This application claims priority to Indian patent application numbered 1N/736/CHE/2012 filed on Feb 28, 2012 and the contents of which are incorporated by reference in their entirety.

FIELD OF INVENTION

The present invention relates to an improved process for the preparation of 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-pyrimidinecarboxamide and its pharmaceutically acceptable salt.

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 HIV-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]-1,6-dihydro-5-hydroxy-1 -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 ®.

Formula I

Raltegravir and its pharmaceutically acceptable salts are disclosed in US 7,169,780.

US 7754731 claims anhydrous crystalline potassium salt of Raltegravir and the process for preparing Raltegravir is exemplified in Example 1. As per the process disclosed in

Step-8, Part-B of example 1; the molar ratio of oxadiazole salt of formula IV and free amine of formula III for the condensation is 2.2:1. . The disadvantage of the above process is utilization of additional amount of oxadiazole salt.

There is a need in the art to provide an improved process, which is cost effective and simple. The present invention provides an improved process which employs comparatively less molar ratio to the aforementioned process.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide an improved process for preparation of Raltegravir.

In one aspect, the present invention provides an improved process for the preparation of Raltegravir comprising, condensing free amine compound of formula III with an oxadiazole derivative of formula IV in presence of a dehydrating agent and a base in a suitable solvent.

DETAILED DESCRIPTAION OF THE INVENTION

The present invention provides an improved process for the preparation of Raltegravir comprising, condensing free amine compound of formula III with an oxadiazole derivative of formula IV in presence of a dehydrating agent and a base in a suitable solvent. The present invention also relates to conversion of Raltegravir into its pharmaceutically acceptable salts.

The schematic representation of the present invention is given in the scheme-I

In one embodiment of the present invention, the condensation of free amine compound of formula III with an oxadiazole derivative of formula IV is carried out in presence of a dehydrating agent and base in a suitable solvent.

In one embodiment of the present invention, the molar ratio of oxadiazole derivative of formula IV employed with respect to formula III is around 1:1 to 1.75:1, preferably 1.3:1 to 1.5: 1.

In one embodiment of the present invention, the dehydrating agent used for the condensation of free amine compound of formula HI with an oxadiazole derivative of formula IV is preferably silylated dehydrating agent. The silylated dehydrating agent is selected from tri alkyl silyl halides, bis (tri methyl silyl) acetate (BSA), tetrachlorosilane, hexamethyldisilazane (HMDS), diphenylmethy chlorosilane; the dehydrating agents also includes tetra butyl ammonium bromide (TBAB), Tetra butyl ammonium chloride (TBAC), tetra butyl ammonium fluoride (TBAF),Crown ethers; preferably tri alkyl silyl halides; most preferably trimethyl silyl chloride.

In another embodiment of the present invention, the base used for the condensation of free amine compound of formula III with an oxadiazole derivative of formula IV is selected from N-methyl morpholine, triethyl amine, diisopropyl ethyl amine, N-ethyl morpholine, N,N-dimethylaniline, pyridine, ethyldiisopropylamine 4-dimethylaminopyridine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU); preferably N-methyl morpholine.

In another embodiment of the present invention, the solvent used for the condensation of free amine compound of formula III with an oxadiazole derivative of formula IV is an organic solvent selected from dichloromethane, acetonitrile, tetrahydrofuran, acetone; preferably dichloromethane to give Raltegravir.

In another embodiment of the present invention, the obtained Raltegravir is purified by treating with polar aprotic solvents selected from dimethyl formamide, methyl tertiarybutylether, acetonitrile, dimethylsulfoxide, acetone, tetrahydrofuran, ethyl acetate, methyl ethyl ketone, preferably acetone.

In another embodiment of the present invention, the obtained Raltegravir is purified by dissolving Raltegravir in polar aprotic solvent selected from dimethyl formamide, methyl tertiarybutylether, acetonitrile, dimethylsulfoxide, acetone, tetrahydrofuran, ethyl acetate, methyl ethyl ketone or mixtures thereof followed by optional charcolization; and cooling to -5 to 5 °C to yield pure Raltegravir.

In one more embodiment of the present invention, the purified product of Raltegravir of formula II is converted into Raltegravir potassium salt of formula I by the processes known in the prior art such as US 7754731. For example Raltegravir is converted into Raltegravir potassium salt by treating Raltegravir with KOH in suitable solvent. The suitable solvent is polar solvent selected from methanol, ethanol, propanol, butanol, acetic acid, formic acid, water or mixtures thereof, preferably mixture of ethanol and water.

As per the present invention, oxadiazole derivative of formula IV, wherein X is preferably Chloro; is condensed with free amine compound of formula III at a molar ratio from 1.3:1 to 1.5: 1 in presence of a silylated dehydrating agent such as trimethyl silyl chloride and an organic base such as N-methyl morpholine in suitable solvent, preferably methylene dichloride. The resulting condensed product of Raltegravir is optionally converted into pharmaceutically acceptable salts, preferably 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.

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 N-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[[(5-methyl-l,3,4-oxadiazol-2-yI)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide 180 g of tri methyl silyl chloride was added to the mixture of 100 g 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 of N-methyl morpholine and maintained for 2 hrs at same temperature.

In another flask 800 ml of dichloro methane, 67.32 g 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 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-1 -methyl-2-[[(5-methyl-1,3,4-oxadiazol-2-yI)carbonyl]amino] ethyl]-6-oxo-4-pyrimidine carboxamide Yield: 120 g; HPLC: 99%.

Example 2: Preparation 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.

172 g of tri methyl silyl chloride was added to the mixture of 100 g of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1 -methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide dehydrate and 800 ml of dichloro methane at 38-42°C. To the reaction mixture was added 96 g of N-methyl morpholine 20 to 25°C and maintain for 1 hr.

