FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Raltegravir of Formula (I).

BACKGROUND OF THE INVENTION

Raltegravir potassium is chemically known as jV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-1 -methyl-2-[ 1 -methyl-1 -[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide.
Raltegravir is an antiretroviral drug used to treat HIV infection. Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Raltegravir potassium salt is marketed under the trade name Isentress™.
Raltegravir is disclosed in US 7,169,780. US '780 also discloses a process for the preparation of Raltegravir (I) by reacting acetone cyanohydrin (II) with ammonia gas in methanol to produce 2-amino-2-methylpropanenitrile (III), which is further reacted with benzylchloroformate in the presence of sodium carbonate (Na2C03) to produce benzyl-1-cyano-1-methylethylcarbamate (IV). Compound (IV) is reacted with hydroxylamine hydrochloride in the presence of KOH in methanol to produce benzyl-2-amino-2-(hydroxyimino)-l,l-dimethylethylcarbamate (V). Compound (V) is reacted with dimethylacetylenedicarboxylate in chloroform to produce methyl-2-(l-{[(benzyloxy)
carbonyl]amino}-l-methylethyl)-5,6-dihydroxypyrimidine-4-carboxylate (VI), which is treated with benzoic anhydride in the presence of pyridine to produce methyl-5-(benzoyloxy)-2-( 1 - {[(benzyloxy)carbonyl]amino} -1 -methylethyl)-6-hydroxypyrimidine-4-carboxylate (VII), which is further methylated using dimethylsulfate (DMS) in the presence of lithium hydride (LiH) in dioxane to produce methyl-5-(benzoyloxy)-2-(l-{[(benzyloxy)carbonyl]amino}-l-methylethyl)-l-methyl-6-oxo-l,6-dihydroxypyrimidine-4-carboxylate (VIII). Compound (VIII) is reacted with p-fluorobenzylamine in methanol to produce benzyl-1 -(4-{ [(4-fluorobenzyl)amino]carbonyl }-5-hydroxy-l -methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-l-methylethylcarbamate (IX), which is hydrogenated in the presence of Pd/C in methanol to produce 2-(l -amino-1 -methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide (X). Compound (X) is condensed with 5-methyl-l,3,4-oxadiazole-2-carboxylic acid (XI) in the presence of oxalyl chloride and triethylamine in anhydrous DMF to produce Raltegravir (I).

The process is as shown in Scheme -I below:

US '780 discloses another variant process for the preparation of Raltegravir (I) by reacting methyl-1,6-dihydro-5-(benzoyloxy)-1 -methyl-2-( 1 -methyl-1 -{[5-methyl-1,3,4-oxadiazol-2-yl)-carbonyl]amino}ethyl)-6-oxo-4-pyrimidine carboxylate (XII) with 4-fluorobenzyl amine to produce Raltegravir (I).
The process is as shown in Scheme-II below:

The major disadvantage with the above processes involves additional protection and de-protection steps for the preparation of Raltegravir. In the chemical synthesis, the number of steps is not advisable for the commercialization of the product. The number of steps is more in a chemical process means the lowering of the overall yield and the time cycle of the production is more. This does not make the suitable chemical process.

US 7,754,731 discloses a process for the preparation of Raltegravir (I) by methylating methyl-2-(l-{[(benzyloxy)carbonyl]amino}-l-methylethyl)-5,6-dihydroxypyrimidine-4-carboxylate (VI) with methyl iodide and magnesium methoxide in dimethylsulfoxide (DMSO) and methanol to produce methyl-5-hydroxy-2-(l-{[(benzyloxy)carbonyl]amino}-l-methylethyl)-l-methyl-6-oxo-l,6-dihydroxypyrimidine-4-carboxylate (XIII), which is further condensed with p-fluorobenzylamine in ethanol to produce benzyl-l-(4-{[(4-
fluorobenzyl)amino]carbonyl}-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidin-2-yl)-l-methylethylcarbamate (IX). Compound (IX) is hydrogentaed using Pd/C in the presence of methanesulfonic acid (MSA) in methanol to produce 2-(l -amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1 -methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (X), which is further condensed with 5-methyl-l,3,4-oxadiazole-2-cabonyl chloride (XIa) in the presence of TV-methylmorpholine (NMM) in tetrahydrofuran (THF) to produce Raltegravir (I).

