Claims:1. An improved process for the preparation of Raltegravir or a pharmaceutically acceptable salt thereof comprises:
(i)hydrogenating a compoundof Formula (IX)

in the presence of amine to produce a compound of Formula (XVII);

wherein R is hydrogen, alkyl or substituted alkyl.
(ii) acetylating the compound of Formula (XVII) with a compound of Formula (XVIII),

or its reactive derivative or its salt to produce Raltegravir or a pharmaceutically acceptable salt thereof.
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 (PtO2), Raney nickel, Chlorotris(triphenylphosphine)Rhodium [RhCl(PPh3)3] and/or mixture thereof.
4. The process according to claim 1, wherein the amineof step (i) is ammonia, triethylamine, diisopropylamine, diisopropyl ethylamine, dicyclohexylamine, cyclohexylamine, tertiary butylamine, n-butylamine, tris, meglumine.
5. The process according to claim 1, wherein the acetylation step (ii) is carried out in the presence of a base in a solvent.
6. 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
7. A process for the preparation of intermediate of formula XVII:

wherein R is hydrogen, alkyl or substituted alkyl;
which comprises:

(i) hydrogenating a compound of Formula (IX):

in the presence of amine to produce a compound of Formula (XVII).

8. The process according to claim 7, wherein the hydrogenation step (i) is carried out in the presence of a hydrogenation catalyst in a solvent.
9. The process according to claim 8, wherein the hydrogenation catalyst is Palladium on Carbon (Pd/C), Palladium hydroxide on Carbon (Pd(OH)2/C), Platinum dioxide (PtO2), Raney nickel, Chlorotris(triphenylphosphine)Rhodium [RhCl(PPh3)3] and/or mixture thereof.
10. The process according to claim 7, wherein the amineof step (i) is ammonia, triethylamine, diisopropylamine, diisopropyl ethylamine, dicyclohexylamine, cyclohexylamine, tertiary butylamine, n-butylamine, tris, meglumine.
11. A compound of formula XVII:

wherein R is hydrogen, alkyl or substituted alkyl;
, Description:Technical field of invention:

The present invention relates to an improved process for the preparation of Raltegravir or a pharmaceutically acceptable salt thereof;and a novel intermediate thereof.

Background of the invention:

Raltegravir potassium is chemically known as potassium N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide. Raltegravir potassium is a potent HL1 integrase inhibitor which is used for treatment of HL1 infections, AIDS, and Aids Related Complex (ARC). Raltegravir potassium salt marketed under the trade name of 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 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 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 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 below:

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 in the presence of N-methylmorpholine (NMM) in tetrahydrofuran (THF) to produce Raltegravir (I).

The process is as shown below:

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 N-[(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 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 below:

The major disadvantage with the above processes involves additional protection and de-protection steps for the preparation of Raltegravir. In the chemical synthesis of a product, a largenumber of steps is not advisable for the commercialization of the product. More steps in a chemical process means the lowering of the overall yield and the time cycle of the production is more. This makes the chemical processless suitable.
Also, attempted hydrogenation of (IX) using the previously employed conditions (Pd/C, MSA, MeOH) was complicated due to the insolubility of the methanesulfonic acid salt of the amine (X) in the reaction medium, making catalyst filtration impossible.
There is always a need for alternative preparative routes, which for example, use reagents, solvents that are less expensive, and/or easier to handle, consume smaller amounts of reagents and solvents, 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.

Summary of the invention:

In one aspect the present invention provides an improved process for the preparation of Raltegravir or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides a novel intermediate of formula XVII.

Still in another aspect the present invention provides a process for the preparation of intermediate of formula XVII.

Description of the invention:

The term “pharmaceutically acceptable salt” refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. When the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
In one embodiment of the invention, the present invention provides an improved process for the preparation of Raltegravir or a pharmaceutically acceptable salt thereof. The process comprises:

(i) hydrogenating a compound of Formula (IX)

in the presence of amine to produce a compound of Formula (XVII);

wherein Ris hydrogen, alkyl or substituted alkyl;
(ii) acetylating the compound of Formula (XVII) with a compound of Formula(XVIII),

or its reactive derivative or its salt to produce Raltegravir or a pharmaceutically acceptable saltthereof.

