaction mixture is washed and the solvent is stripped off under reduced pressure. The residue obtained is taken in ethyl acetate solution and heated to about 60°C and hexane is added to the hot mixture. The temperature of the resulting mixture is brought to about room temperature and stirred for 15-30 hours. The solid obtained is filtered, washed and dried.
The 'base' used is known to a person of ordinary skills in art through several literature references.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF (2S,3S,5S)-5-AMINO-2-(N,N-DIBENZYLAMINO)-3-HYDROXY-1,6-DIPHENYLHEXANE
Sodium borohydride (6 g) in dimethoxy ethane (271.2 ml) was cooled to about -5°C and to this mixture a solution of methane sulphonic acid (38.4 g) in dimethoxy ethane (2.3 ml) was added at -5 to 5°C during 45 minutes. To this resulting mixture, a solution of 2-amino-5S-(N,N-dibenzylamino)-4-oxo-1,6-diphenyl-2-hexene (24.5 g) in a mixture of isopropanol (28 ml) and dimethoxy ethane (62.6 ml) was added at 0 to 5°C over a period of 30 minutes. The reaction mixture was stirred at 0 to 10°C for 12 hours. Triethanolamine (23.6 g) was added to the resulting mixture at 0°C over about 30 minutes. The mixture was stirred at 0 to 5°C for about 30 minutes. A separate solution
of sodium borohydride (5 g) in dimethylacetamide (39.2 ml) was added into the reaction mixture at about 0 to 10°C over a period of about 25 minutes. The solution was stirred at about 15 to 20°C for 2 hours and quenched with water (270 ml) at 10-20°C and to it methyl-f-butyl ether (245 ml) was added and stirred for about 10 minutes. The organic layer was separated, washed with aqueous sodium hydroxide (245 ml), ammonium chloride (245 ml) followed by sodium chloride (245 ml). The solvent was evaporated under reduced pressure to get a residue as an oily mass which was used in the next step without any further purification.
EXAMPLE 2
PREPARATION OF (2S,3S,5S)- 2-(N,N-DIBENZYLAMINO)-3-HYDROXY-5-(f-BUTYLOXYCARBONYLAMINO)-1,6-DIPHENYLHEXANE
To the residue obtained from the example 1 and potassium carbonate (11.76 g) in a mixture of water (120 ml) and methyl-f-butylether (245 ml), was added di-t-butyldicarbonate (15.34 g) at 15-20°C over a period of about 20 minutes. The resulting mixture was stirred at room temperature for about 1.5 hours. The organic layer was separated, washed with water (122.5 ml) and then concentrated under reduced pressure to afford a residue as oil which was used directly in the subsequent step.
EXAMPLE 3
PREPARATION OF (2S,3S,5S)- 2-AMINO-3-HYDROXY-5-(f-BUTYLOXY-CARBONYLAMINO)-1,6-DIPHENYLHEXANE SUCCINATE SALT
To the residue obtained from example 2 and ammonium formate (19.88g) in methanol (200 ml), was added 10% Palladium-Carbon (30.35 g, 50% wet) at room temperature. The mixture was stirred under reflux for 2 hours. The catalyst was filtered off and washed with methanol (100 ml). The residue obtained after removal of methanol under reduced pressure was taken up in methylene chloride (245 ml) and washed with aqueous sodium hydroxide (122.5 ml) then with sodium chloride solution (122.5 ml).
The organic was concentrated to provide a thick oily mass. Isopropanol (588 ml) was added into the residue and stirred to get a clear solution. Isopropanol (24.5 ml) was removed under reduced pressure at NMT 45°C. To the stirred above solution succinic acid (6.35 g) was added at 20-25°C. The mixture was slowly heated to 40-45°C to dissolve all succinic acid crystals and at about 70°C, a white solid started precipitated out. The mixture was kept stirring at 65-70°C for 1 hour and then at 25-30°C for next 12 hours. The solid was filtered, washed with isopropanol (24.5 ml) and then dried under reduced pressure at 45-50°C for 12 hours to furnish the title compound as a white solid. Yield: 18.5 g
