FIELD OF THE INVENTION

The present invention relates to a process for preparing Diaminoalcohol, which is a useful intermediate in the preparation of Darunavir of Formula I.

BACKGROUND 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-l-(phenylmethyl) propyl]carbamic acid, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester, represented by 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.

Prezista® must be co-administered with Ritonavir to exert its therapeutic effect. Failure to correctly co-administer Prezista® with Ritonavir will result in plasma levels of Darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.

Darunavir is generically disclosed in US Patent US 5,843,946, 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]-lS-(phenylmethyl)propylamine, which is referred as Diamino alcohol a compound of Formula II,

a key intermediate in the preparation of Darunavir. The process is as shown below:

This process involves the use of benzyloxycarbonyl (Cbz) protection, which needs to be deprotected by catalytic hydrogenation using palladium on carbon catalyst and hence the process is not industrially and commercially cost effective.

Bioorganic Medicinal Chemistry Letters 8, 1998, 687-690, discloses a process to prepare Darunavir as well as Diamino alcohol a compound of Formula II, which is as shown below:

This process involves the use of highly hazardous azide intermediate and hence not suitable for commercial production.

US 7,772,411 B2 discloses a process to prepare Diamino alcohol a compound of Formula II, which is as shown below:

The present inventors has repeated the above process and found the following disadvantages:

1. Diamino alcohol preparation was carried out in one pot and the purity of obtained product was found to low.

2. Unwanted reactions observed during the formation of nitro compound (A), which is due to the existence of isobutylamine after the completion of epoxide condensation with isobutylamine. The unwanted isobutylamine reacts with p-nitrobenzenesulfonyl chloride to give the N-isobutyl 4-nitrobenzenesulfonamide impurity of Formula XI.

Further, this N-isobutyl 4-nitrobenzenesulfonamide impurity of Formula XI, participate in the next reactions to give corresponding impurities.

3. Sulfonamide reaction is carried out at higher temperature i.e., 82-88°C, wherein the product undergoes degradation and observed that the reaction mass becomes very thick, which is very difficult to stir /mix.

4. The isolation of Diamino alcohol is tedious, wherein it involves pH adjustment, water content adjustment and concentration.

In view of the above and to overcome the prior-art problems the present inventors have now developed an improved process for the preparation of Diamino alcohol having high purity and yield, which is further converted to Darunavir or its pharmaceutically acceptable salts, solvates thereof, having high yield and purity.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a process for preparing Diaminoalcohol, which is a useful intermediate in the preparation of Darunavir or its pharmaceutically acceptable salts, solvates thereof, which is simple, industrially applicable and economically viable.

Another objective of the present invention is to provide a process for preparing Darunavir free of impurity compound of Formula XI and its corresponding impurities.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Darunavir of Formula I, or its pharmaceutically acceptable salts, solvates thereof, which comprises,

a) reacting epoxide compound of Formula V,
wherein P represents a protecting group
with isobutylamine in presence or absence of a solvent to give a compound of
Formula VII;
wherein P represents a protecting group

b) optionally, isolating compound of Formula VII;
c) reacting compound of Formula VII with p-nitrobenzenesulfonyl halide or its acid addition salt to give a compound of Formula VIII or acid addition salt thereof,

wherein P is same as defined above which is free of impurity compound of Formula XI; d) deprotecting the compound of Formula VIII or acid addition salt thereof, to give a compound of Formula IX or acid addition salt thereof;

e) reducing the compound of Formula IX or acid addition salt thereof to give Diamino alcohol of Formula II or acid addition salt thereof;
f) condensing compound of Formula II with l-[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula X,
in a solvent to give Darunavir of Formula I; and g) optionally, converting Darunavir of Formula I in to its pharmaceutically acceptable salt, solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing Darunavir of Formula I, or its pharmaceutically acceptable salts, solvates thereof, reacting epoxide compound of Formula V with isobutylamine in presence or absence of a solvent, selected from alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; hydrocarbons such as toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform; N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or mixtures thereof at a temperature ranging from 35-140°C, preferably at 70-75°C to give a isobutylaminocarbamate of Formula VII.
After the completion of the reaction the obtained isobutylaminocarbamate of Formula VII in a solvent is washed with water and adjusted the pH to ~8 for removing the excess or left over isobutylamine in the reaction mass.