In another flask, 800 ml of dichloro methane, 78.5 g of Potassium 5-methyl-1,3,4-oxadiazole-2-carboxylate, 0.4 g of dimethyl formamide were taken and cooled to 10 to -15°C, to this was added 56.4 g of oxalyl chloride at -8 to -2°C and maintain for 2 hrs at same temperature. The reaction mixture was heated to 15 to 20°C and maintained for 6 to 8 hrs. To this reaction mixture was added previously prepared carboxamide solution at -8 to -2°C, stirred for 2 hrs and heated to 20 to 25°C and continued stirring for 5 to 8 hrs. Water was added to the reaction mixture at 15-20°C and the layers were separated. The organic layer was washed with acetic acid. To the separated organic layer, water was added and pH was adjusted to 9.0 to 9.5 with 20% sodium hydroxide solution at 15-20°C and stirred for 30 mins. The pH of the organic layer was further adjusted to between 4.25 and 4.75 with acetic acid followed by washing with sodium chloride solution. The organic layer was concentrated and solvent traces were removed with methanol at 40-45 °C. 150 ml of acetonitrile wad added to organic layer and stirred at below 40 °C to get clear solution, then 150 ml of methanol was added to the clear solution and heated to 55 to 65°C. The clear solution was charcolized in the mixture of acetonitrile and methanol and cooled to 25 to 30°C; maintained at same temperature for 7 to 8 hrs. The solution was further cooled to -5 to 5°C and holds the same for 4-5 hrs. The solid was filtered; washed with chilled acetonitrile, methanol mixture and dried at 50-55 °C to yield N-(4-fluorobenzyl)-5-hydroxy-1 -methyl-2-(2-{ [(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl] amino}propan-2-yl)-6-oxo-l,6-dihydropyrimidine-4-carboxamide. Yield: 120 g ; HPLC : 99%.

Example 3: Preparation of Potassium N-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[[(5-methyl-1,3, 4-oxadiazol-2-yI)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide.

To the 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 150 mL of ethanol and 150 mL of water and cooled to 10 to 15°C. To this was slowly added aqueous 30% w/v potassium hydroxide 30% w/v (0.94 eq., 0.21 mol) with dosing pump for 30min followed by the filtration and seeding at 10 to 15°C for 120-180 min. To the reaction mixture was added 1300 ml of micron filtered ethanol and stirred for 2-3 hrs at 0-5 °C. The solid was filtered and washed with 100 mL of micron filtered ethanol followed by the washing with 100 mL of acetone and dried 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. Yield: 97 g; HPLC: 99.9%

Example 4: 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]etbyI]-6-oxo-4-pyrimidine carboxamide

100 g of Potassium 4-[(4-fluorobenzyl) carbamoyl]-l-methyl-2-(2-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino} propan-2-yl)-6-oxo-1,6-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-fluorophenyl)methyl]-l,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-methyI-2-[[(5-methyl-13»4-oxadiazol-2-yl)carbonyl]amino] ethyl]-6-oxo-4-pyrimidine carboxamide

100 g of Potassium 4-[(4-fluorobenzyl) carbarnoyl]-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 55-60 °C to yield 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 in amorphous form. Yield: 100 g; HPLC: 99.9%.

Example 6: Preparation of Potassium 4-[(4-fluorobenzyl)carbamoyl]-l-methyl-2-(2-{[(5-methyl-l,3,4-oxadiazol-2-yl)carbonyI]amino}propan-2-yl)-6-oxo-l,6-dihydropyrimidin-5-oIate (Amorphous) 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-1,6-dihydropyrimidine-4-carboxamide was added to 2375 ml of 50% aqueous methanol and maintained for clear solution. The un dissolved particles were filtered from reaction mixture and solvent traces and water was removed with ATFD at 55 to 60 °C to yield amorphous 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. Yield: 100 g ; HPLC : 9.9%.

We Claim:

1. A process for preparing Raltegravir comprising the steps of :

a) condensing free amine compound of formula III with an oxadiazole derivative of formula IV in presence of a dehydrating agent and a base in a suitable solvent; and b) isolating Raltegravir.

2. The process according to the claim 1, wherein the X in oxadiazole derivative of formula IV is chloro.

3. The process according to the claim 1, wherein the dehydrating agent is tri alkyl silyl halide.

4. The process according to the claim 1, wherein the dehydrating agent selected from bis (tri methyl silyl) acetate (BSA), tetrachlorosilane, hexamethyldisilazane (HMDS), diphenylmethy chlorosilane, tetra butyl ammonium bromide (TBAB), tetra butyl ammonium fluoride (TBAF),Tetra butyl ammonium chloride (TBAC) or crown ethers.

5. The process according to the claim 1, wherein the oxadiazole derivative of formula IV and free amine of formula III are at molar ratio from 1:1 to 1.75:1.

6. The process according to the claim 1, wherein the base is selected from N-methyl morpholine, triethyl amine, diisopropyl ethyl amine, N-ethyl morpholine, N,N-dimethylaniline, pyridine, ethyldiisopropylamine 4-dimethylaminopyridine or 1,8-Diazabicyclo[5.4.0]undec-7-ene.

7. The process according to claim 6, wherein the base is N-methyl morpholine.

8. The process according to the claim 1, wherein the solvent is selected from dichloromethane, acetonitrile, tetrahydrofuran and acetone.

9. The process according to the claim 8, wherein the solvent is dichloromethane.

10. A process according to the proceeding claims, wherein the Raltegravir is converted into pharmaceutically acceptable salt.

11. The process according to claim 10; wherein the pharmaceutically acceptable slat is potassium salt.