The present invention relates to an improved process for the preparation of N-[(4-fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxa diazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt compound of formula-1a, which is represented by the following structural formula:
Background of the Invention:
Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective HIV integrase inhibitor is N-[(4-Fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide, also known as raltegravir and its pharmaceutically acceptable salts such as raltegravir potassium. Raltegravir potassium is approved in USA and marketed under the brand name of Isentres. Raltegravir is represented by the following structural formula-1.
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 and its pharmaceutically acceptable salts were firstly described in US7169780 herein after referred as US’780. The said patent also describes its process for the preparation.
US7754731 patent describes crystalline form-I, II and III of N-[(4-Fluorophenyl)methyl] -1,6-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 monopotassium salt.
However there is need for an alternative preparative routs which for example, use reagents that are less expensive and easier to handle, consume smaller amount of reagents, provide a high yield of product, involve fewer steps, have smaller and / or more eco-friendly waste products, to provide a product of higher purity and quantity.
The present inventors developed a modified synthesis process for the preparation of the compound of formula-1 and its pharmaceutically acceptable salts over the existing processes.
Brief Description:
The first aspect of the present invention is to provide an improved process for the preparation of N-[(4-Fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide compound of formula-1 or its pharmaceutically acceptable salts.
The second aspect of the present invention is to provide an improved process for the preparation of the compound of formula-9.
The third aspect of the present invention is to provide an improved process for the preparation of amorphous form of the compound of formula-1a.
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to
“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-

methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane,
dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as
methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol,
2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-
ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or
organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like;
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
and organic bases like dimethylamine, diethylamine, diisopropyl amine,
diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; DBU, organo silicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
The term “pharmaceutically acceptable salts” refers to 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.
The term “acid” used in the present invention refers to inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic

acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid etc.; Lewis acids and like.
The term “coupling agent” used in the present invention is selected form N,N'-dicyclohexylcarbodiimide (DCC), N,N’-diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like; optionally in combination with 1-hydroxy-7-azatriazole (HOAt), 1-hydroxy benzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP).
The first aspect of the present invention provides an improved process for the preparation of N-[(4-Fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide the compound of formula-1
comprising of: a) methylating the 2-cyanoacetamide compound of formula-2

with a suitable methylating agent in a suitable solvent optionally in presence of a base provides the 2-cyano-2-methylpropanamide compound of formula-3
b) reacting the compound of formula-3 with hydroxyl amine hydrochloride in a suitable
solvent provides the (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide
compound of formula-4
c) treating the compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in a suitable solvent provides the compound of formula-5
d) methylating the compound of formula-5 with a suitable methylating agent in a suitable solvent optionally in presence of base provides the compound of formula-6
e) reacting the compound of formula-6 with 4-fluorobenzylamine compound of formula-7 in presence or absence of coupling agent in a suitable solvent optionally in presence of a base provides the compound of formula-8

f) subjecting the compound of formula-8 to Hoffman’s degradation provides the compound of formula-9
g) reacting the compound of formula-9 with the compound of formula-10 or its derivative
Wherein M is H, Na, K or Li etc..
in presence or absence of a coupling agent in the suitable solvent optionally in presence
of a base provides the compound of formula-1, h) optionally purifying the compound of formula-1 in the suitable solvent, i) optionally converting the obtained compound in step-g) or step-h) into its
pharmaceutically acceptable salts.
Wherein, in step-a) to i) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof;
in step-a) and step-d) the suitable methylating agent is selected from bromomethane,
chloromethane, methyl iodide, diazomethane, 2,2-Dimethoxypropane, dimethyl carbonate,
dimethyl dicarbonate, dimethyl sulfate, 1,2-Dimethylhydrazine, dimethylzinc, methyl
fluorosulfonate, methyl methanesulfonate, methyl trifluoromethansulfonate,
methylcobalamin, S-adenosylmethionine synthetase enzyme, trimethyloxonium
tetrafluoroborate, trimethyl sulphonium iodide and optionally in presence of phase transfer catalyst;
in steps-a), d), e) and g) the suitable base is selected from organic or inorganic base; in step-e) and step-g) the suitable coupling agent is selected form DCC, DIC, CDI, EDC.HCl, O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenyl

