FIELD OF INVENTION

The invention related to an improved process for the preparation of N-[(4-fiuorophenyl)methyl]-1,6-dihydro-5-hydroxy-1 -methyl-2-[[(5-methyl-l ,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide and its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

Raltegravir is an antiretroviral drug produced by Merck & Co and marketed as potassium salt
used in combination with other anti-retroviral drugs to treat human immunodeficiency virus
(HIV) infection. It is a first line HTV-integrase strand transfer inhibitor drug that targets Integrase,
an HIV enzyme that integrates the viral genetic material into human chromosomes. The chemical
name for Raltegravir potassium is N-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-
2-[[(5-methyl-1,3,4-oxadiazol -2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide
monopotassium salt and is structurally represented by formula I. Raltegravir potassium salt is marketed under the brand name Isentress ®.

Raltegravir and its pharmaceutically acceptable salts are disclosed in US 7,169,780. US 7754731 claims anhydrous crystalline potassium salt of Raltegravir.

US 7169780 described a process in which Raltegravir is prepared by reducing Benzyl l-(4-{[(4-fluorobenzyl)amino]carbonyl} -5-hydroxy-1 -methyl-6-oxo-1,6-dihydropyrimidin-2-y 1)-1 -methyl ethylcarbamate with Pd/C and H2 gas to give 2-(l-amino-l-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6- -oxo-l,6-dihydropyrimidine-4-carboxamide, which is further condensed with l,3,4-oxadiazole-2-carboxylic acid chloride in acetonitrile in presence of triethyl amine and N,N-dimethylformamide to yield Raltegravir.

US 20100280244 describes a process for preparing Raltegravir comprising esterification of benzyl 1 -(4- {[(4-fluorobenzyl)amino]carbonyl} -5-hydroxy-1 -methyl-6-oxo-1,6-dihydro pyrimidin -2-yl)-l-methylethylcarbamate with pivaloyl chloride gives benzyl l-(4-{[(4-fiuorobenzyl) amino] carbonyl}-5-hydroxy-l-methyl-6-oxo-5-pivalyloxy-l,6-dihydropyrimidin-2-yl)-l-methyl ethylcarbamate, which on hydrogenation with Pd/C gives 2-(l -amino- l-methylethyl)-N-(4-fluorobenzyl)-l-methyl-6-oxo-5-pivalyloxy-l,6-dihydro pyrimidine-4-carboxamide. Coupling of oxadiazole K-salt with 2-(l -amino-1 -methylethyl)-N-(4-fluorobenzyl)-1-methyl-6-oxo-5-pivalyloxy-l,6-dihydropyrimidine-4-carboxamide followed by hydrolysis results into Raltegravir.

In US 7754731, the process for preparing crystalline forms of Raltegravir potassium salt has been carried out in presence of ethanol which is characteristically uphelds the formation of impurities.

There is a need in the art to provide an improved process, which is cost effective, simple and with enhanced purity. The industrial advantage of the present invention is, controls the formation of impurities which were formed by employing ethanol in salt formation and avoids pressure reaction in hydrogenolysis of benzoyloxy carbonyl group.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide an improved process for preparing Raltegravir.
One more object of the present invention is to provide novel impurities of Raltegravir potassium salt.
One aspect of the present invention is to provide an improved process for preparing Raltegravir comprising the steps of:

a) hydrogenolysing compound of formula VII in presence of a hydrogen source and catalyst in a suitable solvent to produce formula III,

Formula VH Formula II]
b) converting formula HI into Raltegravir, and

c) optionally converting Raltegravir into its pharmaceutically acceptable salts.

Another aspect of the present invention is to provide an improved process for preparing Raltegravir potassium salt free of impurities of impurity I, II and III comprising the steps of:

a) dissolving Raltegravir in a ketonic solvent,
b) optionally adding water to the reaction mixture,
c) adding KOH to the reaction mixture, and
d) isolating Raltegravir potassium salt.

DETAILED DESCRIPTAION OF THE INVENTION

The present invention provides an improved process for preparing Raltegravir comprising hydrogenolysing compound of formula VII in presence of a hydrogen source and catalyst to produce formula III and converting it to Raltegravir. It also provides novel impurities of Raltegravir potassium salt and process for the preparation of Raltegravir potassium free of impurities of impurity I, II and III.
The schematic representation of present invention to provide Raltegravir and its pharmaceutically acceptable salts is shown in Scheme I.

