DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of darunavir. In particular, the invention relates to process for the preparation of high purity darunavir free from dimer impurity of formula (C) and difuranyl impurity of formula (D). The present invention also relates to darunavir having substantially free of from dimer impurity of formula (C) and difuranyl impurity of formula (D). Further, the present invention also relates to pharmaceutical composition of darunavir having dimer impurity of formula (C) and difuranyl impurity of formula (D) less than 0.1%.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Darunavir has HIV protease inhibitory activity and is particularly well suited for inhibiting HIV-1 and HIV-2 viruses. Darunavir 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, having the formula (I) is represented by the following structure

Darunavir and its pharmaceutically acceptable salts were disclosed in U.S. Patent No. 6,248,775 and wherein Darunavir is prepared by condensing 2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S(phenylmethyl)propyl-
amine with hexahydro-furo[2,3-b]furan-3-ol in anhydrous acetonitrile in the presence of anhydrous pyridine and ?,?'-disuccinimidyl carbonate at ambient temperature.

U.S. 7,700,645 disclosed amorphous darunavir, various solvates of darunavir including ethanolate and method for their preparation as well as their use as a medicament.

In the prior art process, the process for preparing darunavir involves large excess of solvent or solvent mixture containing large excess of base or mixture of bases for the condensation reaction to two key intermediates to get darunavir. Further, the obtained products by the processes described in the prior art are not satisfactory from purity point of view.

However, a need still remains for an improved and commercially viable process for preparing amorphous darunavir for large-scale preparation, in terms of simplicity, yield and purity of the product. The present invention relates to an improved process for preparation of amorphous darunavir, which is feasible at large scale.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides darunavir or pharmaceutically acceptable salts, substantially free of dimer impurity of formula (C).

In another general aspect, the present invention provides amorphous darunavir substantially free of difuranyl impurity of formula (D).

In one general aspect, the present invention provides an improved process for the preparation of darunavir or its pharmaceutically acceptable salts having substantially free of dimer impurity of formula (C).

In one general aspect, the present invention provides an improved process for the preparation of darunavir or its pharmaceutically acceptable salts having substantially free of difuranyl impurity of formula (D).

In another aspect, the present invention provides amorphous darunavir, having the purity more than 99.5% and dimer impurity formula (C) less than 0.10%.

In another aspect, the present invention provides amorphous darunavir, having the purity more than 99.5% and difuranyl impurity formula (D) less than 0.10%.

In another aspect, the present invention provides an improved process for the preparation of amorphous darunavir containing less than 0.1% of the dimer impurity of formula (C) and difuranyl impurity of formula (D),
the process comprising:

a) reacting 4-amino-N-(2R,3S) (3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide compound of Formula (A) with 2,5-dioxopyrrolidin-1-yl ((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl) carbonate of formula (B) in N,N-dimethyl formamide (DMF), wherein the compound of formula (A) is at a molar excess over the compound of formula (B) to obtain darunavir; and
b) isolating amorphous darunavir.

In yet another aspect, the present invention provides a pharmaceutical composition comprising amorphous darunavir substantially free of dimer impurity of formula (C) and difuranyl impurity of formula (D) and one or more pharmaceutically acceptable carriers, excipients, or diluents.

DETAILED DESCRIPTION OF THE INVENTION
The term "substantially free of dimer impurity of formula (C) and difuranyl impurity formula (D)" as used herein refers to darunavir containing the dimer impurity of formula (C) and difuranyl impuirty of formula (D) in an amount less than 0.10% by area percentage of HPLC. In particular, less than 0.05%, less than 0.01%, in particular, not in detectable (ND) amount by area percentage of HPLC or absent.

Abbreviations:
HPLC: High Performance Liquid Chromatography
ND= Not detectable

In general, the solvents may be removed from the reaction mixture in order to obtain solid or precipitate. The solvents may be removed by one or more of filtration, filtration under vacuum, centrifugation, decantation, distillation, and distillation under vacuum.

The product(s) obtained may further be converted to any other physical forms thereof, which includes, but not specifically limited to salt(s), solvate(s), hydrate(s), co-crystal(s), and solid dispersion(s) in either crystalline or amorphous forms.

In one general aspect, the present invention provides darunavir or pharmaceutically acceptable salts, substantially free of dimer impurity of formula (C).

In another general aspect, the present invention provides darunavir or pharmaceutically acceptable salts, substantially free of difuranyl impurity of formula (D).

In another general aspect, the present invention provides amorphous darunavir substantially free of dimer impurity of formula (C).

In another general aspect, the present invention provides amorphous darunavir substantially free of difuranyl impurity of formula (D).

In another general aspect, the present invention provides amorphous darunavir containing less than 0.01% of dimer impurity of formula (C) by HPLC.