The isobutylaminocarbamate of Formula VII is optionally isolated or in situ condensed with p-nitrobenzenesulfonyl halide, in a solvent selected from methylene chloride, chloroform, toluene, xylene, ethylenechloride in presence of an acid scavenger selected from non-nucleophilic inorganic or organic bases, such as triethylamine, diisoproylethylamine, tributyl amine, N,N-dimethyl aniline, pyridine, DBN, DBU at a temperature ranging from -10 to 100°C, preferably at 15-30°C to give compound of Formula VIII or acid addition salt thereof.

The compound of Formula VIII is deprotected using a suitable deprotecting agent and a solvent depending upon the protecting group to give compound of Formula IX or acid addition salt thereof, preferably monohydrochloride salt having a purity >99.8% by HPLC. Acetyl group, which is deprotected with a base, selected from ammonium, sodium hydroxide, potassium hydroxide, lithium hydroxide; 9-Fluorenylmethyloxycarbonyl (FMOC), which is deprotected using piperidine; tert-Butyloxycarbonyl group, which is deprotected using an acid, selected from hydrochloric acid, trifluoroacetic acid. The solvent is selected from alcohols such as methanol, ethanol, isopropanol, tert-butyl alcohol, ethers such as tetrahydrofuran; dioxane, esters such as ethyl acetate, methyl acetate, hydrocarbons such as toluene; xylene, water, or mixture thereof.

Examples of reagents and methods for deprotecting amines from amino protecting groups can additionally be found in Protecting Groups in Organic Synthesis by Theodora W. Greene, New York, John Wiley and Sons. Inc. 1981.

The compound of Formula IX or acid addition salt thereof is reduced to give Diamino alcohol or acid addition salt thereof of Formula II, preferably monohydrochloride salt having a purity >99.8% by HPLC, using a reducing agent selected from borane complexes, metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel in presence of hydrogen or hydrogen source, selected from ammonium formate, sodium dihydrogen phosphate, hydrazine in a solvent selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; esters such as ethyl acetate, methyl acetate; toluene; xylene; tetrahydrofuran; dioxane or mixture thereof at a temperature ranging from 5-50°C , preferably at 25-30°C.

The Diamino alcohol or acid addition salt thereof of Formula II is condensed with 1-[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula X in a solvent selected from methylene chloride, chloroform, methanol, acetonitrile, tetrahydrofuran at a temperature ranging from -40 to 50°C, preferably at -25 to -15°C to give Darunavir of Formula I.

In another aspect of the present invention the acid addition salt of compound of Formula VIII; compound of Formula IX and compound of Formula II (Diamino alcohol) is selected from hydrochloride, hydrobromide, sulfate, preferably as hydrochloride salt.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE 1

Preparation of (1 S,2R)-3-[[4-(aminophenyl)-sulfonyl](2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]amine hydrochloride (Diamino alcohol Monohydrochloride)

a) Preparation of (1 S,2R)-[3-(2-methylpropylamino)]-2-hydroxy-1 -(phenylmethyl)-
carbamic acid, tert-butyl ester

(2S)-[(rS)-(tert-Butoxycarbonyl)amino-2'-phenylethyl]oxirane (250 g) and isobutylamine (750 ml) were heated at 70-75°C for 3 h. Thereafter, the reaction mass was cooled to 55-60°C and concentrated under reduced pressure at below 60°C to remove isobutylamine. The residue is dissolved in methylene chloride (3000 ml) and diluted with DM water (1000 ml). The pH of the reaction mass was adjusted to ~8 with aqueous hydrochloride and separated the organic layer. This organic layer containing [(1 S,2R)-[3-(2-methylpropylamino)]-2-hydroxy-1 -(phenylmethyl)carbamic acid, tert-butyl ester was taken as such for the next step.

b) Preparation of [(lS,2R)-3-[[(4-Nitrophenylsulfonyl)(2-methylpropyl)]amino]-2-
hydroxy-1-(phenyl methyl)propyl]carbamic acid, tert-butyl ester