phosphoroazidate (DPPA), thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like; optionally in combination with HOAt, HOBt, HOCt, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), DMAP; optionally in presence of a base;
in step-f) the term “Hoffmann’s degradation” also known as Hofmann rearrangement is the reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide) aqueous medium, which converts the amide to a primary amine.
Preferred embodiment of the present invention provides an improved process for the
preparation of N-[(4-fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-
[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-pyrimidinecarbox amide
compound of formula-1 comprising of:
a) reacting the 2-cyanoacetamide compound of formula-2 with dimethylsulfate in presence of potassium carbonate and Tetrabutyl ammonium bromide in acetone to provides 2-cyano-2-methylpropanamide compound of formula-3,
b) reacting the 2-cyano-2-methylpropanamide compound of formula-3 with hydroxylamine hydrochloride in presence of potassium hydroxide in methanol to provides (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide compound of formula-4,
c) treating the compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in methanol provides methyl-2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-5,
d) methylating the compound of formula-5 with trimethylsulfoxonium iodide in presence of calcium hydroxide in N-methylprrolidone provides methyl-2-(1-amino-2-methyl-1-oxo propan-2-yl)-5-hydroxy-1 -methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-6,
e) reacting the compound of formula-6 with 4-fluorobenzylamine compound of formula-7 in presence of triethylamine in methanol to provides 2-(1-amino-2-methyl-1-oxopropan-2-yl)-

N-4-fluorobenzyl-5-hydroxy-1-methyl-6-oxo-1,6-dihydopyrimidine-4-carboxamide compound of formula-8,
f) subjecting the compound of formula-8 with sodium hydroxide and bromine in water and tetrahydrofuran provides 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide compound of formula-9,
g) reacting the compound of formula-9 with 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride compound of formula-10a in presence of triethylamine in dichloromethane to provides the compound of formula-1,
h) purifying the compound obtained in step-g) using methanol provides pure compound of
formula-1.
Another embodiment of the present invention is provides an improved process for the
preparation of 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride compound of formula-10a
comprising of; reacting of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid compound of
formula 10 with oxalylchloride in presence of dimetylformamide in dichloromethane provides 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride compound of formula-10a.
The second aspect of the present invention provides an improved process for the preparation of the compound of formula-9, comprising of:
a) methylating the 2-cyanoacetamide compound of formula-2 with a suitable methylating agent in a suitable solvent optionally in presence of a base provides the 2-cyano-2-methylpropanamide compound of formula-3,
b) reacting the compound of formula-3 with hydroxyl amine hydrochloride in a suitable base, solvent to provides (Z)-3-amino-3-(hydroxyimino)-2,2-dimethyl propanamide compound of formula-4,
c) treating the compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in a suitable solvent provides the compound of formula-5,
d) methylating the compound of formula-5 with a suitable methylating agent in a suitable solvent optionally in presence of base provides the compound of formula-6,
e) reacting the compound of formula-6 with 4-fluorobenzylamine compound of formula-7 in presence or absence of coupling agent in a suitable solvent optionally in presence of a base provides the compound of formula-8,

f) subjecting the compound of formula-8 to Hoffman’s degradation provides the compound
of formula-9.
Wherein, in step-a) to f) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof;
in step-a) and step-d) the suitable methylating agent is selected from bromomethane,
chloromethane, methyl iodide, diazomethane, 2,2-Dimethoxypropane, dimethyl carbonate,
dimethyl dicarbonate, dimethyl sulfate, 1,2-Dimethylhydrazine, dimethylzinc, methyl
fluorosulfonate, methyl methanesulfonate, methyl trifluoromethansulfonate,
methylcobalamin, S-adenosylmethionine synthetase enzyme, trimethyloxonium
tetrafluoroborate, trimethyl sulphonium iodide and optionally in presence of phase transfer catalyst;
in steps-a), d) and e) the suitable base is selected from organic or inorganic base;
in step-e) the suitable coupling agent is same as defined in the first aspect of the present invention;
in step-f) the term “Hoffmann’s degradation” also known as Hofmann rearrangement is the reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide) aqueous medium, which converts the amide to a primary amine.
Preferred embodiment of the present invention provides an improved process for the preparation of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihy dropyrimidine-4-carboxamide compound of formula-9: comprising of:
a) reacting the 2-cyanoacetamide compound of formula-2 with dimethylsulfate in presence of postassium carbonate and tetrabutyl ammonium bromide in acetone to provides 2-cyano-2-methylpropanamide compound of formula-3,
b) reacting the 2-cyano-2-methylpropanamide compound of formula-3 with hydroxylamine hydrochloride in presence of potassium hydroxide in methanol to provides (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide compound of formula-4,