The hydrogenation catalyst used in the hydrogenation step is Palladium on Carbon (Pd/C), Palladium hydroxide on Carbon (Pd(OH)2/C), Platinum dioxide (PtO2), Raney nickel, Chlorotris(triphenylphosphine)Rhodium [RhCl(PPh3)3] or the like.

The amine used in the hydrogenation step is ammonia, triethylamine, diisopropylamine, diisopropyl ethylamine, dicyclohexylamine, cyclohexylamine, tertiary butylamine, n-butylamine, tris, meglumineor the like.

Exemplary solvents for step-(i) include, but are not limited to, water, alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters, amide solvents and the like, and mixtures thereof. Specific solvents are water, hydrocarbons, alcohols, chlorinated hydrocarbons, amide solventsand mixtures thereof. Exemplary alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol and mixtures thereof. Exemplary ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, and the like, and mixtures thereof. Exemplary cyclic ether solvents include, but are not limited to, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and the like, and mixtures thereof. Exemplary hydrocarbon solvents include, but are not limited to, n-pentane, n-hexane and n-heptane and isomers or mixtures thereof, cyclohexane, toluene, xyleneand mixtures thereof.Exemplary chlorinated hydrocarbon solvents include, but are not limited to, methylene chloride, ethyl dichloride, chloroform and carbon tetrachloride or mixtures thereof. Exemplary nitrile solvents include, but are not limited to, acetonitrile, and the like, and mixtures thereof. Exemplary ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and the like and mixtures thereof. Exemplary amide solvents include, but are not limited to, dimethylformamide, dimethylacetamide, and the like and mixtures thereof. Specific solvents are water, methanol, toluene, methylene chloride, tetrahydrofuran,2-methyl tetrahydrofuran, acetone, acetonitrile, dimethylformamide, and mixtures 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 (XVII) is filtered to remove the catalyst. The filtered cake is then washed with the solventas defined aboveto yield the compound (XVII), which is optionally isolatedas a solid.

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, N-methylmorpholine and/or mixture thereof.

Exemplary solvents for acetylation step-(ii) include, but are not limited to, water, alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters, amide solvents and the like, and mixtures thereof. Specific solvents are water, hydrocarbons, alcohols, chlorinated hydrocarbons, amide solventsand mixtures thereof. Exemplary alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol and mixtures thereof. Exemplary ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, and the like, and mixtures thereof. Exemplary cyclic ether solvents include, but are not limited to, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and the like, and mixtures thereof. Exemplary hydrocarbon solvents include, but are not limited to, n-pentane, n-hexane and n-heptane and isomers or mixtures thereof, cyclohexane, toluene, xyleneand mixtures thereof.Exemplary chlorinated hydrocarbon solvents include, but are not limited to, methylene chloride, ethyl dichloride, chloroform and carbon tetrachloride or mixtures thereof. Exemplary nitrile solvents include, but are not limited to, acetonitrile, and the like, and mixtures thereof. Exemplary ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and the like and mixtures thereof. Exemplary amide solvents include, but are not limited to, dimethylformamide, dimethylacetamide, and the like and mixtures thereof. Specific solvents are water, methanol, toluene, methylene chloride, tetrahydrofuran,2-methyl tetrahydrofuran, acetone, acetonitrile, dimethylformamide, and mixtures thereof.

Acetylation step is carried out at a temperature of about 0°C to about 50°C. After completion of acetylation reaction, Raltegravir or a pharmaceutically acceptable salt thereofis isolated from the reaction mass by conventional methods.

In another embodiment, the invention provides present invention provides a novel intermediate of formula XVII.

wherein R is hydrogen, alkyl or substituted alkyl.
Still in another embodiment, the invention provides present invention providesa process for the preparation of intermediate of formula XVII. The process comprises:

(i) hydrogenating a compound of Formula (IX)

in the presence of amine to produce a compound of Formula (XVII);

The hydrogenation catalyst used in the hydrogenation step is Palladium on Carbon (Pd/C), Palladium hydroxide on Carbon (Pd(OH)2/C), Platinum dioxide (PtO2), Raney nickel, Chlorotris(triphenylphosphine)Rhodium [RhCl(PPh3)3] or the like.

