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 ;V-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-l-methyl-2-[l -methyl- l-[[(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-carboxyIate (VI), which is treated with benzoic anhydride in the presence of pyridine to produce methyl-5-(benzoyloxy)-2-( 1 - {[(benzy loxy)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}- 1-methylethyl)-1 -methyl-6-oxo-1,6-dihydroxypyrimidine-4-carboxylate (VIII). Compound (VIII) is reacted with p-fluorobenzylamine in methanol to produce benzyl-1 -(4- {[(4-fluorobenzyl)amino]carbonyl} -5-hydroxy-1 -methy 1-6-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-l-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide (X). Compound (X) is condensed with 5-methyI-l,3,4-oxadiazoIe-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-( 1 -{[(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-( 1-amino-1-methylethyl)-N-(4-
fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide (X),
which is further condensed with 5-methyl-l,3,4-oxadiazole-2-cabonyl chloride (XIa) in the presence of iV-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-methylethylcarbamate (IX) with pivaloyl chloride in the presence of triethylamine in ethyl acetate to produce JV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-pivaloyloxy-l-methyl-2-[l -methyl- l-[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XIV). Compound (XIV) is hydrogenated with source of hydrogen in methanol to produce JV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-pivalyloxy-l-methyl-2-[1 -amino- l-methylethyl]-6-oxo-4-pyrimidinecarboxamide (XV), which is further condensed with 5-methyl-l,3,4-oxadiazole-2-carbonylchloride (XIa) in the presence of NMM in acetonitrile to produce JV-[(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 Raltegravir (I) with high purity and good yield on a commercial scale.

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);

wherein, P represents hydrogen;

to produce a compound of Formula (XVIII),

(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) methylating the compound of Formula (XIX) to produce Raltegravir (I).

In another embodiment the present invention provides a variant process for the preparation of Raltegravir of Formula I, which comprises:

(i) hydrogenating a compound of Formula (XVII);
wherein, P represents hydroxyl protecting group; to produce a compound of Formula (XVIII),

(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 produce a compound of formula (XX);

(iv) methylating the compound of Formula (XX) 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), wherein, 'P' represents hydrogen; (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) methylating the compound of Formula (XIX) to produce Raltegravir (I).

Hydrogenation step (i) is carried out in the presence of a hydrogenation catalyst in a solvent.

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.

Methylation step (iii) is carried out in the presence of a methylating agent and a base in a solvent.

Methylating agent is methyl halide, dimethyl sulfate, trimethyl silyldiazomethane, dimethyl sulfoxide (DMSO), trimethyl sulfoxonium iodide and/or mixture thereof. Methyl halide comprises methyl iodide, methyl chloride, methyl bromide, methyl fluoride or mixture thereof.

The base used in methylation step is hydride, hydroxide and/or oxides of metals comprises hydride, carbonate, hydroxide and/or oxide of magnesium, sodium, potassium and calcium; and magnesium base comprising MgH2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt and/or mixture thereof.

The solvent used in methylation step is a polar aprotic solvent comprising dichloromethane (DCM), tetrahydrofuron (THF), ethyl acetate, acetone, dimethyl formamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO), propylene carbonate and/or mixture thereof.
Methylation step is carried out at a temperature of about -20°C to 50°C. Raltegravir (I) obtained is then isolated from the reaction mixture either directly or by conventional workup and optionally purified by crystallization or precipitation.

In another embodiment the present invention provides a variant 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), wherein, P represents hydroxyl protecting group; (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 produce a compound of

Formula (XX); (iv) methylating the compound (XX) to produce Raltegravir (I).

Hydroxyl protecting group comprises pivaloyloxy group and carboxybenzyl (Cbz), tertiary butyloxy, allyloxy, Methoxymethyl oxy, Tetrahydropyranyl oxy, tertiary-butyldimethylsilyl oxy, tertiary-butyldiphenylsilyloxy, acetyloxy, benzoyloxy.

Hydrolysis step is carried out in the presence of a base in a solvent. The base used in hydrolysis step is inorganic base comprises sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, ammonia and/or mixture thereof.

The solvent used in hydrolysis step is polar protic solvent comprises water, alcohols and/or mixture thereof.