The process is as shown in Scheme-Ill below:

The major disadvantage with the above process is that 2 equivalents acylating agent is used for the completion of acylation step. The acylating agent is more expensive and this process is not suitable for large-scale production of Raltegravir.

US 2010/0280244 Al discloses a process for the preparation of Raltegravir (I) by reacting benzyl-1 -(4-{ [(4-fluorobenzyl)amino]carbonyl }-5-hydroxy-1 -methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-l-methylethylcarbarnate (IX) with pivaloyl chloride in the presence of triethylamine in ethyl acetate to produce A^-[(4-fluorophenyl)methyl]-l,6-dihydro-5-pivaloyloxy-l-methyl-2-[l-methyl-l-[[(phenylmethoxy)carbonyl]amino]ethyI]-6-oxo-4-pyrimidine carboxamide (XIV). Compound (XIV) is hydrogenated with source of hydrogen in methanol to produce N-[(4-fluorophenyl)methyl]-l,6-dihydro-5-pivalyloxy-l-methyl-2-[1 -amino- l-methylethyl]-6-oxo-4-pyrirnidinecarboxamide (XV), which is further condensed with 5-methyl-l,3,4-oxadiazole-2-carbonylchIoride (XIa) in the presence of NMM in acetonitrile to produce A4(4-fluorophenyl)methyl]-l,6-dihydro-5-pivalyloxy-l-methyl-2-[ 1 -methyl-1 -[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XVI). Compound (XVI) is hydrolyzed in the presence of aqueous KOH to produce Raltegravir (I).

The process is as shown in Scheme -IV below:
However, there is always a need for alternative preparative routes, which for example, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, involve fewer steps, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

Hence, there is a need to develop cost effective and commercially viable process for the preparation of Raltegravir.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the preparation of N -substituted hydroxypyrimidinone carboxamide derivative, with high purity and good yield on a commercial scale.

More particularly the present invention relates to a simple and cost effective process for the preparation of Raltegravir (I).

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of Raltegravir of Formula I, which comprises:
(i) hydrogenating a compound of Formula (XVII);

to produce a compound of Formula (XVIII) or its salt,

(ii) acetylating the compound of Formula (XVIII) with a compound of Formula (XI),
or its reactive derivative to produce a compound of Formula (XIX),

(iii) hydrolyzing the compound of Formula (XIX) to compound of Formula (XX),

(iv) reacting the compound of Formula (XX) with 4-fluorobenzylamine to produce Raltegravir (I).

Another embodiment of the present invention provides a variant process for the preparation of Raltegravir (I),

which comprises:

(i) hydrogenating the compound of Formula (IX);
to produce compound of Formula (X), hydrate or solvate thereof,

(ii) acetylating the compound of Formula (X) with compound of Formula (XI),
or its reactive derivative to produce Raltegravir (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of Raltegravir of Formula I. The process comprises:

(i) hydrogenating a compound of Formula (XVII) to produce a compound of
Formula (XVIII) or its salt; (ii) acetylating the compound of Formula (XVIII) with a compound of Formula
(XI), or its reactive derivative to produce compound of Formula (XIX); (iii) hydrolyzing the compound of Formula (XIX) to compound of Formula (XX); (iv) reacting the compound of Formula (XX) with 4-fluorobenzylamine to produce Raltegravir (I).

The hydrogenation catalyst used in the hydrogenation step is Palladium on Carbon (Pd/C), Palladium hydroxide on Carbon (Pd(OH)2/C), Platinum dioxide (Pt02), Raney nickel, Chlorotris(triphenylphosphine)Rhodium [RhCl(PPh3)3] or the like.

The solvent used in the hydrogenation step is alcohol comprises C1-C4 aliphatic, straight chain or branched alcohol or mixture thereof.

Hydrogenation step (i) is carried out at a pressure of about 1 atmosphere to about 1000 psi and at a temperature about 0°C to 100°C.

After completion of the hydrogenation reaction, the reaction mixture containing Compound (XVIII) is filtered to remove the catalyst. The filtered cake is then washed with the solvent as defined above and filtrated the compound (XVIII), which is optionally purified by crystallization.