c) treating the compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in methanol to provides methyl-2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-5,
d) methylating the compound of formula-5 with trimethylsulfoxonium iodide in presence of calcium hydroxide in N-methyl-2-pyrrolidone (NMP) to provides methyl-2-(1-amino-2-methyl-1-oxo propan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-6,

e) reacting the compound of formula-6 with 4-fluorobenzylamine compound of formula-7 in presence of triethylamine in methanol to provides 2-(1-amino-2-methyl-1-oxopropan-2-yl)-N-4-fluorobenzyl-5-hydroxy-1-methyl-6-oxo-1,6-dihydopyrimidine-4-carboxamide compound of formula-8,
f) subjecting the compound of formula-8 with sodium hydroxide, bromine in water and tetrahydrofuran provides 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide compound of formula-9.
The third aspect of the present invention is provides an improved process for the preparation of amorphous form of N-[(4-fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4-pyrimi dinecarboxamide monopotassium salt compound of formula-1a comprising of:
a) reacting the compound of formula-9 with the compound of formula-10 or its derivative in
presence or absence of coupling agent in the suitable solvent optionally in presence of a base
provides the compound of formula-1,
b) optionally purifying the compound obtained in step-a) using the suitable solvent to get
pure compound of formula-1,
c) treating the compound of formula-1 potassium source in a suitable solvent,
d) filtering the reaction mixture,
e) concentrating the filtrate obtained in step-d),
f) isolating amorphous compound of formula-1a by adding hydrocarbon solvent to the
compound obtained in step-e).

Wherein, in step-a) to b) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof;
in step-c) the suitable potassium source selected form potassium bases comprises potassium hydroxide, potassium carbonate, potassium bicarbonate, or potassium alkoxide. The term “potassium alkoxide” refers to a potassium salt of an alkyl alcohol. The potassium alkoxide is suitably the salt of a C1-6 alkyl alcohol (i.e., KOR where R is C1-6 alkyl), and is typically the salt of a C1-4alkyl alcohol. Suitable potassium alkoxides include, for example, potassium methoxide, potassium ethoxide, potassium propoxide, and potassium isopropoxide.. in step-f) hydrocarbon solvents is selected from n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like or mixture thereof.
The preferred embodiment of the present invention provides an improved process for the preparation of amorphous form of the compound of formula-1a comprising of:
a) reacting the 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide compound of formula-9 with 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride compound of formula-10a in presence of triethylamine in dichloromethane provides N-[(4-Fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxa diazol-2-yl) carbonyl] amino] ethyl] -6-oxo-4-pyrimi dinecarboxamide compound of formula-1,
b) purifying the compound obtained in step-a) in methanol provides the compound of formula-1,
c) treating the compound of formula-1 with aqueous potassium hydroxide in water,
d) filtering the reaction mixture,
e) concentrating the filtrate obtained in step-d),
f) isolating amorphous compound of formula-1a by adding heptane to the compound obtained in step-e).
The compound of the formula-1 or its pharmaceutically acceptable salts produced by the present invention can be further micronized or milled using conventional techniques to get the desired particle size. Techniques that may be used for particle size reduction include,

but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may
be performed before drying, or after the completion of drying of the product.
The process of the present invention can be represented schematically as follows:
n
Further aspect of the present invention provides an improved process for the preparation of the compound of formula-1a as described in the below scheme:

