DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Darunavir or solvates or a pharmaceutically acceptable salt thereof.

BACK GROUND OF THE INVENTION
Darunavir is a potent HIV protease inhibitor, which is chemically known as [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl) propyl]carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester, is represented by Formula I.

Formula I

Darunavir is a new generation of non-peptide protease inhibitor (PI). It is exceeding potent and has shown impressive broad-spectrum activity against highly cross-resistant HIV mutants. Darunavir is being marketed under the brand name Prezista® as an oral tablet and oral suspension in the form of monoethanolate solvate.

Darunavir is generically disclosed in US Patent US 5,843,946 and specifically disclosed in US patent US 6,248,775. However, in these patents, there is no specific example for preparing Darunavir.

US 6,248,775 discloses a process for preparing 2R-hydroxy-3-[[4-aminophenyl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine, which is referred as Diamino alcohol, a compound of Formula II and the process is as shown below:

The first synthesis of Darunavir is described in A.K. Ghosh et al. Bioorganic & Medicinal Chemistry Letters 8 (1998) 687-690, which is herein incorporated by reference. The synthesis includes reacting azido epoxide with isobutylamine and treatment of the resultant azido alcohol with p-nitrobenzene sulfonyl chloride to afford nitro compound. The nitro compound is hydrogenated with Palladium catalyst and then resultant amine compound is transformed to Darunavir upon reaction with hexahydrofuro[2,3-b]furan-3-yl derivative in methylene chloride in the presence of 3 equivalents of triethylamine at 23°C for 12 hours.

The process disclosed in the A.K. Ghosh et al. is not suitable for large-scale production because it involves hazardous azide compounds; thus it requires utmost care to use. The process disclosed in the A.K. Ghosh et al. is schematically represented as follows:

To overcome the difficulties associated with the process disclosed in A.K. Ghosh et al., an alternate process is disclosed, for example U.S. Patent No. 7,772,411 (“US ‘411 patent”). US ‘411 patent describes the preparation of Darunavir using boc-epoxide instead of azido epoxide as starting material. US ‘411 patent process involves a) reaction of boc-epoxide with isobutylamine, b) introducing the p-nitrobenzene sulfonyl chloride c) reducing the nitro moiety d) deprotecting the boc protection and e) coupling the amine compound with hexahydrofuro[2,3-b]furan-3-yl derivative in a mixture of ethyl acetate and acetonitrile and in the presence of triethyl amine and methyl amine in aqueous ethanol. The process disclosed in US ‘411 patent is schematically represented as follows:

Apart from the above patents, US Patents US 8,153,829 B2, US 8,580,981 B2, US 8,703,980 B2, US Patent applications US 20120237770 A1, US 20120251826 A1, US20120296101A1 and PCT publications WO 2013011485A1, WO 2014016660 A2 describes processes for preparing Darunavir or solvates thereof.

The processes for the preparation of Darunavir, described in the above mentioned patents, publications suffer from many disadvantages like it involves tedious and cumbersome work up procedures, high temperature reactions, longer reaction times and multiple crystallizations or isolation steps, use of excess reagents and solvents, column chromatographic purifications etc. which effects the overall yield as well as the quality of the final product. Darunavir as a product obtained by the processes described in the prior publications does not have satisfactory purity and has unacceptable amounts of impurities which get carried forward in the subsequent steps and are difficult to remove in final stages.

Based on the above facts there is a need to get an improved process for the preparation of Darunavir or solvates or a pharmaceutically acceptable salt thereof of high purity and yield which overcome the drawback of prior publications. The present inventors have found an efficient process for the preparation of Darunavir or solvates or a pharmaceutically acceptable salt thereof which offers the following advantages over the prior publications such as simple scalable procedures suitable for large scale production, high yields, less effluent and highly pure Darunavir or solvates or a pharmaceutically acceptable salt thereof.