Acetylation step (ii) is carried out in the presence of a base in a solvent. The base is organic base or inorganic base comprises triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, l,4-diazabicyclo-[2.2.2]octane, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, morpholine derivative, pyridine, dimethylaminopyridine, JV-methylmorpholine and/or mixture thereof.

The solvent used in acetylation step (ii) is acetonitrile, methyl acetate, ethyl acetate and propyl acetate, chloroform, dichloromethne and/or mixture thereof.

Acetylation step is carried out at a temperature of about 0°C to 50°C. After, completion of acetylation reaction, Compound (XIX) is isolated either by conventional methods such as by removal of solvent or by crystallization.

Hydrolysis step (iii) is carried out in the presence of a base in a solvent. The base is alkali metal alkoxide comprises sodium methoxide, sodium ethoxide, sodium propoxide, potassium methoxide, potassium ethoxide and potassium propoxide and /or mixture thereof..

The solvent used in hydrolysis step (iii) is polar aprotic solvent comprises dichloromethane (DCM), tetrahydrofuron (THF), ethyl acetate, acetone, dimethyl formamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO), propylene carbonate and/or mixture thereof.

After completion of hydrolysis step, the reaction mass is treated with acid comprises mineral acid or organic acid and/or mixture thereof; filtering the Compound (XX).

Compound (XX) is reacted with 4-fluorobenzylamine in the presence of a base in a solvent to produce Raltegravir. The base is organic base comprises triethylamine, pyridine, dimethylaminopyridine, Af-methylmorpholine and/or mixture thereof.

Solvent used in above reaction is lower alcohol comprising C1-C4 aliphatic, straight chain or branched alcohol or mixture thereof.

Above condensation reaction is carried out at a temperature about 5°C to 80°C. Raltegravir (I) obtained is then isolated from the reaction mixture either directly or by conventional workup and optionally purified by crystallization or precipitation.

Compound (XVII) used in the present invention is prepared by reacting the methyl-2-[l-[[(phenylmethoxy)carbonyl]amino]-1 -methylethyl]-1,6-dihydro-5-hydroxy-1 -methyl-pyrimidine-4-carboxylate (XXI) with a pivaloyl chloride in the presence of a base in a solvent.

In another embodiment, the present invention provides a variant process for preparation of Raltegravir of Formula (I). The process comprises:

(i) hydrogenating the compound of Formula (IX) to produce compound of Formula
(X), hydrate or solvate thereof; (ii) acetylating the compound of Formula (X) with compound of Formula (XI), or its reactive derivative to produce Raltegravir (I).

The hydrogenation catalyst used in the hydrogenation step is Palladium on Carbon (Pd/C), Palladium hydroxide on Carbon (Pd(OH)2/C), Platinum dioxide (Pt02), Raney nickel, Chlorotris(triphenylphosphine)Rhodium [RhCl(PPh3)3] or the like.

The solvent used in the hydrogenation step is alcohol comprises C1-C4 aliphatic, straight chain or branched alcohol or mixture thereof.

Hydrogenation step (i) is carried out at a pressure of about 1 atmosphere to about 1000 psi and at a temperature about 0°C to 100°C.

After completion of the hydrogenation reaction, the reaction mixture containing Compound (X) is filtered to remove the catalyst. The filtered cake is then washed with solvent as defined above and filtrated the compound (X), which is optionally purified by crystallized.

Optionally, the hydrogenation is carried out in the presence of acid is organic acid comprising methanesulfonic acid, benzenesulphonic acid and /?-toluenesulphonic acid to produce Compound (X).
After completion of reaction the reaction mass is treated with a base comprising sodium hydroxide, potassium hydroxide; in a solvent comprising water and isolated the Compound (X) from the reaction mixture.

Acetylation step (ii) is carried out in the presence of a base in a solvent. The base is organic base or inorganic base. The organic base is comprises triethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, l,4-diazabicyclo-[2.2.2]octane; The inorganic base is potassium bicarbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, morpholine derivative, pyridine, dimethylaminopyridine, N-methylmorpholine and/or mixture thereof.

The solvent used in acetylation step (ii) is acetonitrile, methyl acetate, ethyl acetate and propyl acetate, chloroform, dichloromethne and/or mixture thereof.

Acetylation step is carried out at a temperature of about 0°C to 50°C. After completion of acetylation reaction, Raltegravir (I) is isolated from the reaction mass by conventional methods.