One aspect of the present invention is to provide Raltegravir and its pharmaceutically acceptable salts comprising the steps of:

a) hydrogenolysing compound of formula VII in presence of a hydrogen source and catalyst in a suitable solvent to produce formula III,

b) converting formula in into Raltegravir, and

c) optionally converting Raltegravir into its pharmaceutically acceptable salts.

In one embodiment of the present invention, the benzyl protected compound of formula VII is hydrogenolysed by contacting with a catalyst in presence of hydrogen source and suitable solvent. The hydrogenolysis catalyst is selected from palladium on carbon, Raney nickel, platinum, irdium and ruthenium, preferably palladium on carbon, the hydrogen source is selected from ammonium formate, ammonium acetate or ammonium oxalate, preferably ammonium formate. The suitable solvent is selected from polar solvent or mixtures thereof, wherein the polar solvent is selected from methanol, ethanol, isopropanol, butanol, N,N-dimethyl formamide, tetrahydrofuran, acetone, acetonitrile, N-Methyl-2-pyrrolidine, dimethyl sulfoxide, preferably N,N-dimethyl formamide.

In one more embodiment of the present invention, the hydrogenolysed product of formula III is further converted into Raltegravir and its pharmaceutically acceptable salt as per the process known in prior arts US 7754731, WO 2011024192, WO 2010140156 and our co-pending application IN 736/CHE/2012.
In one more embodiment of the present invention, the compound of formula III is can be converted into Raltegravir by a process described in scheme II. The process comprising by treating free amine compound of formula III with a dehydrating agent such as trimethyl silyl chloride to get a silyl protected OH-compound, which is condensed with oxadiazole compound of formula IV to give silyl protected Raltegravir. The silyl protected Raltegravir is insituly treated with an acid to obtain Raltegravir.

It is observed that, by following the processes disclosed in prior art for preparing Raltegravir salt comprises impurities namely Impurity I, Impurity II and Impurity III which impacts the purity of the product. The present invention provides pure Raltegravir free of Impurity I, Impurity II and Impurity III.

Another aspect of the present invention is to provide Raltegravir potassium salt with free of Impurity I, Impurity II and Impurity III comprising the steps of:

a) dissolving Raltegravir in a ketonic solvent,

b) optionally adding water to the reaction mixture,

c) adding KOH to the reaction mixture, and

d) isolating Raltegravir potassium salt.

As per the present invention, Raltegravir is dissolved in a ketonic solvent selected from acetone, methyl ethyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, preferably acetone and optionally added water to the reaction mixture. To the obtained reaction mixture is added potassium hydroxide, preferably aqueous 30% w/v potassium hydroxide by adjusting pH range 9-11, preferably 10. 25 ± 0.25. The reaction mixture is cooled to -5 to 10 °C, preferably 0-5 °C. The obtained Raltegravir potassium solid is filtered and washed with ketonic solvent such acetone to isolate pure Raltegravir potassium salt.

Yet another embodiment of the present invention, the obtained Raltegravir potassium salt is further converted into amorphous form of Raltegravir potassium salt by the processes as described in prior art US 7754731, WO 2011024192 A2 and WO 2010140156 A2. For example Raltegravir potassium salt is further converted into amorphous form of Raltegravir potassium salt comprising: dissolving Raltegravir potassium in a suitable solvent; and freeze-drying the solution to yield amorphous Raltegravir potassium.

One more aspect of the present invention is to provide novel impurities of formula Impurity I,
As per the present invention, the benzyl protected compound of formula VII is hydrogenolysed by contacting formula VII with hydrogenolysis catalyst such as palladium on carbon in presence of hydrogen source such as ammonium formate and suitable solvent preferably N,N-dimethyl formamide gives formula III, which is further converted into Raltegravir of formula la. The obtained Raltegravir of formula la is on treating with KOH in suitable solvent such as acetone gives Raltegravir potassium salt of formula I free of impurities impurity I, II and III. The formula I is further washed with a solvent such as acetone to give pure Raltegravir potassium salt.

Raltegravir Potassium prepared according to the invention may be used in the preparation of suitable dosage form such as granules, pellets, tablets, mini-tablets, chewable tablets, orally disintegrating tablets, capsules, suspensions, solutions or emulsions. Other dosage forms included within the scope of the invention, but not restricted to extended or modified release tablets or capsules etc.