OBJECTS OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of highly pure Darunavir or solvates or hydrates or a pharmaceutically acceptable salt thereof either without the formation or minimizing the formation of undesired impurities.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of highly pure Darunavir or solvates or hydrates or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for preparation of Darunavir of Formula I or a solvate or hydrates or a pharmaceutically acceptable salt thereof; comprising:

Formula I
a) treating a compound of Formula VI

Formula VI
with isobutyl amine and isopropanol at 20-30°C; to obtain a compound of Formula V,

Formula V
Formula V
b) reacting compound of Formula V with 4-nitrobenzenesulfonyl chloride to obtain a compound of Formula IV,

Formula IV
c) reducing the compound of above Formula IV with Zn/NH4Cl/KH2PO4 or Raney Ni to obtain a compound of Formula III,

Formula III
d) deprotecting the compound of Formula III with a hydrochloric acid medium to obtain a compound of Formula IIa,

. 2 HCl

Formula IIa
e) optionally desaltifying the resultant dihydrochloride salt of Formula IIa with a base to obtain a compound of Formula II,

Formula II
f) condensing compound of Formula II or IIa with 1-[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula VIII

Formula VIII
in dimethylsulfoxide (DMSO) or sulpholane to give Darunavir of Formula I; and
g) optionally, converting Darunavir of Formula I in to its pharmaceutically acceptable salt, solvate, hydrate thereof.
In another aspect, the present invention provides a process for preparation of Darunavir of Formula I or a solvate or a pharmaceutically acceptable salt or solvate or hydrate thereof; comprising:

Formula I
a) condensing compound of Formula II

Formula II
with 1-[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula VIII in dimethylsulfoxide (DMSO) or sulpholane to give Darunavir of Formula I; and

Formula VIII
b) optionally, converting Darunavir of Formula I in to its pharmaceutically acceptable salt or solvate or hydrate thereof.

BRIEF DESCRIPTION OF DRAWING

Figure 1 of the present invention illustrates X-ray powder diffraction (XRPD) pattern of Darunavir ethanolate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a process for the preparation of Darunavir or solvates or hydrates or a pharmaceutically acceptable salt thereof with high product yield and purity. In particular, the present invention provides a process to prepare Darunavir, wherein the process excludes the use of multiple solvents and harsh nitro reduction steps, which is more convenient, economical and safe to use on an industrial scale.

In one embodiment, the present invention provides a process for preparation of Darunavir of Formula I or a solvate or a hydrate or a pharmaceutically acceptable salt thereof; comprising:

Formula I
a) treating a compound of Formula VI

Formula VI
with isobutyl amine and isopropanol at 20-30°C; to obtain a compound of Formula V,

Formula V
b) reacting compound of Formula V with 4-nitrobenzenesulfonyl chloride to obtain a compound of Formula IV,

Formula IV
c) reducing the compound of above Formula IV with Zn/NH4Cl/KH2PO4 or Raney Ni to obtain a compound of Formula III,

Formula III
d) deprotecting the compound of Formula III with hydrochloric acid medium to obtain a compound of Formula IIa,

. 2 HCl

Formula IIa
Formula IIa
e) optionally desaltifying the resultant dihydrochloride salt of Formula IIa with a base to obtain a compound of Formula II,

Formula II
f) condensing compound of Formula II with 1-[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula VIII in dimethylsulfoxide (DMSO) or sulpholane to give Darunavir of Formula I; and

Formula VIII
g) optionally, converting Darunavir of Formula I in to its pharmaceutically acceptable salt or solvate or hydrate thereof.

In another embodiment, the present invention provides a process for preparation of Darunavir of Formula I or a solvate or hydrate or a pharmaceutically acceptable salt thereof; comprising:

Formula I
a) condensing compound of Formula II

Formula II
with 1-[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula VIII in dimethylsulfoxide (DMSO) or sulpholane to give Darunavir of Formula I; and

Formula VIII
b) optionally, converting Darunavir of Formula I in to its pharmaceutically acceptable salt or hydrate or solvate thereof.

In first embodiment the present invention provides a process for the preparation of Darunavir or solvate or hydrate or pharmaceutically acceptable salt thereof as represented by the following scheme 1 which involves six stages:
Scheme 1

The first stage involves the reaction of compound of Formula VI or its salts thereof with isobutyl amine in isopropanol. The reaction is suitably carried out at a temperature between 20°C and 30°C, preferably between 20°C and 25°C.

The stage 1 product optionally can also be used directly for the stage 2 reaction without isolation.

Stage 2 involves condensation of compound of Formula V with 4-nitrobenzenesulfonyl chloride.

The solvent used in the above step is selected from group comprising toluene, ethylacetate, methylene chloride, tetrahydrofuran or mixtures thereof. Solvent preferably used is methylene chloride.

The above condensation is carried out in a suitable organic base selected from trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N,N-diisopropylethylamine, pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or an excess of an appropriate piperidine compound may be used. Preferably, triethylamine is used.

The above condensation of compound of Formula V with 4-nitrobenzenesulfonyl chloride can be carried out in the presence of a solvent under heating, approximately between 10°C to 100°C, preferably between 10°C and 30°C and agitation.