The amine used in the hydrogenation step is ammonia, triethylamine, diisopropylamine, diisopropyl ethylamine, dicyclohexylamine, cyclohexylamine, tertiary butylamine, n-butylamine, tris, meglumineor the like.

Exemplary solvents for step-(i) include, but are not limited to, water, alcohols, ketones, cyclic ethers, aliphatic ethers, hydrocarbons, chlorinated hydrocarbons, nitriles, esters, amide solvents and the like, and mixtures thereof. Specific solvents are water, hydrocarbons, alcohols, chlorinated hydrocarbons, amide solventsand mixtures thereof. Exemplary alcohol solvents include, but are not limited to, methanol, ethanol, isopropanol and mixtures thereof. Exemplary ketone solvents include, but are not limited to, acetone, methyl isobutyl ketone, and the like, and mixtures thereof. Exemplary cyclic ether solvents include, but are not limited to, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and the like, and mixtures thereof. Exemplary hydrocarbon solvents include, but are not limited to, n-pentane, n-hexane and n-heptane and isomers or mixtures thereof, cyclohexane, toluene, xyleneand mixtures thereof.Exemplary chlorinated hydrocarbon solvents include, but are not limited to, methylene chloride, ethyl dichloride, chloroform and carbon tetrachloride or mixtures thereof. Exemplary nitrile solvents include, but are not limited to, acetonitrile, and the like, and mixtures thereof. Exemplary ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, and the like and mixtures thereof. Exemplary amide solvents include, but are not limited to, dimethylformamide, dimethylacetamide, and the like and mixtures thereof. Specific solvents are water, methanol, toluene, methylene chloride, tetrahydrofuran,2-methyl tetrahydrofuran, acetone, acetonitrile, dimethylformamide, and mixtures 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 about 100°C.

The compound of Formula (IX) used in the present invention can be prepared according to the methods disclosed in prior art.

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.
Examples:
Example 1:

Preparation of 2-(l -amino-1 -methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-l,6-dihydropyrimidine-4-carboxamide tertiary butyl amine salt (XVII):

To the suspension 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(IX) in methanol (1500 ml) was added tertiary butyl amine(200 ml) drop wise and stirred it. Resulted reaction mass was hydrogenated using 10 % Pd-C(7.5g, 50% w/w wet) under 5kg/cm2hydrogen gas pressure. After completion of reaction,the reaction mass was filtered through celite bed, filtrate was concentrated under vacuum, stripped out with 400ml of methanol. Filtered the reaction mass and washed with400 ml of dichloromethane. The product was dried to get 65 g of compound of formula XVII.

Example 2:
Preparation of N-(2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (I):

Compound (XVII) (65 g) was suspended in dichloromethane (455 ml), triethyl amine (41.4 g) at 20-25°C and cooled to 10°C.
In another vessel, A slurry of 5-methyl-l,3,4-oxadiazole-2- carboxylic acid potassium salt (67.84 g) in dichloromethane (650 ml) and DMF (3.9 ml) was cooled to 0°C. Oxalyl chloride (44.8 g) was added at 0 to 5°C slowly and stirred. This slurry was added to above reaction mass of compound (XVII) drop wise at 10-15°C and stirred. After complete consumption of starting, water was added to reaction mass,stirred, separated the layer. Concentrated organic layer on rotavapour. The product was dried to give 52.4 g of N-(2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (I).

Example 3:
Preparation of Raltegravir potassium salt:

50 g of N-(2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide was dissolved in 800 ml of acetone. To the above solution, solution of potassium hydroxide (6.62g) in water (50 ml) was added at 0-5°C stirred for 1-2 hoursand filtered.The product was dried under vacuum to give 45.3 g of Raltegravir potassium salt.