After completion of hydrolysis step the reaction mass is treated with an acid comprises mineral acid or organic acid and/or mixture thereof. Extracting the reaction mixture with a solvent comprises methyl acetate, ethyl acetate, propyl acetate, methylene chloride, or aromatic hydrocarbon and/or mixture thereof.

Compound (XVII) used in the present invention is prepared by condensing methyl-2-(l-{[(benzyloxy)carbonyl]amino}-l-methylethyl)-5,6-dihydroxypyrimidine-4-carboxylate (VI) with 4-fluorobenzylamine in the presence of a base in a solvent to produce N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-2-[ 1 -methyl-1 -[[(phenylmethoxy)-carbonyl]-amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXI), which is further protected with a protecting agent selected from pivaloyl chloride in the presence of a base in a solvent to produce Compound (XVII).

Raltegravir prepared by 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:
Step 1:
Prepa ration of N- [(4-fluoropheny l)methy 1] -1,6-dihy dro-5-hyd roxy-2- [ 1 - methyl-1 -[[(phenylmethoxy)carbonyl]amino]ethyl]- 6-oxo-4-pyrimidine carboxamide (XXI).
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 added water (170 ml) at 60°C. 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 7V-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-1 -[[(phenylmethoxy)carbonyl]-amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXI).

Step 2:
Preparation of 2-(l-amino-l-methylethyl)-A'-[(4-fluorophenyl)methyI]-l,6-dihydro-5-[(2,2-dimethylpropanoyl)oxy]-l-methyl-6-oxo-4-pyrimidine carboxamide (XVIIIa)
To a slurry of jV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-1-[[(phenylmethoxy) carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXI; 50 g;0.11mole) in ethyl acetate (150 ml) trimethylamine(15.6 g,0.154 mole) and 4-(Dimethyl amino)pyridine(0.1g,0.82mmole) were added at 10-15°C. Pivaloyl chloride (16.0 g, 0.133 mole) was added over 30 min. The resulting mass was stirred for 60 min. at 10-15°C.Then the temperature of the reaction mass was warmed to 20-25°C and mass was aged for 30 min. at 20-25°C. After completion of reaction, water (50 ml) was added and mixture warmed to 25-30°C. The aqueous layer was discarded. Methanol (100 ml) and 67wt% glycolic acid (16.6g, 0.146 mole) were added to the organic layer and reaction mass was hydrogenated at 5kg/cm2 at 20-25°C using 10%pd/c (2.5g, 50%wet). The resulting reaction mixture was aged for 2h at 20-25°C.After completion of reaction, the catalyst was removed by filtration through celite and the cake was washed with methanol (3><50 mI).The filtrates were combined and distilled off methanol and ethyl acetate at 35-40°C under reduced pressure to get oily mass. The resulting mass was dissolved in ethyl acetate (150 ml) and methanol (150 ml) at 25-30°C.Triethyl amine (22.3g, 0.22 mole) was added to above solution at 25-30°C in single lot. The solution was kept at 25-30°C for overnight then product was precipitated out. The product was filtered and washed with ethyl acetate(20 ml).The product was dried at 40-50°C under reduced pressure to afford 13.5 g(30.34 %) of of 2-( 1 -amino-1 -methylethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-[(2,2-dimethyl-propanoyl)oxy]-l -methyl-6-oxo-4-pyrimidine carboxamide (XVIIIa).

Step 3:
Preparation of iV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-l-[[(5-methyl-l,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl-6-oxo-4-pyrirnidine carboxamide
(XX):

A slurry of 5-methyl-l,3,4-oxadiazole-2-carboxylic acid potassium salt (6.2g,0.0373 mole) in acetonitrile(62 ml) and DMF(0.1 ml) was cooled to 0-5°C and oxalyl chloride (4.73g,0.0373 mole) was added over 20 min at 0-5°C. The resulting slurry was aged for lh at 0-5°C.