The stage 2 product optionally can also be used directly for the stage 3 reaction without isolation.

Stage 3 involves reduction of compound of Formula IV with Zn/NH4Cl/KH2PO4 or Raney Ni to obtain a compound of Formula III.

Solvents suitable for the reduction of the nitro moiety may be selected from water, alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol, esters such as ethyl acetate, amides such as N,N-dimethylformamide, acetic acid, dichloromethane/methylene chloride, toluene, xylene, benzene, pentane, hexane, heptane, petrol ether, 1,4-thioxane, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethyl sulfoxide, or mixtures thereof. In general, any solvent susceptible to being used in a chemical reduction process may be used. Preferably, methanol is used.

The reduction step can be carried out at temperatures that range between -15°C and 55°C, preferably between -10°C and 50°C, the preferred temperatures lying between 0°C and 50°C, more preferably between 5°C and 30°C. The reaction time may range from 30 minutes to 2 days, more suitably from 1 hour to 24 hours.

The stage 3 product optionally can also be used directly for the stage 4 reaction without isolation.

Stage 4 involves de-protecting the compound of Formula III, followed by acidification with hydrochloric acid medium to obtain a compound of Formula IIa. Stage 4 also involves optionally converting dihydrochloride salt of Formula IIa to obtain a compound of Formula II.

The solvent employed during the deprotection of intermediates of Formula III is not particularly limited provided that it has no adverse effect on the reaction and dissolves the starting materials to at least some extent. Suitable solvents are aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride/dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; esters such as methyl acetate, ethyl acetate, methyl propionate and ethyl propionate; nitriles such asacetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof. Preferably, ethyl acetate is used.

The reaction temperature employed in above deprotection step is usually between -20°C and 150°C, and is preferably between 10°C and 30°C. The reaction time employed depends on the reaction temperature and the like. It is typically from 5 minutes to 72 hours, and preferably from 4 hours to 10 hours.

Stage 4 optionally involves de-saltifying the resultant dihydrochloride salt of Formula IIa with a base to obtain a compound of Formula II.

De-saltifying compound of Formula IIa may be accomplished by the addition of basic
compound such as sodium hydroxide, sodium carbonate, potassium hydroxide, lithium hydroxide, ammonia, hydrazine, calcium hydroxide, methylamine, ethylamine, aniline, ethylenediamine, triethylamine, tetraethyl ammonium hydroxide. Preferably, sodium hydroxide is used.

The stage 4 product i.e. compound of Formula IIa or Formula II optionally can also be used directly for the stage 5 reaction without isolation.

Stage 5 involves condensing the compound of Formula II with 1-[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula VIII in dimethylsulfoxide (DMSO) or sulpholane to give Darunavir of Formula I.

The reaction temperature employed in above condensation step is usually between -20°C and 150°C, and is preferably between 10°C and 30°C. The reaction time employed depends on the reaction temperature and the like. It is typically from 5 minutes to 72 hours, and preferably from 2 hours to 5 hours.

Stage 6 involves converting Darunavir of Formula I into its pharmaceutically acceptable salt or solvate or hydratethereof as per the known methods in literature. The above solvates of Darunavir preferably ethanol solvate can be prepared by treating Darunavir of Formula I with ethanol applying any suitable technique to induce crystallization, and isolating the desired solvate form.

In an embodiment of the present invention, the above processes for the preparation or purification of Darunavir or its pharmaceutically acceptable salt provides substantially pure Darunavir or its pharmaceutically acceptable salt having purity greater than or equal to about 99.5% w/w, or greater than or equal to about 99.8% w/w, or greater than or equal to about 99.9% w/w as determined using HPLC.

In a further embodiment, the present invention includes substantially pure Darunavir ethanolate, wherein the amount of each individual process-related impurity listed in Table 1 is less than about 0.15% w/w, or less than about 0.1% w/w, and/or the sum of all of these impurities is less than about 0.1% w/w.
Table 1
Impurity Structure
Impurity A

Impurity B

Impurity C

Impurity D

Impurity E

X-ray powder diffraction (XRPD) was performed on X-Ray powder diffractometer: PanAlytical X'pert Pro powder diffractometer, CuKa radiation, ? = 1.5405980 A. PIXcel detector active length (2 theta) = 3.3473, laboratory temperature 22-25°C. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a microscopic glass slide.