Compound (IX) used in the present invention is prepared by methylating the A^-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-l-[[(phenylmethoxy)-carbonyl]-amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXII) with a methylating agent in the presence of a base in a solvent.

Raltegravir prepared by any of the above processes is converted to its potassium salt by conventional methods by treating Raltegravir with potassium source and isolated.

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

EXAMPLE-1:
Stepl:
Preparation of methyl-2-(l-amino-l-methylethyl)-l,6-dihydro-5-[(2,2-dimethyl-propanoyl)oxy]-l-methyl-6-oxo-pyrimidine-4-carboxylate glycolic acid salt (XVIII).

To slurry of methyl-2-[l-[[(phenylmethoxy)carbonyl]amino]-l-methylethyl]-l,6-dihydro-5-hydroxy-l-methyl-pyrimidine-4-carboxylate (XXI; 25g 0.066 mole) in ethyl acetate(75ml) was added triethyl amine(8.74 g,0.0863) and 4-(dimethyIamino)pyridine (6.35 mg,0.052 mmole) 10-15°C. Pivaloyl chloride (9.63 g, 0.0799) was added over a period of 15-20 min. The resulting mass was stirred for 60 min at 10-15°C. Then reaction mass was warmed and mass was aged for 30 min at 20-25°C. After completion of reaction, water (25 ml) was added and stirred for 10-15 min at 20-25°C. The aqueous layer discarded. Methanol (100 ml), 67%w/w glycolic acid solution (9.08 g, 0.080 mole) were added to organic layer and reaction mass was hydrogenated at 5 kg/cm at 20-25°C, using 10% Pd/C(2.5 g, 50%w/w wet). The resulting reaction mass was aged for 24 h at 20-25°C. After completion of reaction, the catalyst was removed by filtration through celite and cake was washed with methanol (25 ml). The filtrate were combined and distilled off methanol and ethyl acetate at 40-45°C. Toluene (100 ml) was added to the concentrated mass and continued the distillation under reduced pressure at 45°C.To the concentrated residue, ethyl acetate (50 ml) was added and stirred for lh at 20-25°C. The solid was filtered and washed with ethyl acetate (2x10 ml). The sample was dried under reduced pressure at 45-50°C to afford 15 g (56.17%) of methyl-2-(l -amino-l-methylethyl)-l,6-dihydro-5-[(2,2-dimethylpropanoyl)oxy]-l-methyl-6-oxo-pyrimidine-4-carboxylate glycolic acid salt (XVIII).

Step 2:
Preparation of Methyl-l,6-dihydro-5-hydroxy-l-methyI-2-[l-methyI-l-[[(5-methyl-l,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl]-6-oxo-pyrimidine-4-carboxylate(XX).

A slurry of 5-methyl-l,3,4-oxadiazole-2- carboxylic acid potassium salt (1.9 g,0.011 mole) in acetonitrile (10 ml) and DMF(0.1 ml) was cooled to -5°C. Oxalyl chloride (1.38 g, 0.0108) was added at -5to 5°C over a period of 10-15min. The slurry was aged for lhr at -5to 5°C to yield oxadiazole-5-methyl-2-carbonylchloride.

In a separate vessel, a free base of Compound (XVIII) (3.20g, 0.00984 moles) was suspended in acetonitrile (20ml), jV-methylmorpholine (l.Og, 0.0099) at 20-25°C and cooled to-10 to 0°C. OxadiazoIe-5-methyI-2-carbonyIchloride was added to the above mass slowly at -10 to 0°C in 10-15 min. After completion of reaction, acetonitrile was distilled off under reduced pressure at 35-40°C. Tetrahydrofuran (20ml) and sodium methoxide (1.06 g, 0.0196 moles) were added to concentrated mass at 25-30°C. Stirred the reaction mass for lh at 25-30°C and maintained at refluxed temperature for 4h. The mass was cooled to 20-25°C and pH was adjusted to 6.5 with acetic acid (1.80 g) at 20-25°C. The slurry was stirred for lh at 20-25°C. The product was filtered and washed with tetrahydrofuran (10 ml). The product was dried under reduced pressure at 40-45°C to afford 3.3 g (95.65%) of methyl-l,6-dihydro-5-hydroxy-l-methyl-2-[l-methyl-l-[[(5-methyl-l,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl]-6-oxo-pyrimidine-4-carboxylate(XX).