A slurry of 2-(l-amino-l-methylethyl)-Af-[(4-fluorophenyl)methyl]-l,6-dihydro-5-[(2,2-dimethyl- propanoyl)oxy]-l-methyl-6-oxo-4-pyrimidine carboxamide (XVIIIa; lOg, 0.0247 mole) and acetonitrile (60 ml) was cooled to 15-20°C and JV-methylmorpholine (2.9g, 0.0287 mole) was added. The resulting slurry was added to the oxadiazole acid chloride at -5-0°C over 20 min and aged for lh at 0-5°C. After completion of the reaction, the reaction mass was quenched with aqueous potassium hydroxide (50 ml) and pH was adjusted to 5 with acetic acid and ethyl acetate (100 ml) was added to reaction mass. The reaction mixture was aged for 10-15 min at 25-30°C Separate the aqueous layer and extracted the aqueous layer with ethyl acetate(5Q ml) at 25-30°C.The combined organic layers were washed with DM water(50 ml), followed by brine (50 ml). The organic layer was concentrated at 40-50°C under reduced pressure to afford 7.2 g(67.66%) of JV-[[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-2-[ 1 -methyl-1 -[[(5-methyl-1,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl-6-oxo-4-pyrimidine carboxamide (XX).

Step 4:
Preparation of Ar-[(4-fluorophenyI)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-pyrimidine carboxamide (Raltegravir (I)).
A mixture of A^-[[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-1-[[(5-methyl-l,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl-6-oxo-4-pyrimidine carboxamide (XX; 6.0g,0.014mole), JV-methyl-2-Pyrrolidone(24ml), magnesiumhydroxide (2.04g, 0.035 mole), trimethyl sulfoxonium iodide (7.7g, 0.035 mole) and water (0.25 ml) was heated to 90-95°C over lh and maintained at 90-95°C for 6h. The mixture was cooled to 25-30°C and methanol (11 ml) was added .The resulting reaction mixture was aged for 10-15 min at 25-30°C. 5N HC1 (5 ml) was added over 10-15 min, followed by the addition of 2.4M aqueous sodium bisulfite solution (10 ml) at 25-30°C. The resulting reaction mixture was aged for lh at 25-30°C. Again 5N HC1 (2 ml) was added at 25-30°C, after that the product was extracted with ethyl acetate (3><50 ml). The combined organic layers were washed with water (2x25 ml) at 25-30°C.The Organic layer was concentrated at 40-50°C under reduced pressure to afford 3.8 g(61.3%) of A/-[(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 Ar-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-l-[[(phenyImethoxy)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide(XXI):
Methyl-2-( 1 -{[(benzyloxy)carbonyl]amino}-1 -methylethyl)-5,6-dihydroxypyrimidine-4-carboxylate (VI; lOOg; 0.277mole), 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) was added at 60°C. The slurry was cooled to 20°C, solid was filtered, 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 JV-[(4-fluorophenyl)methyl]-l ,6-dihydro-5-hydroxy-2-[1-methyl-l-[[(phenylmethoxy)carbonyl]-amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXI).

Step 2:
Preparation of 2-(l-amino-l-methylethyl)-iV-[(4-fluorophenyl) methyl]-l,6-dihydro-5-hydroxy-6-oxo-4-pyrimidine carboxamide (XVHIb):

A mixture of iV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]-6-oxo-4-pyrimidine carboxamide (XXI; 40g,0.088mole) methanesulfonic acid (8.8 g,0.0915 mole), water (9ml) and 10% Pd/c (4.0g, 50% wet) in methanol (320 ml) 15-20°C was hydrogenated at 5 kg/cm2 for 2h. After completion of reaction the resulting reaction mass was filtered through celite and washed with methanol (3><40 ml). The combined filtrate was partially concentrated at 35-40°C under reduced pressure. The resulting solution was cooled to 5-10°C and neutralized to pH -7.5 by 2.5 N sodium hydroxide solution (36 ml) at 5-10°C.The resulting slurry was aged for ~lh 30min at 5-10°C. The product was filtered and washed with methanol (2x20 ml, 0-5°C). The product was dried at 40-50°C under reduced pressure to afford 23.2 g(82.8%) of 2-( 1 -amino-1 -methylethyl)-JV-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-6-oxo-4-pyrimidine carboxamide (XVIIIb)

Step 3:
Preparation of iV-[(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-l-[[(5-methyl-l,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl]-6-axo-4-pyrimidine carboxamide
(XX):

A slurry of 5-methyl-l,3,4-oxadiazole-2-carboxylic acid potassium salt (10.4 g,0.0626 mole) in acetonitrile (100 ml) and dimethylformamide (0.1 ml) was cooled to -5-0°C and oxalyl chloride (7.9 g,0.0622 mole) was added in 10-20 min at -5-0°C. The slurry was aged for Ihat0-5°C.