EXAMPLES

The invention is described in more detail by the following examples. These examples
are designated to illustrate the invention, but do not limit its scope.

Example 1: Preparation of (1-Benzyl-2-hydroxy-3-isobutylaminopropyl) carbamic acid tert-butyl ester (Formula V)
(1-Oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester of Formula VI (200 g), isopropyl alcohol (200 mL) and isobutylamine (700 g) were charged into a round bottom flask at room temperature and stirred for 12-14 hours. The obtained reaction mass was concentrated under vacuum followed by dilution with water (1000 mL) and further concentrated it to 2/3rd of the reaction mass . The obtained reaction mass was cooled to room temperature and stirred. The obtained solid was filtered, washed with water and dried under vacuum at 50-60°C to obtain the title compound.

Example 2: Preparation of (1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro benzene sulfonyl)amino]propyl]carbamic acid tert-butyl ester (Formula IV)
(1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitrobenzenesulfonyl)amino]propyl]carbamic acid tert-butyl ester (Formula IV) as obtained in Example 1, methylene chloride (700 mL), triethylamine (100 mL) were charged into a round bottom flask at room temperature. The obtained solution was cooled to 15-20°C and 4-nitrobenzenesulfonyl chloride solution (150 gms in methylene chloride) was added to the reaction mass . The reaction mass was stirred of 1-2 hours. The obtained reaction mass was concentrated under vacuum and water (1500 mL) was added . The reaction mass was concentrated to 2/3rd of the total volumeat 50-55°C followed by cooling to room temperature. Further sodium hydroxide solution (28 g in water) was added and stirred for 2 hours. The obtained solid was filtered, washed with water (200 mL) and dried under vacuum at 55-60°C to obtain the title compound.

Example 3: Preparation of (1-benzyl-2-hydroxy-3-[isobutyl-(4-aminobenzene sulfonyl)amino]propyl)carbamic aicd tert-butyl ester (Formula III).
(1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitrobenzenesulfonyl)amino]propyl]carbamic acid tert-butyl ester (300 g) was suspended in methanol (1500 mL) at room temperature, and then hydrogenated using hydrogen pressure in presence of Raney nickel (60 g) . After completion of the reaction the resulting reaction mixture was filtered to remove the Raney nickel, the filtrate was concentrated under reduced pressure at 40-50°C. The obtained residue was cooled to room temperature and ethyl acetate (600 mL) was added. The obtained reaction mass was concentrated completely under vacuum at 40-50°C to obtain the title compound.

Example 4: Preparation of (1-benzyl-2-hydroxy-3-[isobutyl-(4-aminobenzene sulfonyl)amino]propyl)carbamic aicd tert-butyl ester (Formula III).
(1-Benzyl-2-hydroxy-3-[isobutyl-(4-nitrobenzenesulfonyl)amino]propyl]carbamic acid tert-butyl ester (10 g), methanol (100 mL), zinc dust (5 g), ammonium chloride (4 g) and potassium dihydrogen phosphate (2.6 g) were charged into a round bottom flask at room temperature. The reaction mass temperature was raised to 60-70°C and stirred for 5 hours. After the completion of reaction, reaction mixture was filtered and filtrate was concentrated under reduced pressure at 40-50°C. The obtained residue was cooled to 20-30°C and ethyl acetate (600 mL) was added. The obtained reaction mass was concentrated completely under vacuum at 40-50°C to obtain the title compound.

Example 5: Preparation of 4-amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenyl butyl)-N-isobutylbenzenesulfonamide (Formula II)
(1-Benzyl-2-hydroxy-3-[isobutyl-(4-aminobenzenesulfonyl)amino]propyl)carbamic aicd tert-butyl ester obtained in Example 3 and ethyl acetate (2100 mL) was charged into a round bottom flask at room temperature. Concentrated hydrochloric acid (250 mL) was added to above reaction mass and stirred for 4-5 hours. The reaction mass was filtered, washed with ethyl acetate (600 mL) and suck dried to obtain 4-amino-N-(2R,3S) (3-amino-2-hydroxy-4-phenyl butyl)-N-isobutylbenzenesulfonamide as hydrochloric acid salt. To the obtained solid, water (2000 mL) and methanol (750 mL) were added and cooled to 5-15°C. Sodium hydroxide solution (69 g water) was added slowly to above solution at 5-20°C and stirred at same temperature for 2 hours. The obtained solid was filtered, washed with water (300 mL) and dried under vacuum at 40-45°C to obtain the title compound.