EXAMPLE 4
PREPARATION OF (2S,3S,5S)-2-(2,6-DIMETHYLPHENOXYACETYL)AMINO-3-HYDROXY-5-(f-BUTYLOXYCARBONYLAMINO)-1,6-DIPHENYLHEXANE
Stepl:
2,6-Dimethylphenoxy acetic acid (2.3 g) in ethyl acetate (30 ml), was added thionyl chloride (1.82 g) at room temperature followed by 2 drops of dimethyl formamide. The reaction mixture was stirred at about 50°C for 1.5 hours, cooled to room temperature and concentrated to dryness under reduced pressure. The excess thionyl chloride was further removed azeotropically with ethyl acetate (2 X 30 ml) and the residue was redissolved in ethyl acetate (30 ml) and used immediately to couple with the succinate salt obtained from example 3.
Step 2:
Succinate salt (5.0 g) obtained from example 3 was added portion wise to a vigorously stirred mixture of sodium bicarbonate (4.7 g) in water (40 ml) and ethyl acetate (30 ml) at room temperature over a period of 10 minutes. On stirring at room temperature for 30 minutes, the reaction mixture became almost homogeneous, however suddenly a white solid separated out from the upper ethyl acetate layer. To a cooled at about 15 °C, of the above suspended reaction mixture, a solution of acid chloride in ethyl acetate (from
step 1 of example 4) at 15-20°C was slowly added over about 15 minutes. The resulting mixture was stirred at room temperature for 1.5 hours. After 1 hour stirring at room temperature, a white solid again precipitated out from the solution. Ethyl acetate (30 ml) was added and stirred for next 30 minutes. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layer was washed successively with aqueous sodium hydroxide (2 X 20 ml), hydrochloric acid (2 X 20 ml), water (1 X 20 ml) and brine (1 X 20 ml). It was then filtered through hyflo bed and dried over sodium sulfate. Concentration of ethyl acetate solution under reduced pressure resulted the title compound as an off-white solid. Yield: 5.6 g
EXAMPLE 5
PREPARATION OF (2S,3S,5S)-2-(2,6-DIMETHYLPHENOXYACETYL)AMINO-3-
HYDROXY-5-[2S-(1-TETRAHYDRO-PYRIMID-2-ONYL)-3-METHYL-
BUTANOYL]AMINO-1,6-DIPHENYLHEXANE
Stepl:
To a cooled at about 0°C and stirred mixture of 2S-(1-tetrahydro-pyrimid-2-onyl)-3-methylbutanoic acid, (2.1 g) in tetrahydrofuran (42 ml) was added thionyl chloride (1.56 g) at about 0 to +5°C over about 5 minutes. The reaction mixture was warmed to room temperature and stirred at this temperature for 1.5 hours. The solution became homogeneous on warming to room temperature. The reaction mixture was concentrated to dryness under reduced pressure. Excess thionyl chloride was further removed azeotropically with heptane (2 X 20 ml). The residue was dissolved in dimethyl formamide (15 ml) at 35-40 °C, cooled down to room temperature and reacted immediately to couple with the compound obtained ffbm example 4. Step 2:
To a stirred solution of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(f-butyloxycarbonylamino)-1,6-diphenylhexane (5.1 g) in methylene chloride (50 ml) was added trifluroacetic acid (10.65 g) at room temperature over a period of 20 minutes. The
reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and then water (100 ml) was added followed by methylene chloride (100 ml). To the cooled at about 10-15°C biphasic mixture, solid sodium bicarbonate (12 g) was added portionwise, and finally its pH was adjusted to about 8.5 with aqueous sodium hydroxide. The organic layer was separated and washed with water (50 ml). Concentration of methylene chloride layer provided a residue as thick oil. Ethyl acetate (50 ml) was added into the above residue and stirred to get a clear solution. To the stirred solution imidazole (2.1 g) was added at room temperature. The mixture was cooled to 0°C. To the cold reaction mixture a suspension of acid chloride