A slurry of 2-(l -amino- l-methylethyl)-jV-[(4-fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-6-oxo-4-pyrimidine carboxamide (XVIIIb; 10.0 g,0.0312 mole) and acetonitrile(100 ml) was azeotropically dried under reduced pressure at 40-50°C to a moisture content of slurry <0.2%. The resulting slurry (~60 ml) was cooled to 20-25°C and jV-methylmorpholine (15.8 g, 0.156 mole) was added. The acetonitrile slurry of XVIIIb was added to the above oxadiazole acid chloride at -5-0°C over 20 min. The resulting slurry was aged for lh at 0-5°C. After completion of reaction, the reaction mass was quenched with water (70 ml) and solution stirred for 10 min at 0-5°C. The reaction mass was acidified to pH 4.6 with 2N HC1, followed by addition of ethyl acetate (100 ml).Then the reaction mixture was warmed to 25-30°C and aged for 10-15 min. The aqueous layer was filtered and extracted the product with ethyl acetate (50 ml) at 25-30°C. The combined organic layers were washed with DM Water (50 ml), followed by brine (50 ml). The organic layer was concentrated at 40-45°C under reduced pressure to afford 10.7 g(80%) of JV-[(4-fluoropheny l)methyl]-1,6-dihydro-5-hydroxy-2-[ 1 -methyl-1 -[[(5-methy 1-1,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl-6-oxo-4-pyrimidine carboxamide (XX).

Step 4:
Preparation of N-[(4-fluorophenyI)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-pyrimidine carboxamide(Raltegravir (I)):
A mixture of A4(4-fluorophenyl)methyl]-l,6-dihydro-5-hydroxy-2-[l-methyl-1 -[[(5-methyl-l,3,4-oxadiazole-2-yl)carbonyl]amino]ethyl-6-oxo-4-pyrimidinecarboxamide (XX; 6.0g,0.014 mole), jV-methyl-2-pyrrolidone (24ml), magnesium hydroxide (2.04g,0.035 mole), trimethyl sulfoxonium iodide(7.7g,0.035 mole) and water (0.25 ml) was heated to 90-95°C over lh and maintained at 90-95°C for 6h.The mixture was cooled to 25-30°C and methanol (11 ml) added .The resulting reaction mixture was aged for 10-15 min at 25-30°C.5N HC1 (5 ml) was added over 10-15 min, followed by the addition of 2.4M aqueous sodium bisulfite solution(10 ml) at 25-30°C.The resulting reaction mixture was aged for lh at 25-30°C. Again 5N HC1 (2 ml) was added at 25-30°C, after that the product was extracted with ethyl acetate(3><50 ml).The combined organic layers were washed with water (2x25 ml) at 25-30°C. The Organic layer was concentrated at 40-50°C under reduced pressure to afford 3.8 g(61.3%) of A4(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))

WE CLAIM

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

(i) hydrogenating a compound of Formula (XVII);
wherein, P represents hydrogen;
to produce a compound of Formula (XVIII),

or its reactive derivative to produce a compound of Formula (XIX),

(iii) methylating the compound of Formula (XIX) 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 1, wherein the methylation step (iii) is carried out in the presence of a methylating agent and a base in a solvent.

6. The process according to claim 4, wherein the methylating agent is methyl halide, dimethyl sulfate, trimethyl silyldiazomethane, dimethyl sulfoxide (DMSO) and/or mixture thereof.

7. The process according to claim 4, wherein the base is hydride, hydroxide or oxides of metals.

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

(i) hydrogenating a compound of Formula (XVII);
wherein, P represents hydroxyl protecting group; to produce a compound of Formula (XVIII),

(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 produce a compound of formula (XX);
(iv) methylating the compound of Formula (XX) to produce Raltegravir (I).

9. The process according to claim 8, wherein hydroxyl protecting group comprises
pivaloyloxy group and carboxybenzyl (Cbz), tertiary butyloxy, allyloxy,

Methoxymethyloxy, Tetrahydropyranyl oxy, tertiary-butyldimethylsilyloxy,
tertiary-butyldiphenylsilyl oxy, acetyloxy, benzoyloxy.

10. The process according to claim 1, wherein hydrolysis is carried out in the presence
of a suitable base in a suitable solvent.