Triethylamine (105.60 g) was added to the methylene chloride solution of step (a), at 20-22°C. Thereafter, to the resulting reaction mixture a solution of 4-nitrobenzenesulfonyl chloride (221.10 g) in methylene chloride (750 ml) was added at 15-30°C over a period of 1 h and the mass was stirred at 25-30°C for 1 h. The reaction mixture was washed sequentially with DM water (500 ml), aqueous sodium bicarbonate solution (2 x 750 ml) and water (500 ml) at 25-3 0°C. This solution containing [(lS,2R)-3-[[(4-nitrophenylsulfonyl)(2-methylpropyl)]amino]-2-hydroxy-l-(phenyl methyl)propyl]carbamic acid, tert-butyl ester was taken as such for the next step.

c) Preparation of (lS,2R)-3-[[4-(Nitrophenyl)sulfonyl](2-methylpropylamino)]-2-
hydroxy-1-(phenyl methyl)propyl]-amine as its hydrochloride salt. (Amino nitro
alcohol hydrochloride) Methylene chloride solution of step (b) was concentrated at 30-45°C under reduced pressure. To the concentrated mass, ethanol (2375 ml) and hydrochloric acid (-35% w/w, 170 ml) was added and heated at 75-80°C for 1 h. Thereafter the reaction mixture was cooled to 5-10°C and stirred at this temperature for 1 h. The product obtained was filtered, washed with ethanol (440 ml) and dried at 45-55°C under reduced pressure to obtain amino nitro alcohol hydrochloride. Yield: 330 g Chromatographic Purity (by HPLC): 99.92 %

d) Preparation of (lS,2R)-3-[[4-(Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-
hydroxy-l-(phenyl-methyl)propyl] amine Hydrochloride (Diamino alcohol
monohydrochloride)

Amino nitro alcohol hydrochloride (260 g) obtained as per step (c) was suspended in methanol (2600 ml) at 25-30°C and hydrogenated in the presence of Raney nickel catalyst (13 g) under 4-6 Kg/cm2 pressure at 25-3 0°C for 10 h. After completion of the reaction, the catalyst was filtered and the filtrate was concentrated at 40-5 5 °C under reduced pressure to remove methanol. The residue was stirred in toluene (1040 ml) at 40-50°C for 20 min, thereafter cooled to 25-30°C and stirred at this temperature for lh.

The product obtained was filtered, washed with toluene (120 ml) and dried at 45-50°C under reduced pressure to obtain diamino alcohol monohydrochloride.

Yield: 221 g
Chromatographic Purity (by HPLC): 99.97 %

EXAMPLE 2
Preparation of (lS,2R)-[3-(2-Methylpropyl-amino)]-2-hydroxy-l-(phenylmethyl) carbamic acid tert-butyl ester
(2S)-[(rS)-(tert-Butoxycarbonyl)amino-2'-phenylethyl]oxirane (200 g) and isobutylamine (600 ml) were heated to 70-75°C for 3 h. Thereafter, the reaction mass was concentrated under reduced pressure to remove isobutylamine.. The obtained residue was dissolved in a mixture of toluene (500 ml) and diisopropyl ether (1600 ml) at 45-50°C, cooled to 10-15°C and stirred at 10-15°C for about 1 h. The product was filtered, washed with pre-cooled diisopropyl ether (400 ml, 10-15°C) and dried at 45-
50°C under reduced pressure to yield title compound as white solid.
Yield: 231 g

Chromatographic Purity (by HPLC): 99.41 %

EXAMPLE 3
Preparation of [(1 S,2R)-3- [ [(4-Nitrophenylsulfonyl)(2-methylpropyl)] amino]-2-hydroxy-l-(phenyl methyl)propyl]carbamic acid tert-butyl ester (lS,2R)-[3-(2-Methylpropyl-amino)]-2-hydroxy-l-(phenylmethyl) carbamic acid tert-butyl ester (170 g) was dissolved in methylene chloride (2040 ml) and added triethylamine (56.20 g) at 15-20°C. Thereafter, a solution of 4-nitrobenzenesulfonyl chloride (117.70 g) in methylene chloride (510 ml) was added to the above solution at 15-30°C and stirred at 25-30°C for 1 h. After completion of the reaction the reaction mixture was washed sequentially with DM water (340 ml), aqueous sodium bicarbonate solution (2 x 425 ml) and DM water (340 ml) at 25-30°C. The organic layer was concentrated under reduced pressure at 30-45°C. Toluene (1530 ml) was added to the residue, stirred .at 50-55°C for 30 min, thereafter cooled to 25-30°C and stirred at this temperature for 1 h. The obtained product was filtered, washed with toluene (170 ml) and dried at 50-55°C under reduced pressure to obtain title compound. Yield: 260 g Chromatographic Purity (by HPLC): 99.95 %