in dimethyl formamide (from step 1 of example 5) was slowly added at about 0 to 5°C during 30 minutes. The reaction mixture was stirred at 0 to 5°C for next 30 minutes, then warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was cooled down to 10°C and quenched with aqueous hydrochloric acid (100 ml) at 10-15°C. Ethyl acetate (50 ml) was added to the mixture and stirred at room temperature for 30 minutes. The organic layer was separated and washed with aqueous sodium bicarbonate (50 ml) followed by water (2 X 50 ml). Evaporation of the solvent under reduced pressure afforded crude material as an off-white solid which was dissolved in ethyl acetate (28 ml) at 45-50°C and then heptane (28 ml) was slowly added at 50-45°C. The resulting clear solution was slowly allowed to cooled to room temperature and stirred at room temperature for 12 hours. A white solid, precipited out from the solution was filtered and washed with 1:1 mixture of ethyl acetate and heptane (5 ml). The solid was dried under vacuum at 50-60°C for 12 hours to get the title compound as a white solid. Yield: 3.5 g
added. The stirring was continued and the reaction mixture was allowed to attain 0°C at which the mixture was stirred for another 90 minutes. Step 2:
A pre-cooled mixture at about 0°C of residue (3.2 g) obtained from example 6 in ethyl acetate (12 ml) was added to the mixture obtained from step 1 of example 7 and the resultant combined mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was washed successively twice with 10% potassium carbonate solution (30 ml), thrice with 10% citric acid solution (45 ml) and thrice with water (25 ml). The solvent was stripped off under vacuum and the residue obtained as oil was taken in ethyl acetate solution (28 ml). The solution was heated at 60°C and hexane (21 ml) was added to the hot solution. The resultant mixture was brought to 25°C and stirred for 24 hours. The solid material was filtered, washed twice with ethyl acetate and hexane mixture (1:1, 10 ml) and dried under vacuum at 55°C for overnight. Yield: 2.6 g.
EXAMPLE 6
PREPARATION OF (2S,3S,5S)-5-AMINO-2-(N-((5-THIAZOLYL) METHOXYCARBONYL)AMINO)-1.6-DIPHENYL-3-HYDROXY HEXANE
To a stirred mixture of succinate salt obtained from example 3 (3.8 g) in ethylacetate solution (45 ml) was added 5-(p-nitrophenyloxycarbonyl-oxymethyl)thiazole hydrochloride (3.0 g) and sodium bicarbonate (4.0 g). Water (40 ml) was charged to the resultant mixture and stirred of two hours at room temperature. The organic layer was separated and heated at 60°C for 7 hours. The solution was cooled to about 30°C and 28% aqueous ammonia (0.41 g) was added. After stirring for two hours, the reaction mixture was washed thrice with 10% potassium carbonate solution (40 ml). Concentrated hydrochloric acid (2.7ml) was added to the organic layer and resultant slurry was stirred at 50°C for three hours. The solid obtained was filtered and washed with ethyl acetate (10ml) twice. The wet solid was taken in ethyl acetate (35 ml) and the mixture was treated with dilute ammonia water (9 ml). The organic layer was separated and concentrated to get desired oil residue. Yield: 3.3 g
EXAMPLE 7
PREPARATION OF (2S,3S,5S)-5-(N-(N-((N-METHYL-N-((2-ISOPROPYL-4-THIAZOLYL)METHYL)AMINO)CARBONYL)-L-VALINYL)AMINO)-2-(N-((5-THIAZOLYL)METHOXY CARBONYL)AMINO)-1,6 DIPHENYL-3-HYDROXY HEXANE
Stepl:
N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (2.5 g) in ethyl acetate (35 ml) was added N-methyl morpholine (1.35 g). The resultant mixture was cooled to about -18°C and isobutylchloroformate (1.15 g) in ethylacetate (5.3 ml) was added drop wise maintaining the temperature between -18 to -15°C. The reaction mixture was stirred for 45 minutes at -15°C and then N-hydroxysuccinimide (1.0 g) was