Process for the preparation of methyl 2-(2-(((benzyloxy) carbonyl) amino) propan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-11 proceeds through the disclosed process in US 7169780B2 and US 7754731B2.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:
Example-1: Preparation of 2-Cyano-2-methylpropanamide (Formula-3):
Potassium carbonate (207 gm) and tetrabutylammoniumbromide (9.5 gm) were added to a solution of 2-cyanoacetamide (25 gm) in acetone (500 ml) at 25-30°C. The reaction mixture was cooled to 0-5° C and dimethylsulfate (83.43 gm) was slowly added to the reaction mixture. Raised the temperature of the reaction mixture to 25-30°C and stirred for 9 hours at the same temperature. The resulting mixture was distilled off completely under reduced pressure, the obtained residue was cooled and diluted with water and ethyl acetate. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and dried over sodium sulphate. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 31.6 gm
Example-2: Preparation of (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide (Formula-4):
A solution of potassium hydroxide (18.72 gm) in methanol (60 ml) was added to a mixture of hydroxylamine hydrochloride (23.24 gm) and methanol (60 ml) and stirred for 20 minutes. The obtained unwanted solid was filtered and washed with methanol. A solution of 2-cyano-2-methylpropanamide (30 gm) in methanol (60 ml) was added to the above filtrate and heated the reaction mixture at 40-45°C for 12 hours. The reaction mixture was distilled off completely under reduced pressure. To the obtained residue, water (15 ml) was added and stirred for 1 hour at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 15.0 gm.
Example-3: Preparation of methyl 2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (Formula-5):
Dimethylacetylenedicarboxylate (36.66 gm) was slowly added to a solution of (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide (35 gm) in methanol (122.5 ml) at 10-15°C. Heated the reaction mixture to 60-65°C and stirred for 8 hours at the same temperature. Distilled off the reaction mixture under reduced pressure and ortho-xylene (87.5 ml) was added to the obtained residue. Heated the reaction mixture to 130-140°C and stirred for 13 hours. Distilled off the solvent completely from the reaction mixture under reduced pressure. The obtained residue was cooled and diluted with water and dichloromethane. Both the

organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and dried over sodium sulphate. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 16.80 gm.
Example-4: Preparation of methyl 2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (Formula-6):
To a suspension of methyl 2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydro pyrimidine-4-carboxylate (48 gm) in N-methyl-2-pyrrolidone (120 ml) was added trimethylsulfoxonium iodide (43 gm) at 25-30°C. To the above reaction mixture calcium hydroxide (14.47 gm) in water (1.5 ml) was added at 25-30°C. Heated the reaction mixture to 105-110°C and stirred for 11 hours. The reaction mixture was cooled to 25-30°C, added 2N HCl (300 ml) solution, followed by water (600 ml) and dichloromethane (300 ml) and stirred for 30 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers, dried over sodium sulphate and distilled off the solvent completely to get the tile compound. Yield: 32.60 gm.
Example-5: Preparation of 2-(1-amino-2-methyl-1-oxopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Formula-8):
4-Fluorobenzylamine (40.8 gm) and triethylamine (22.54 gm) were added to a solution of
methyl 2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro
pyrimidine-4-carboxylate (50 gm) in methanol (100 ml) at 25-30°C. Heated the reaction mixture to 60-70°C and stirred for 7 hours at the same temperature. Cooled the reaction mixture to 50-55°C, added a solution of acetic acid (22.28 gm) in water (100 ml) and stirred for 30 minutes at same temperature. Further cooled the reaction mixture to room temperature, added dichloromethane and stirred for 30 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers, dried over sodium sulphate and distilled off the solvent from the organic layer to get the title compound. Yield: 34.0 gm.
Example-6: Preparation of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl - 6-oxo-1,6-dihydropyrimidine-4-carboxamide (Formula-9):
Bromine (1 ml) was added drop wise to a mixture of 2-(2-aminopropan-2-yl)-N-(4-fluoro benzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (15 gm), sodium

hydroxide (6.6 gm), tetrahydrofuran (100 ml) and water (100 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 7 hours at the same temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and distilled off completely to get the title compound. Yield: 7.5 gm
Example-7: Preparation of the compound of formula-1:
To a suspension of 5-methyl-1,3,4-oxadiazole -2-carboxylic acid (25 gm) and dimethyl formamide (0.5 ml) in dichloromethane (350 ml) was added oxalyl chloride (28 gm) at 5-10°C and the resulting solution was refluxed for 2 hours. Distilled off the solvent completely form the reaction mixture to get acid chloride compound as residue. A solution of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (50 gm) and triethylamine (27.5 gm) in dichloromethane (450 ml) was added to the above residue at 10-15°C and stirred for 12 hours at room temperature. The reaction mixture was diluted with water, dichloromethane and stirred for 20 minutes. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers, dried over sodium sulphate and distilled off the solvent to get the title compound. Yield: 28 gm.
Example-8: Preparation of the compound of formula-1a:
A mixture of the compound of formula-1 (10 gm) and potassium hydroxide (1.3 gm) in water (200 ml) was stirred at 25-30°C for 1 hour. Filtered the reaction mixture and distilled off the solvent from the filtrate under reduced pressure and co-distilled with heptane. Heptane (170 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour at same temperature. Filtered the solid, washed with n-heptane and dried to the title compound. Yield: 8.20 gm.
Example-9: Preparation of benzyl (2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)carbamate (Formula-12)
32.8 gm of triethylamine was added to the mixture of methyl 2-(2-(((benzyloxy) carbonyl) amino) propan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (100 gm) and methanol (200 ml) at 25-30°C. 4-fluorobenzylamine (40.8 gm) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred the