EXAMPLE 4
Preparation of (1 S,2R)-3- [ [4-(Nitrophenyl)-sulfony 1] (2-methylpropylamino)] -2-hydroxy-l- phenylmethyl)propyl]amine hydrochloride. (Amino nitro alcohol hydrochloride)

[(1S,2R)-3-[[(4-Nitrophenylsulfonyl)(2-methylpropyl)]amino]-2-hydroxy-l-(phenyl methyl)propyl]carbamic acid tert-butyl ester (220 g) was dissolved in ethanol (2200 ml) and hydrochloric acid (-35% w/w, 77 ml) was added at 75-80°C. The reaction mixture was stirred at 75-80°C for 1 h. Thereafter the reaction mass was cooled to 5-10°C and stirred for 1 h. The product obtained was filtered, washed with ethanol (440 ml) and dried at 45-55°C under reduced pressure to obtain Amino nitro alcohol hydrochloride. Yield: 173 g
Chromatographic purity (by HPLC): 99.89% Chloride content: 7.7 % w/w
lH NMR (300 MHz, DMSO-d6): 8 8.38 (d, 2H), 8.05-8.09 (m, 5H), 7.29-7.36 (m, 5H), 5.62 (d, 1H), 3.96 (m, 1H), 3.33-3.43 (m, 2H), 2.96-3.08 (m, 3H), 2.83-2.89 (m, 2H), 1.88-1.91 (m, 1H), 0.82 (d,3H), 0.75 (d,3H).

EXAMPLE 5
Preparation of (lS,2R)-3-[[4-(Aminophenyl)-sulfonyl](2-methylpropyl)amino]-2-hydroxy-l-(phenyl-methyl)propyl] amine Hydrochloride (Diamino alcohol monohydrochloride)
Amino nitro alcohol hydrochloride (120 g) was suspended in methanol (1200 ml) at 25-30°C and hydrogenated in the presence of Raney nickel catalyst (36 g) under 5-6 Kg/cm2 pressure at 25-30°C for 2h. After completion of the reaction, the catalyst was filtered and the filtrate was concentrated at 40-55°C under reduced pressure to remove methanol. The residue was stirred in toluene (480 ml) at 50-55°C for 20 min, thereafter cooled to 25-30°C and stirred at this temperature for 1 h. The product obtained was filtered, washed with toluene (120 ml) and dried at 45-50°C under reduced pressure to obtain Diamino alcohol monohydrochloride. Yield: 103 g

Chromatographic purity (by HPLC): 99.90% Chloride content: 8.2% w/w

lH NMR (500 MHz, DMSO-d6): 5 7.88 (brs, 3H), 7.27-7.39 (m, 7H), 6.62 (d, 2H), 6.04 (s, 2H), 5.55 (d, 1H), 4.01 (m, 1H), 3.46 (m, 1H), 3.34 (m,lH), 3.0-3.1 (m, 1H), 2.72-2.89 (m, 3H), 2.59-2.72 (m, 1H), 1.88-1.91 (m, 1H), 0.83 (d, 3H), 0.75 (d, 3H).

EXAMPLE 6
Preparation of Darunavir
To the mixture of Diamino alcohol monohydrochloride (5 g), methylene chloride (50 ml), DM water (15 ml), 10 %w/w aqueous sodium hydroxide solution (5 ml) was added to adjust the pH to 10 at 20-30°C. The organic layer was separated and washed with DM water (10 ml). Methylene chloride extract was dried over anhydrous sodium sulphate and 1 -[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione (3.17 g) was added and cooled to 5-10°C. Thereafter, triethylamine (1.18 g) was added and the temperature of reaction mass was raised to 25-30°C and stirred at this temperature for 3 h. The reaction mass was washed with 7% w/w aqueous sodium bicarbonate solution (20 ml), followed by DM water (2 x 15 ml) and then concentrated under reduced pressure at 30-40°C to obtain Darunavir as viscuous oily mass. Yield: 8 g (Viscous oily mass)