Step 3:
Preparation of A^-[(4-fluorophenyI)methyI]-l,6-dihydro-5-hydroxy-l-methyl-2-[l-methyl-l-[[(5-methyl-l,3,4-oxadiazoIe-2-yl)carbonyl]-amino]ethyl]-6-oxo-4-pyrimidine carboxamide (Raltegravir (I)).

The compound (XX; 0.35g, 0.997 mmole) was suspended in methanol (10ml) at 25-30°C. Triethylamine (0.15g, 1.48 mmole) and 4-fluorobenzylamine (0.19g, 1.47 mmole) were added and heated to reflux temperature and refluxed for 3hrs. Methanol was distilled off under reduced pressure at 45°C. Water (5ml) was added and pH was adjusted to acidic with acetic acid at 20-25 C and stirred for 30 min at 20-25°C and cooled to 0-5°C and stirred for lh. The product was filtered, washed with water (1ml) and dried under reduced pressure at 50°C to afford 0.3 g (67.76%) of AT-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[ 1 -methyl-1 -[[(5-methyl-1,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide(Raltegravir (I)).

EXAMPLE-2:
Step 1:
Preparation of A'-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-l-[[(phenylmethoxy)carbonyl]amino]ethyl]- 6-oxo-4-pyrimidine carboxamide (XXII).
Methyl-2-(l-{[(benzyloxy)carbonyl]amino}-l-methylethyl)-5,6-dihydroxypyrimidine-4-carboxylate (VI; 100 g; 0.277 mole), triethylamine (32.8 g; 0.324 mole) and 4-fluorobenzylamine (40.8 g; 0.326 mole) were added to methanol (162 ml) and heated for 7h at 65°C. The reaction mass was acidified with acetic acid (32.6 g; 0.543 mole) and water (170 ml) at 60°Cwas added and the slurry was cooled to 20°C, filtered the solid, washed with 1:1 mixture of methanol-water (120 ml) and dried at 50°C under reduced pressure to afford 116.1 g (92%) of iV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[1-methyl-l-[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXII)

Step 2:
Preparation of 7V-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[l-methyl-l-[[[(phenylmethoxy)-carbonyl]amino]ethyI]-6-oxo-4-pyrimidine carboxamide
(IX).

N-[(4-Fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-l-[[(phenylmethoxy) carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXII; 4.0 g; 0.0088 mole), magnesium hydroxide (1.03 g; 0.0176 mole), trimethylsulfoxonium iodide (3.87 g; 0.0176 mole) and water (0.16 g) were added to JV-methyl-2- pyrrolidinone (16 ml) and heated for 6 h at 100°C. Methanol (7.2 ml) was added to the reaction mass at 25°C, acidified with 5N aqueous hydrochloric acid (3.6 ml) and treated with 25% w/w sodium bisulfite solution (0.2 ml). The reaction mass was acidified with 5N aqueous hydrochloric acid (3.6 ml), water (32 ml) was added and cooled to 10°C. The solid was filtered, washed with 1:1 mixture of methanol-water and dried at 50°C under reduced pressure to afford 3.5 g (85%) of Af-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[l -methyl- l-[[(phenylmethoxy)-carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide (IX)

Step 3:
Preparation of 2-(l-amino-l-methyIethyl)-iV-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide monohydrate (X).

N-[(4-Fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-l -methyl-2-[ 1 -methyl-1 -[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide (IX; 50 g; 0.107 mole) and methanesulfonic acid (10.26 g; 0.107 mole) were added to methanol (500 ml) at 20°C. 10% Palladium on carbon (2.5 g, 50% w/w, wet) was added to the reaction mass and hydrogenated at 15-20°C at 1-2 Kg/Cm2 hydrogen pressure for 3 h. The reaction mass was filtered, washed with methanol (50 ml) and concentrated to 250 ml under reduce pressure at below 40°C. The concentrated mass was cooled to 5-10°C and neutralized to pH 7.5-8 with 2.5N aqueous sodium hydroxide solution. The resulting slurry was stirred for 1 h at 5-10°C, filtered the solid, washed with cold methanol (50 ml) and dried at 45-50°C under reduced pressure to afford 32.5 g (86.43%) of 2-(l -amino- l-methylethyl)-Af-(4-fluorobenzyl)-5-hydroxy-1 -methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide monohydrate (X).