Example 6: Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-amionophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxy propylcarbamate (Darunavir of Formula I)
4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide (100 g) and dimethyl sulfoxide (300 mL) were charged into a round bottom flask at room temperature and cooled to 15-20°C. 1-[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione solution (70 g in DMSO) was added to the above reaction mixture at 15-20°C and stirred for 1 hour. Ammonium hydroxide solution (6 mL in water) was added slowly to reaction mass and stirred for 30 minutes. Water (1000 mL) was added to the reaction mass and further stirred for 1 hour. The obtained solid was filtered, washed with water (100 mL X 2) and suck dried. The obtained compound and isopropyl alcohol (1000 mL) were charged into a round bottom flask and heated to 70-75°C. The solution was stirred for 30 minutes, cooled to 5-10°C and stirred for 2 hours. The obtained solid was filtered, washed with isopropyl alcohol (200 mL) and dried under vacuum at 50-60°C to obtain the title compound.

Example 7: Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-amionophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxy propylcarbamate (Darunavir of Formula I)
4-Amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzene sulfonamide (5 g) and sulfolane (30 mL) were charged into a round bottom flask at room temperature and cooled to 15-20°C. 1-[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione solution (5 g in sulfolane) was added to the above reaction mixture and stirred for 1 hour. The obtained reaction mass was diluted with ammonium hydroxide solution (0.5%, 20 mL) and ethyl acetate (100 mL) . The obtained organic layer was separated, washed with water (100 mL) and concentrated completely under vacuum to obtain the title compound.
,CLAIMS:WE CLAIM:

1. A process for preparation of Darunavir of Formula I or a solvate or a hydrate or a pharmaceutically acceptable salt thereof; comprising:

Formula I
a) treating a compound of Formula VI

Formula VI
with isobutyl amine and isopropanol at 20-30°C; to obtain a compound of Formula V,

Formula V
b) reacting compound of Formula V with 4-nitrobenzenesulfonyl chloride to obtain a compound of Formula IV,

Formula IV
c) reducing the compound of above Formula IV with Zn/NH4Cl/KH2PO4 or Raney Ni to obtain a compound of formula III,

Formula III
d) deprotecting the compound of Formula III with hydrochloric acid medium to obtain a compound of Formula IIa,

. 2 HCl

Formula IIa
Formula IIa
e) optionally desaltifying the resultant dihydrochloride salt of Formula IIa with a base to obtain a compound of Formula II,

Formula II
f) condensing compound of Formula II or IIa with 1-[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula VIII in dimethylsulfoxide (DMSO) or sulpholane to give Darunavir of Formula I; and

Formula VIII
g) optionally, converting Darunavir of Formula I in to its pharmaceutically acceptable salt or hydrate or solvate thereof.

2. A process according to claim 1, wherein step b) is carried out in toluene, ethylacetate, methylene chloride, tetrahydrofuran or mixture thereof.

3. A process according to claim 1, wherein step b) is carried out in base selected from trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, N,N-diisopropylethylamine or pyridine thereof.

4. A process according to claim 1, wherein step c) is carried out in water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethyl acetate, N,N-dimethylformamide, acetic acid, methylene chloride, toluene, xylene, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylsulfoxide, or mixture thereof.

5. A process according to claim 1, wherein step d) is carried out in hexane, heptane, benzene, toluene, xylene, methylene chloride, chloroform, dichloroethane, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, propanol, isopropanol, butanol, methyl acetate, ethyl acetate, methyl propionate, ethyl propionate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or mixtures thereof.

6. The process according to claim 1, wherein step f) is carried out in bases selected from sodium hydroxide, sodium carbonate, potassium hydroxide, lithium hydroxide, ammonia, hydrazine, calcium hydroxide, methylamine, ethylamine, aniline, ethylenediamine, triethylamine or tetraethyl ammonium hydroxide.

7. A process for preparation of Darunavir of Formula I or its ethanol solvate; comprising:

Formula I
a) condensing compound of Formula II

Formula II
with 1-[[[(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula VIII in dimethylsulfoxide (DMSO) or sulpholane to give Darunavir of Formula I; and

Formula VIII
b) optionally, converting Darunavir of Formula I in to its ethanol solvate thereof.

8. The process according to claim 1, provide substantially pure Darunavir of Formula I or a solvate or a pharmaceutically acceptable salt thereof having purity greater than or equal to about 99.8%.

9. The process according to claim 1, wherein the sum of all process-related impurity listed in table 1 is less than about 0.1%, by weight.