EXAMPLE 7
Preparation of amorphous Darunavir
Darunavir (3 g) was dissolved in methanol (4 ml) at 45-50°C and diluted with DM water (20 ml). Thereafter, the mass was concentrated at 40-50°C under reduced pressure to a volume of -18 ml, which was cooled to 25-30°C and stirred at this temperature for 15 h. The obtained solid was filtered, washed with DM water and dried at 55-60°C under reduced pressure to obtain amorphous Darunavir.
Yield: 2.2 g Water content (by Karl-Fisher): 0.71%

EXAMPLE 8
Preparation of Darunavir Ethanolate
Triethylamine (56.70g) was added to the mixture of diamino alcohol monohydrochloride (120g), 1 -[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy] carbonyl]oxy]-2,5-pyrrolidinedione (73.80g) and methylene chloride (600ml) at -25°C to -15°C and stirred for 2 h. The reaction mass was treated with monomethyl amine (solution in methanol, ~20%w/w, 4.70g) for 30 min. The reaction mass was sequentially washed with ~7%w/w aqueous sodium bicarbonate solution (240 ml), -2% w/w aqueous hydrochloric acid (2 x 240 ml), ~7%w/w aqueous sodium bicarbonate solution (240 ml) and water (240 ml) at 5-25°C. Thereafter, methylene chloride solution was treated with carbon (6.0 g) and concentrated under reduced pressure at 30-40°C. The residue was stirred with ethanol (600 ml) at 50-55°C for 30 min. The resulting slurry was cooled to 25-30°C and stirred at this temperature for 1 h. The product was filtered, washed with ethanol (120 ml) and dried at 40-50°C under reduced pressure to obtain Darunavir ethanolate. Yield: 133 g

Chromatographic purity (by HPLC): 99.86% DSC: Single endotherm peak at 104.97°C Ethanol content: 7.40 % w/w

We Claim;

1) An improved process for the preparation of Darunavir of Formula I, or its pharmaceutically acceptable salts, solvates thereof, which comprises,

a) reacting epoxide compound of Formula V,

wherein P represents a protecting group with isobutylamine in presence or absence of a solvent to give a compound of Formula VII;

wherein P represents a protecting group

b) optionally, isolating compound of Formula VII;

c) reacting compound of Formula VII with p-nitrobenzenesulfonyl halide or its acid addition salts to give a compound of Formula VIII or acid addition salt thereof

wherein P represents a protecting group which is free of impurity compound of Formula XI;

d) deprotecting the compound of Formula VIII or acid addition salt thereof, to give a compound of Formula IX or acid addition salt thereof;

e) reducing the compound of Formula IX or acid addition salt thereof to give Diamino alcohol of Formula II or acid addition salt thereof; and

f) condensing compound of Formula II with l-[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy]-2,5-pyrrolidine-dione of Formula X, in a solvent to give Darunavir of Formula I; g) optionally, converting Darunavir of Formula I into its pharmaceutically acceptable salt, solvate thereof.

2) The process according to claim 1, wherein the solvent in step (a) is selected from the group comprising of alcohols, ethers, hydrocarbons, halogenated hydrocarbons, N,N-imethylformamide,N,N-dimethylacetamide, dimethylsulfoxide or mixtures thereof.

3) The process according to claim 2, wherein the solvent is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, toluene, xylene, cyclohexane, hexane, ethylene chloride, ethylene chloride, chloroform or mixtures thereof.

4) The process according to claim 1, wherein the acid scavenger is selected from group comprising non-nucleophilic inorganic or organic bases.

5) The process according to claim 1, wherein the non-nucleophilic inorganic or organic bases is selected from the group comprising triethylamine, diisoproylethylamine, tributyl amine, N,N-dimethyl aniline, pyridine, DBN, DBU.

6) The process according to claim 1, wherein the reducing agent is selected from borane complexes, metals such as iron, tin, zinc; transition metals such as. palladium-carbon, platinum oxide, Raney nickel in presence of hydrogen or hydrogen source selected from ammonium formate, sodium dihydrogen phosphate and hydrazine.

7) The process according to claim 6, wherein the reducing agent catalyst is Raney nickel.

8) The process according to claim 1, wherein the solvent in step (f), is selected from methylene chloride, chloroform, methanol, acetonitrile and tetrahydrofuran.

9) The process according to claim 1, wherein the acid addition salt is selected from hydrochloride, hydrobromide, sulfate, preferably as hydrochloride salt.

10) The process as claimed in claim 1, wherein Darunavir or its pharmaceutically acceptable salts, solvates thereof is prepared using the process as described in the examples.