reaction mixture for 7 hours at the same temperature. Dilute acetic acid (32.6 gm glacial acetic acid in 170 ml of water) was added to the reaction mixture at 55-60°C and cooled the reaction mixture to 25-30°C. Stirred the reaction mixture for 1 hour at same temperature. Filtered the precipitated solid, washed with the mixture of methanol and water and dried to get the title compound. Yield: 122 gm.
Example-10:Preparation of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (Formula-9):
A mixture of the compound of formula-12 (50 gm), methanol (500 ml), methane sulphonic acid (10.24 gm) and 2 gm of palladium on carbon taken into autoclave vessel at 25-30°C. Cooled the reaction to 10-15°C and applied hydrogen pressure to the reaction mixture at the same temperature. Reaction mixture was filtered through high flow bed and washed with methanol. Distilled off 40% of the solvent from the filtrate, cooled to 0-5°C and neutralized the reaction mixture using aqueous sodium hydroxide solution at 0-5°C. Stirred the reaction mixture for 1 hour at same temperature. Filtered the precipitated solid, washed water and dried to get the title compound. Yield: 34.5 gm.
Example-11: Preparation of amorphous compound of formula-1a:
A mixture of potassium 5-methyl-1,3,4-oxadiazole-2-carboxylate (25 gm), dichloromethane (200 ml), dimethylformamide (1 gm) was stirred for 10 minutes at 25-30°C. Cooled the reaction mixture to 0-5°C and oxalyl chloride (20 gm) was slowly added to the reaction mixture at the same temperature and stirred the reaction mixture for 3 hours at 0-5°C to get acid chloride. Azeotrophically distilled the mixture of the compound of formula-9 (25 gm) and toluene (100 ml) at 110-115°C and collected water from the reaction mixture. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with dichloromethane. Cooled the obtained compound to 25-30°C and dichloromethane (50 ml) was added. Further cooled the reaction mixture to 0-5°C. Triethylamine (30.25 gm) followed by above obtained acid chloride was slowly added to this reaction mixture at 0-5°C. Stirred the reaction mixture for 5 hours at 0-5°C. Adding water to the reaction mixture and raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and the aqueous was extracted with dichloromethane. Combined the organic layers and basified the organic layer using aqueous potassium hydroxide solution.

Both the organic and aqueous layers were separated. Acidified the aqueous layer using dilute hydrochloric acid and extracted the compound with ethyl acetate. Organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methanol. Methanol (50 ml) was added to the obtained compound at 25-30°C and heated the reaction mixture to 60-65°C and stirred it for 45 minutes at the same temperature. Cooled to reaction mixture to 25-30°C and further cooled to 0-5°C. The reaction mixture was stirred for 45 minutes at 0-5°C. Filtered the precipitated solid and washed with methanol. To the obtained compound, 100 ml of water was added 25-30°C. Stirred the reaction mixture for 30-40 minutes at 25-30°C, filtered and washed with water. The obtained wet compound was added to the mixture of water (255 ml) and potassium hydroxide (2.14 gm) at 25-30°C and stirred the reaction mixture for 1 hour at the same temperature. Filtered the reaction mixture and distilled off the solvent from the filtrate under reduced pressure and co-distilled with heptane. Heptane (170 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour at same temperature. Filtered the solid, washed with n-heptane and dried to the title compound. Yield: 15 gm.
Example-12: Purification of the compound of formula-1:
Heating the mixture of the compound of formula-1 (5 gm) and methanol (30 ml) to 60-65°C and stirring the reaction mixture for 45 minutes. Cooled the reaction mixture to 25-30°C and further cooled to 10-15°C. The reaction mixture was stirred for 45 minutes at 0-5°C. Filtered the solid, washed with methanol and dried to get pure title compound. Yield: 4 gm.
Example-13: Purification of the compound of formula-1:
Heating the mixture of the compound of formula-1 (10 gm), acetonitrile (11 ml) and isopropanol (22 ml) to 80-85°C and stirring the reaction mixture for 45 minutes. Cooled the reaction mixture to 25-30°C and further cooled to 10-15°C. The reaction mixture was stirred for 45 minutes at 10-15°C. Filtered the solid, washed with isopropanol and dried to get pure title compound. Yield: 8 gm.