In another general aspect, the present invention provides amorphous darunavir containing dimer impurity of formula (C) in not detectable amount by HPLC.

In another general aspect, the present invention provides amorphous darunavir containing less than 0.01% of difuranyl impurity of formula (D) by HPLC.

In another general aspect, the present invention provides amorphous darunavir containing difuranyl impurity of formula (D) in not detectable amount by HPLC.

In another aspect, the present invention provides an improved process for the preparation of amorphous darunavir containing less than 0.1% of the dimer impurity of formula (C) and difuranyl impurity of formula (D),

the process comprising:
a) reacting 4-amino-N-(2R,3S) (3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide compound of formula (A) with 2,5-dioxopyrrolidin-1-yl ((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)carbonate of formula (B) in N,N-dimethyl formamide (DMF) solvent, wherein the compound of formula (B) and the compound of formula (A) are at a molar ratio of from about 0.95:1 to 0.98:1 respectively to obtain darunavir; and
b) converting darunavir to amorphous darunavir.

The solvent used in the step a) is selected from N,N-dimethyl formamide (DMF), water, methylene dichloride, methanol, ethanol, 3-propanol, n-butanol, 2-butanol, ethyl acetate, isopropyl acetate, toluene, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone (NMPO), dimethyl sulfoxide or mixture thereof.

The preferred solvent for performing step (a) is N,N-dimethyl formamide (DMF).

The mole ratio of compound of formula (A) and compound of formula (B) plays an important role in the control of dimer impurity of formula (C) and difuranyl impurity of formula (D) and for obtaining high purity darunavir.

Preferably, the compound of formula (A) is at a molar excess over the compound of Formula (B). The compound of formula (B) and the compound of formula (A) are preferably at a molar ratio from about 0.90:1 to about 0.99:1. More preferably, the compound of formula (B) and the compound of formula (A) are at a molar ratio from about 0.93:1 to about 0.99:1. Most preferably, the compound of formula (B) and the compound of formula (A) are at a molar ratio from about 0.95:1 to about 0.99:1.

The most preferred molar ratio for obtaining darunavir having dimer impurity of formula (C) and difuranyl impurity of formula (D) in not detectable (ND) amount is at molar ratio of 0.98:1 for the compound of formula (B) and the compound of formula (A) respectively.

The step (a) reaction was performed at temperature of 25 to 35 °C over a period of 2 hours.

The solvent used to prepare amorphous darunavir in step (b) is selected from acetone, water, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran, ethyl acetate or mixture thereof.
The preferred solvent for preparing amorphous darunavir in step (b) is acetone and water.

The technique to evaporate the solvent is selected from distillation, evaporation, spray drying, freeze drying, lyophilization or agitated thin film drier (ATFD).

In another aspect, the present invention provides an improved process for the preparation of amorphous darunavir containing less than 0.1% of the dimer impurity of formula (C) and difuranyl impurity of formula (D),

the process comprising:

a) reacting 4-amino-N-(2R,3S) (3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide compound of formula (A) with 2,5-dioxopyrrolidin-1-yl ((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl) carbonate of formula (B) in N,N-dimethyl formamide (DMF) solvent, wherein the compound of formula (A) is at a
at a molar excess over the compound of formula (B) to obtain darunavir;
b) isolating amorphous darunavir.

The compound of formula (A) is at a molar excess over the compound of formula (B). The compound of formula (B) and the compound of formula (A) are preferably at a molar ratio from about 0.90:1 to about 0.99:1. More preferably, the compound of formula (B) and the compound of formula (A) are at a molar ratio from about 0.93:1 to about 0.99:1. Most preferably, the compound of formula (B) and the compound of formula (A) are at a molar ratio from about 0.95:1 to about 0.99:1.

The present invention results in a higher yield of darunavir than has been reported in the prior art. In addition, darunavir prepared by present invention is nearly free of dimer impurity of formula (C) and difuranyl impurity of formula (D) and the reaction is more rapid.

In another general aspect, the present invention provides a pharmaceutical composition comprising darunavir substantially free of dimer impurity of formula (C) and difuranyl impurity of formula (D) and one or more pharmaceutically acceptable carriers, excipients, or diluents.