The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in any way.

Examples:
Example-1: Preparation of 2-(2-aminopropan-2-yI)-N-(4-fluorobenzyl)-5-hydroxy-l-methyl-
6-oxo-l,6-dihydropyrimidine-4-carboxamide.

50% wet 5% Pd/C was added to the mixture of 100 g of Benzyl(2-{4-[(4-fluorobenzyl) carbamoyl]-5-hydroxy-1 -methyl-6-oxo-1,6-dihydropyrimidin-2-yl} propan-2-yl)-carbamate (1.0 mole) and 200 ml of N,N-Dimethyl formamide. 54 g of Ammonium formate (4.01 mol) was dissolved in 100 ml of purified water and this solution was added to the above reaction mixture and heated to 35 to 45°C and maintained the same to complete the reaction. After completion of the reaction, the reaction mixture was filtered and cooled to 0-5 °C. The obtained crystallized product was washed with chilled methanol and dried at 50-55 °C to get 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1 -methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide dihydrate. Yield: 71 g; HPLC: 99%.

Example-2: Preparation of N-[(4-fluorophenyI)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[[(5-methyl-l,3,4-oxadiazol-2-yI)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide 180 g (6.13 mol) of Tri methyl silyl chloride was added to the mixture of 100 g (1.0 mole) of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1 -methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide dihydrate and 800 ml of dichloro methane at 38-42°C. The reaction mass was cooled to -10 to -15 °C and added 80 g (2.93 mol) of N-methyl morpholine and maintained for 2 hrs at same temperature.

In another flask 800 ml of dichloro methane, 67.32 g (1.5 mol) of Potassium 5-methyl-1,3,4-oxadiazole-2-carboxylate and 0.4 g of dimethyl formamide were taken and cooled to -10 to -15°C; and oxalyl chloride 48.72 g, (1.42 mol) was slowly added at the same temperature. To this was added the above prepared carboxamide solution at -10 to -15 °C and stirred fro 2 hrs. To the reaction mass was added 400 mL of water and stirred for 30 mins at 20-25 °C followed by the separation of organic layer. The organic layer was washed with acetic acid solution followed by sodium bicarbonate solution and sodium chloride solution. The organic layer was concentrated and solvent traces were removed with acetone at 40-45 °C under reduced pressure. To the residue, acetone was added and treated with charcoal followed by cooling the reaction mass to 0-5 °C for 2 hrs. The solid was filtered; washed with acetone and dried at 50-55 °C to yield N-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[[(5-methyl-l,3,4-oxadiazol-2-yl)carbonyl]amino] ethyl]-6-oxo-4-pyrimidine carboxamide. Yield: 120 g; HPLC: 99%.

Example 3: Preparation of Potassium N-[(441uorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-
methyl-2-[[(5-methyl-13»4-oxadiazol-2-yl)carbonyl}amino]ethyl]-6-oxo-4-pyrimidine
carboxamide.

100 g of N-(4-fluorobenzyl)-5-hydroxy-l-methyl-2-(2-{[(5-methyl-l,3,4-oxadiazol-2-yl)carbonyl]amino}propan-2-yl)-6-oxo-l,6-dihydropyrimidine-4-carboxamide was added to 1700 mL of acetone at ambient temperature. To the reaction mass was added 150 mL of purified water and cooled to 10-15 °C and adjusted pH 10.25 ± 0.25 with aqueous 30% w/v potassium hydroxide 30% w/v. The reaction mass was stirred for 120-180 mins at 0-5 °C. The obtained solid was filtered and washed with chilled micron filtered acetone and dried at 35-40 °C to yield Potassium N-[(4-fluorophenyI)methyl]-1,6-dihydro-5-hydroxy-1 -methyl-2-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide. Yield: 97 g; HPLC: 99.9%.

Example 4: Preparation of amorphous potassium N-[(4-fluorophenyl)methyl]-l,6-dihydro-
5-hydroxy-l-methyI-2-[[(5-methyI-l,3,4-oxadiazol-2-yl)carbonyI] amino]ethyl]-6-oxo-4-pyrimidine carboxamide 100 g (1 mole) of Potassium 4-[(4-fluorobenzyl) carbamoyl]-l-methyl-2-(2-{[(5-methyl-l,3,4-oxadiazol-2-yl)carbonyl]amino} propan-2-yl)-6-oxo-l,6-dihydropyrimidin-5-olate was added into 1500 mL of purified water; maintained for the clear solution; filtered undissolved particles. From the obtained mass water was removed by freeze drying technique at -75 to -80 °C to yield potassium N-[(4-fiuorophenyl)methyl]-1,6-dihydro-5-hydroxy-1 -methyl-2-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino] ethyl]-6-oxo-4-pyrimidine carboxamide in amorphous form. Yield: 100 g; HPLC: 99.9%.