WE CLAIM:
1. A process for preparation of a compound of Formula III
(FORMULA REMOVED)

Formula III wherein R1, R2 are hydrogen and R3 is an acid labile amino protecting group; or an acid addition salt thereof which comprises of:
a) reducing a compound of Formula IV:

(FORMULA REMOVED)

Formula IV wherein R1, R2 are non-acid labile amino protecting groups and R3 is hydrogen in presence of sodium borohydride, methanesulphonic acid and triethanolamine to obtain a compound of Formula V
(FORMULA REMOVED)

Formula V wherein R1, R2 are non-acid labile amino protecting groups,
b) reacting compound of Formula V with acid labile amino protecting reagent to yield a compound of Formula VI
(FORMULA REMOVED)

Formula VI wherein R1 R2 are non-acid labile amino protecting groups and R3 is acid labile amino protecting group,
deprotecting the compound of Formula VI to obtain a compound of Formula III,
optionally converting the compound of Formula III to its acid addition salt, wherein the process is characterized by the fact that, the entire reaction sequence is carried out in-situ.
2. A process for preparation of Lopinavir, which comprises of: a) reducing a compound of Formula IV:
(FORMULA REMOVED)

Formula IV wherein R1, R2 are non-acid labile amino protecting groups and R3 is hydrogen in presence of sodium borohydride, methanesulphonic acid and triethanolamine to obtain a compound of Formula V
(FORMULA REMOVED)

Formula V wherein R1, R2 are non-acid labile amino protecting groups,
b) reacting compound of Formula V with acid labile amino protecting reagent to yield a compound of Formula VI
(FORMULA REMOVED)

Formula VI wherein R1, R2 are non-acid labile amino protecting groups and R3 is acid labile amino protecting group,
d) deprotecting the compound of Formula VI to obtain a compound of Formula III,
(FORMULA REMOVED)

Formula III wherein R1, R2 are hydrogen and R3 is an acid labile amino protecting group,
optionally converting the compound of Formula III to its acid addition salt,
coupling the acid addition salt with compound of Formula VII
(FORMULA REMOVED)

Formula VII wherein R is hydrogen or a leaving group to obtain a compound of Formula VIII,
(FORMULA REMOVED)

Formula VIII wherein R3 is acid labile amino protecting group,
g) deprotecting the acid labile amino protecting group in the compound of Formula VIII to obtain compound of Formula IX,

(FORMULA REMOVED)

Formula IX h) reacting compound of Formula IX with a compound of Formula X
(FORMULA REMOVED)

Formula X wherein R is hydrogen or leaving group to obtain lopinavir or salt thereof, wherein the process is characterized by the fact that, the reaction sequence up to step e) is carried out in-situ.
3. A process for preparation of Ritonavir, which comprises of: a) reducing a compound of Formula IV
(FORMULA REMOVED)

Formula IV wherein R1, R2 are non-acid labile amino protecting groups and R3 is hydrogen in presence of sodium borohydride, methanesulphonic acid and triethanolamine to obtain a compound of Formula V

(FORMULA REMOVED)

Formula V wherein R1, R2 are non-acid labile amino protecting groups,
b) reacting compound of Formula V with acid labile amino protecting reagent to yield a compound of Formula VI
(FORMULA REMOVED)

Formula VI wherein R1, R2 are non-acid labile amino protecting groups and R3 is acid labile amino protecting group, d) deprotecting the compound of Formula VI to obtain a compound of Formula III,
(FORMULA REMOVED)

Formula
wherein R-i, R2 are hydrogen and R3 is an acid labile amino protecting group,
optionally converting the compound of Formula III to its acid addition salt,
coupling the acid addition salt with 5-(p-nitrophenyloxycarbonyloxymethyl) thiazole hydrochloride and treating the resulting residue with a mixed anhydride of N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine to obtain ritonavir, wherein the process is characterized by the fact that, the reaction sequence up to step e) is carried out in-situ.

A process according to claims 1, 2, 3, wherein the non-acid labile amino protecting group is benzyl group.
A process according to claims 1,2,3, wherein acid labile amino protecting reagent is di-f-butyldicarbonate.
A process according to claims 1, 2, 3, wherein the acid labile amino protecting group is f-butyloxycarbonyl.
A process according to claims 1,2,3, wherein deprotection in step d) is carried out in the presence of palladium on carbon.
A process according to claims 1, 2, 3, wherein the compound of Formula III is optionally converted to its acid addition salt.
9. A process according to claims 1,2,3, wherein the acid addition salt is succinate salt.