The dimer impurity of formula (C) and difuranyl impurity of formula (D) in darunavir was determined by HPLC method.
The Analytical method for the determination of dimer impurity of formula (C) and difuranyl impurity of formula (D) in Darunavir

Description of Analytical Method:
Instrument Name : Waters Alliance e2695 HPLC system or equivalent
Software : Chromeleon or equivalent

Chromatographic conditions:
Equipment : HPLC system equivalent with a UV-VIS detector or equivalent
Column : Zorbax RX C8 (250 mm x 4.6 mm, 5 µm)
Detector : UV-VIS or PDA detector
Wavelength : 265 nm
Flow Rate : 0.8 mL/min
Column temp. : 30°C
Sampler cooler : 25°C
Injection Volume : 10 µL
Run time : 75 Minutes
Gradient Programme:

Time (minutes) %Mobile phase A %Mobile phase B
0 65 35
10 53 47
20 53 47
30 44 56
35 44 56
50 27 73
55 13 87
65 13 87
65.1 65 35
75 65 35

Preparation of buffer:
Weigh accurately and transfer about 1.36 g of potassium dihydrogen orthophosphate into a suitable container. Add 1000 ml of Milli-Q water and sonicate to dissolve the content and mix well. Adjust the pH 4.2±0.05 with controlled addition of dilute orthophosphoric acid solution and mix well. Filter through 0.45 µm PVDF filter paper.
Preparation of Mobile phase-A
Prepared a degassed mixture of buffer:acetonitrile in the volume ratio of 95:05 % v/v.
Preparation of Mobile phase-B
Prepared a degassed mixture of buffer:acetonitrile in the volume ratio of 20:80 % v/v.
Preparation of diluent:
Use methanol as diluent.
Preparation of Blank:
Use diluent as a blank.

In another general aspect, there is provided a process for the preparation of darunavir substantially free of dimer impurity of formula (C) and difuranyl impurity of formula (D) as depicted in Scheme-1.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in various publications.

EXAMPLES:
Example-1: Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-((4-amino-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbut- an-2-yl)carbamate

A solution of 2,5-dioxopyrrolidin-1-yl ((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl) carbonate of formula (B) (67.86 g), in N,N-dimethyl formamide (200 ml) was added to a solution of 4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-isobutylbenzenesulfonamide of formula (A) (100 g) in N,N-dimethyl formamide (200 ml) at 25 to 35 °C over a period of 2 hr and maintain it for 2 hr. After completion of reaction water (600 ml) and ethyl acetate (500 ml) were added to the reaction mass. The layers were separated and organic layer was washed with aq. sodium carbonate (200 ml) followed by aq. sodium chloride solution (200 ml). The organic layer was concentrated, ethanol (300 ml) were added and stirred at 50 to 60 °C, and maintained for 1 hr. Then cool it to 25 to 35 °C, stirred it for 1 hr. Filter the solid and washed it with ethanol (100 ml). The wet compound dried at 50 to 60 °C to obtain 132 g (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-((4-amino-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate.

Example-2: Preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-((4-amino-N-isobutylphenyl)sulfonamido)-3-hydroxy-1-phenylbut-an-2-yl)carbamate Amorphous

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl((2S,3R)-4-((4-amino-N-isobutylphe -nyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate of formula (I) (100 g) dissolved in acetone (225 ml) then purified water (225 ml) was added to it over the period of 2 hr. at 5 to 15 °C and maintained it at same temperature for 1 hr. The solid was filtered and washed it with mixture of acetone and water to get wet material. This wet compound dried at 75 to 85 °C to get 85 g of amorphous form of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl((2S,3R)-4-((4-amino-N-isobutylphe -nyl)sulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate.
,CLAIMS:We Claim:
1. Darunavir or pharmaceutically acceptable salts, substantially free of dimer impurity of formula (C)
.

2. Darunavir or pharmaceutically acceptable salts, substantially free of difuranyl impurity of formula (D).

3. Amorphous darunavir substantially free of dimer impurity of formula (C).

4. Amorphous darunavir substantially free of difuranyl impurity of formula (D).

5. Amorphous darunavir containing less than 0.01% of dimer impurity of formula (C) and difuranyl impurity of formula (D) by HPLC.

6. An improved process for the preparation of amorphous darunavir containing less than 0.1% of the dimer impurity of formula (C) and difuranyl impurity of formula (D),

the process comprising:
a) reacting 4-amino-N-(2R,3S) (3-amino-2-hydroxy-4-phenylbutyl)-N-isobutyl-benzenesulfonamide compound of formula (A) with 2,5-dioxopyrrolidin-1-yl ((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)carbonate of formula (B) N,N-dimethyl formamide (DMF) solvent, wherein the compound of formula (A) is at a at a molar excess over the compound of formula (B) to obtain darunavir;
b) converting darunavir to amorphous darunavir.

7. The process as claimed in claim 6, wherein the compound of formula (B) and the compound of formula (A) are preferably at a molar ratio from about 0.95:1 to about 0.99:1.

8. The process as claimed in claim 6, wherein the preferred ratio of compound of formula (B) and the compound of formula (A) is 0.98:1.

9. The process as claimed in claim 6, wherein reaction is performed at temperature of 25 to 35 °C over a period of 2 hours.

10. The process as claimed in claim 6, wherein solvent for preparing amorphous darunavir is selected from acetone, water, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran, ethyl acetate or mixture thereof.