Step 4:
Preparation of ^-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[l-methyl-l-[[(5-methyl-l,3,4-oxadiazole-2-yl)carbonyl]-amino]ethyl]-6-oxo-4-pyriinidine carboxamide (Raltegravir (I)).
Oxalyl chloride (3.81 g; 0.03 mole) was added to the suspension of oxadizole-5-methyl-2-carboxylic acid potassium salt (4.97 g; 0.03 mole) in acetonitrile (30 ml) and N,N-dimethylformamide (0.1 ml) at 0-5° and stirred the slurry for 2 h to yield oxadizole-5-methyl-2-carbonylchloride.
2-( 1 -Amino-1 -methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1 -methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxamide monohydrate (X; 5.0 g; 0.0142 mole) was suspended in methylene chloride (50 ml), azeotropically dried at reflux temperature and concentrated. To the concentrated mass, acetonitrile (15 ml) and N-methylmorpholine (4.28 g; 0.0423 mole) were added and the resulting slurry was added to the slurry of oxadizole-5-methyl-2-carbonylchloride at 0-5°C and stirred for lh. To the reaction mass, water (31 ml) was added at 0-5°C, adjusted pH to 4.5 with 2N aqueous hydrochloric acid at 0-10°C and extracted with ethyl acetate (3 x 50 ml) at 20-25°C. The combined ethyl acetate layer was washed with water (50 ml) followed by brine solution (50 ml) at 20-25 °C and concentrated under reduced pressure at below 40°C. The concentrated reaction mass was dissolved in methylene chloride (50 ml) and extracted with 5% w/w aqueous potassium hydroxide solution at pH 11 at 20-25°C. Aqueous layer was washed with methylene chloride (25 ml) and acidified with acetic acid to pH 5 at below 5°C. The resulting slurry was stirred for 1 h at 0-5°C, filtered the solid, washed with cold water (30 ml) and dried at 50°C under reduced pressure to afford 4 g (63%) of JV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-1 -methyl-2-[ 1 -methyl-1 -[[(5-methyl-1,3,4-oxadiazole-2-yl)carbonyl]-amino]-ethyl]-6-oxo-4-pyrimidine carboxamide (Raltegravir (I)).

WE CLAIM
1. A process for the preparation of Raltegravir of Formula I,
which comprises:

(i) hydrogenating a compound of Formula (XVII);
to produce a compound of Formula (XVIII) or its salt,

(ii) acetylating the compound of Formula (XVIII) with a compound of Formula (XI),
or its reactive derivative to produce a compound of Formula (XIX),

(iv) reacting the compound of Formula (XX) with 4-fluorobenzylamine to produce Raltegravir (I).

2. The process according to claim 1, wherein the hydrogenation step (i) is carried out in the presence of a hydrogenation catalyst in a solvent.

3. The process according to claim 2, wherein the hydrogenation catalyst is Palladium on Carbon (Pd/C), Palladium hydroxide on Carbon (Pd(OH)2/C), Platinum dioxide (Pt02), Raney nickel, Chlorotris(triphenylphosphine)Rhodium [RhCl(PPh3)3] and/or mixture thereof.

4. The process according to claim 1, wherein the acetylation step (ii) is carried out in the presence of a base in a solvent.

5. The process according to claim 4, wherein the base is triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo-[2.2.2]octane, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, morpholine derivative, pyridine, dimethylaminopyridine, N-methylmorpholine and mixture thereof

6. The process according to claim 1, wherein the hydrolysis step (iii) is carried out in the presence of a base selected and a solvent.

7. The process according to claim 1, wherein the step (iv) is carried out in the presence of a base a solvent.

8. A process for the preparation of Raltegravir of Formula (I),
which comprises:

(i) hydrogenating the compound of Formula (IX);
to produce compound of Formula (X), hydrate or solvate thereof,

(ii) acetylating the compound of Formula (X) with a compound of Formula (XI),
or its reactive derivative to produce Raltegravir (I).

9. The process according to claim 8, wherein the hydrogenation step (i) is carried out in the presence of hydrogenation catalyst in a solvent.

10. The process according to claim 8, wherein the acetylation step (ii) is carried out in the presence of a base in a solvent.