Claims:
1. A process for the preparation of N-[(4-fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl) carbonyl] amino] ethyl]-6-oxo-4-pyrimidinecarboxamide the compound of formula-1 and its pharmaceutically acceptable slats,
comprising of: a) methylating the 2-cyanoacetamide compound of formula-2
with a suitable methylating agent in a suitable solvent optionally in presence of a base provides the 2-cyano-2-methylpropanamide compound of formula-3
b) reacting the compound of formula-3 with hydroxyl amine hydrochloride in a suitable
solvent provides the (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide
compound of formula-4
c) treating the compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in a suitable solvent provides the compound of formula-5

d) methylating the compound of formula-5 with a suitable methylating agent in a suitable solvent optionally in presence of base provides the compound of formula-6
e) reacting the compound of formula-6 with 4-fluorobenzylamine compound of formula-7 in presence or absence of coupling agent in the suitable solvent optionally in presence of a base provides the compound of formula-8
f) subjecting the compound of formula-8 to Hoffman’s degradation provides the compound of formula-9
g) reacting the compound of formula-9 with the compound of formula-10 or its derivative
wherein M=H, Na, K or Li;
in presence or absence of a coupling agent in a suitable solvent optionally in presence of a base provides the compound of formula-1,
h) optionally purifying the compound of formula-1 in the suitable solvent,
i) optionally converting the obtained compound in step-g) or step-h) into its pharmaceutically acceptable salts.

2. The process according to claim-1, wherein, in step-a) to i) the suitable solvent is selected
from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro
solvents, ether solvents, polar aprotic solvents and polar solvent like water or their
mixture thereof;
in step-a) and step-d) the suitable methylating agent is selected from bromomethane, chloromethane, methyl iodide, diazomethane, 2,2-Dimethoxypropane, dimethyl carbonate, dimethyl dicarbonate, dimethyl sulfate, 1,2-Dimethylhydrazine, dimethylzinc, methyl fluorosulfonate, methyl methanesulfonate, methyl trifluoromethansulfonate, methylcobalamin, S-adenosylmethionine synthetase enzyme, trimethyloxonium tetrafluoroborate, trimethyl sulphonium iodide and optionally in presence of phase transfer catalyst; in steps-a), d), e) and g) the suitable base is selected from organic or inorganic base;
3. A process for the preparation of N-[(4-Fluorophenyl) methyl]-1,6-dihydro-5-hydroxy-1 -
methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-
-pyrimidinecarboxamide compound of formula-1 comprising of:
a) reacting the 2-cyanoacetamide compound of formula-2 with dimethyl sulfate in presence of potassium carbonate in acetone to provide 2-cyano-2-methylpropanamide compound of formula-3,
b) reacting the compound of formula-3 with hydroxylamine hydrochloride in presence of potassium hydroxide in methanol to provide (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide compound of formula-4,
c) treating the compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in methanol to provide methyl-2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-5,
d) methylating the compound of formula-5 with trimethylsulfoxonium iodide in presence of calcium hydroxide in N-methylprrolidone (NMP) to provide methyl-2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxylate compound of formula-6,

e) reacting the compound of formula-6 with 4-fluorobenzylamine compound of formula-7 in presence of triethylamine in methanol provides 2-(1-amino-2-methyl-1-oxopropan-2-yl)-N-4-fluorobenzyl-5-hydroxy-1-methyl-6-oxo-1,6-dihydopyrimidine-4-carboxamide compound of formula-8,
f) subjecting the compound of formula-8 with sodium hydroxide, bromine in water and tetrahydrofuran provides 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide compound of formula-9,
g) reacting the compound of formula-9 with 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride compound of formula-10a in presence of triethylamine in dichloromethane provides the compound of formula-1,
h) purifying the compound obtained in step-g) using methanol to provide pure compound of formula-1.
4. A process for the preparation of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide the compound of formula-9 comprising:
a) reacting the 2-cyanoacetamide compound of formula-2 with dimethylsulfate in presence of potassium carbonate in acetone to provide 2-cyano-2-methylpropanamide compound of formula-3,
b) reacting the 2-cyano-2-methylpropanamide compound of formula-3 with hydroxylamine hydrochloride in presence of potassium hydroxide in methanol to provide (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide compound of formula-4,
c) treating the compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in methanol to provide methyl-2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-5,
d) methylating the compound of formula-5 with trimethylsulfoxonium iodide in presence of calcium hydroxide in N-Methyl-2-pyrrolidone (NMP) to provide methyl-2-(1-amino-2-methyl-1-oxo propan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxylate compound of formula-6,