Example 5: Preparation of amorphous potassium N-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[[(5-methyl-l,3,4-oxadiazol-2-yl)carbonyl]amino] ethyl]-6-oxo-4-pyrimidine carboxamide
100 g (1 mole) of Potassium 4-[(4-ftuorobenzyl) carbamoyl]-l-methyl-2-(2-{[(5-methyl-l,3,4-oxadiazol-2-yl)carbonyl] amino} propan-2-yl)-6-oxo-l,6-dihydropyrimidin-5-olate was added into 1500 mL of purified water; maintained for the clear solution; filtered undissolved particles. From the obtained mass water was removed by ATFD technique at -75 to -80 °C to yield potassium N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1 -methyl-2-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide in amorphous form. Yield: 100 g; HPLC: 99.9%.

Example 6: Unit Composition

Brief Manufacturing Procedure:

1. Add Raltegravir potassium slowly added to purified water under continuous stirring till clear dispersion;

2. Add Plasdone S-360 ™ to step no. 1 solution under stirring till it get clear dispersion;

3. Sift Silicified microcrystalline cellulose through sieve # 30 ASTM and load in a fluid bed processor;

4. Granulate the step no.3 material by using step no.2 dispersion;

5. After drying, sift through sieve # 25 ASTM and retained materials were milled through suitable screen in quadra-co-mill;

6. Sift the extra-granular materials (fructose, crosscarmellose sodium, saccharin sodium, sodium citrate, Avicel CE15™) through sieve # 30 ASTM;

7. Blend the material of step no.5 and step no.6 in blender for suitable time;

8. Sift Sodium stearyl fumarate through sieve # 40 ASTM, and lubricate with the material of step no. 7 blend for suitable time;

9. Compress the lubricated blend into tablets by using suitable toolings.

Example 7: Unit Composition

Brief Manufacturing Procedure:

1. Sift Raltegravir potassium, silicified microcrystalline cellulose, colloidal silicon dioxide, Poloxamer 407™, hydroxypropylmethyl cellulose through suitable sieve and mix for suitable time;

2. Sift Stear-o-Wet™ (Part 1) through suitable sieve and lubricate with step no.l material for suitable time;

3. Compact the step no 2 blend in a roll compactor;

4. Mill the step no. 3 compacts through suitable screen and sift through suitable sieve;

5. Repeat the step no. 3 and 4 to get desired granules to fines ratio;

6. Sift the granules of step no. 5 through suitable screen and mill the oversized granules through suitable screen / sieve;

7. Sift silicified microcrystalline cellulose and hydroxypropylmethyl cellulose through suitable sieve and blend with the material of step no.6 for suitable time;

8. Sift Stear-o-Wet™ (Part 2) through suitable sieve, and lubricate the material of step no.7 for suitable time;

9. Compress the lubricated blend into tablets;

10. Coat the tablets using aqueous dispersion of Opadry™.

Claims:

1. An improved process for preparing Raltegravir comprising the steps of:

a) hydrogenolysing compound of formula VII in presence of a hydrogen source and catalyst in a suitable solvent to produce formula III,

b) converting formula III into Raltegravir, and

c) optionally converting Raltegravir into its pharmaceutically acceptable salts.

2. The process according to the claim 1, wherein the hydrogen source is ammonium formate.

3. The process according to the claim 1, wherein the suitable solvent is selected from polar solvent.

4. The process according to the claim 3, wherein polar solvent is N,N-dimethyl formamide.

5. A process for preparing Raltegravir potassium salt with free of Impurity I, Impurity II and Impurity III comprising the steps of:

a) dissolving Raltegravir in a ketonic solvent,

b) optionally adding water to the reaction mixture,

c) adding KOH to the reaction mixture, and

d) isolating Raltegravir potassium salt.

6. The process according to the claim 5, wherein the ketone solvent is acetone.

7. A pharmaceutical composition comprising Raltegravir or its salts thereof obtained by any of the claims 1-6.