e) reacting the compound of formula-6 with 4-fluorobenzylamine compound of formula-7 in presence of triethylamine in methanol to provide 2-(1-amino-2-methyl-1-oxopropan-2-yl)-N-4-fluorobenzyl-5-hydroxy-1-methyl-6-oxo-1,6-dihydopyrimidine-4-carboxamide compound of formula-8,
f) subjecting the compound of formula-8 with sodium hydroxide, bromine in water and tetrahydrofuran to provide 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide compound of formula-9.
5. A process for the preparation of amorphous form of N-[(4-Fluorophenyl) methyl]-1,6-
dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]
amino]ethyl]-6-oxo-4-pyrimidinecarboxamide mono potassium salt compound of
formula-1a comprising of:
a) reacting the 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide compound of formula-9 with 5-methyl-1,3,4-oxadiazole-2-carbonyl chloride compound of formula-10a in presence of triethylamine in dichloromethane to provide N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl) carbonyl]amino]ethyl]-6-oxo-4-pyrimidinecarboxamide compound of formula-1,
b) purifying the compound obtained in step-a) in methanol to provide the compound of formula-1,
c) treating the compound of formula-1 with aqueous potassium hydroxide in water,
d) filtering the reaction mixture,
e) concentrating the filtrate obtained in step-d),
f) isolating amorphous compound of formula-1a by adding heptane to the compound
obtained in step-e).
6. A process for the preparation of (Z)-3-amino-3-(hydroxyimino)-2,2-dimethyl
propanamide compound of formula-4 comprising; reacting the 2-cyano-2-
methylpropanamide compound of formula-3 with hydroxylamine hydrochloride in
presence of a suitable base in a suitable solvent to provide (Z)-3-amino-3-

(hydroxyimino)-2,2-dimethylpropanamide compound of formula-4; wherein the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof and the suitable base is selected from organic or inorganic base.
7. A process for the preparation of methyl-2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-5 comprising; treating (Z)-3-amino-3-(hydroxyimino)-2,2-dimethylpropanamide compound of formula-4 with dimethyl acetylene dicarboxylate (DMADC) in a suitable solvent to provide methyl-2-(1-amino-2-methyl-1-oxopropan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-5; wherein the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof.
8. A process for the preparation of 2-(2-aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro pyrimidine-4-carboxamide compound of formula-9 comprising: subjecting the 2-(1-amino-2-methyl-1-oxopropan-2-yl)-N-4-fluorobenzyl-5-hydroxy-1-methyl-6-oxo-1,6-dihydopyrimidine-4-carboxamide compound of formula-8 to Hoffman’s degradation provides the compound of formula-9.
9. A process for the preparation of methyl-2-(1-amino-2-methyl-1-oxo propan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-6 comprising; methylating the compound of formula-5 with a suitable methylating agent in a suitable solvent optionally in presence of a base to provide provides methyl-2-(1-amino-2-methyl-1-oxo propan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate compound of formula-6.

10. The process according to claim 9, wherein the suitable methylating agent is selected
from bromomethane, chloromethane, methyl iodide, diazomethane, 2,2-
dimethoxypropane, dimethyl carbonate, dimethyl dicarbonate, dimethyl sulfate, 1,2-dimethylhydrazine, dimethylzinc, methyl fluorosulfonate, methyl methanesulfonate, methyl trifluoromethansulfonate, methylcobalamin, S-adenosylmethionine synthetase enzyme, trimethyloxonium tetrafluoroborate, trimethyl sulphonium iodide and optionally in presence of phase transfer catalyst; the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water or their mixture thereof; the base is selected from organic or inorganic base.