DESC:Field of the Invention:
The present invention relates to a process for the preparation of N-[(4-Fluoro phenyl)
methyl]-1,6-dihydro5-
hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)
carbonyl]amino]ethyl]-6-oxo-4pyrimidinecarboxamide
monopotassium salt compound of
5 formula-1a, which is represented by the following structural formula:
Formula-1a
Background of the Invention:
Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use
10 in the treatment of HIV infection for several years. A particularly effective HIV integrase
inhibitor is N-[(4-Fluorophenyl) methyl]-1,6-dihydro5-
hydroxy-1-methyl-2-[1-methyl-1-[[(5-
methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4pyrimidinecarboxamide,
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 Isentress.
15 Raltegravir is represented by the following structural formula-1.
Formaula-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
20 acceptable salts were firstly described in US7169780 herein after referred as US’780. The said
patent also describes process for the preparation of raltegravir.
The patent US7754731B2 describes crystalline form-I, II and III of N-[(4-Fluorophenyl)
methyl]-1,6-dihydro5-
hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)
25 carbonyl] amino]ethyl]-6-oxo-4pyrimidinecarboxamide
monopotassium salt.
3
The patent US8686141B2 and in the corresponding publication [Organic Process
Research & Development 2011, 15, 73-83] reported a process for the preparation of raltegravir potassium.
However, based on the prior art processes drawbacks, there is a need for providing an improved process for the preparation raltegravir, which involves simple experimental procedures, 5 well suited to industrial production, less expensive and easier to handle reagents, solvents, which avoids the use of column chromatography purification, and which affords high pure and quantity product.
The present invention is a process for the preparation of compound of formula-1 and its pharmaceutically acceptable salts over the existing processes. 10
Brief Description:
The first aspect of the present invention is to provide a process for the preparation of N-[(4-Fluorophenyl)methyl]-1,6-dihydro5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxa diazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4pyrimidinecarboxamide mono potassium salt 15 compound of formula-1a or its pharmaceutically acceptable salts.
The second aspect of the present invention is to provide a process for the preparation of compound of formula-6.
Detailed Description: 20
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 25 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; “chlorinated solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra 30
4
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-5 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 10 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 15 such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethyl amine, pyridine, 4-dimethylamino pyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; DBU, organo silicon bases such as lithium hexamethyl disilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide 20 (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 25 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'-dicyclo hexylcarbodiimide (DCC), N,N’-diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), 1-30 ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), O-(7-aza-benzo
5
triazole-1-yl)-N,N,N',N'-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloro
formates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA),
thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous penta
chloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidino
5 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'-tetramethyl
uronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide
(Sulfo-NHS), 4-dimethylaminopyridine (DMAP).
10
The first aspect of the present invention provides an improved process for the preparation
of N-[(4-Fluorophenyl) methyl]-1,6-dihydro5-
hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-
1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4pyrimidinecarboxamide
the compound of
formula-1a,
15
Formula-1a
20 comprising of:
a) reacting the compound of formula-2
Formula-2
with 4-fluorobenzylamine in suitable solvent, optionally in the presence of suitable base to
25 provide compound of formula-4,
6
Formula-4
b) N-methylating the compound of formula-5 4 with a suitable methylating agent in a suitable
solvent to provide compound of formula-5,
Formula-5
c) debenzylating the compound of formula-5 with suitable reagent, solvent to provide
10 compound of formula-6 ,
Formula-6
d) reacting the compound of formula-6 with the compound of formula-7 or its derivative
15 Formula-7
in presence or absence of a coupling agent in a suitable solvent optionally in presence of a
base provides the compound of formula-1,
e) optionally purifying the compound of formula-1 in the suitable solvent,
f) converting the compound obtained in step-d) or step-e) into its pharmaceutically acceptable
20 salts.
7
Wherein, in step-a) to f) the suitable solvent is selected from hydrocarbon solvents, ketone
solvents, nitrile solvents, ester solvents, alcohol solvents, chlorinated solvents, ether solvents,
polar aprotic solvents and polar solvent like water or their mixture thereof;
in step-a) the suitable base is selected from organic or inorganic base;
5 in step-b) the suitable methylating agent is selected from trimethyl sulphoxoniumiodide, bromo
methane, chloromethane, methyl iodide, diazomethane, 2,2-Dimethoxypropane, dimethyl
carbonate, dimethyl dicarbonate, dimethyl sulfate, 1,2-Dimethylhydrazine, dimethylzinc, methyl
fluoro sulfonate, methyl methanesulfonate, methyl trifluoromethansulfonate, trimethyloxonium
tetrafluoroborate, and optionally in presence of phase transfer catalyst; suitable reagents MgO,
10 Mg(OH)2, Ca (OH)2, CaO.
in step-c) the suitable reagents are inorganic base, organic base, Pd/C hydrogen gas and mixture
thereof.
in step-d) the suitable coupling agent is selected form DCC, DIC, CDI, EDC.HCl, O-(7-azabenzotriazole-
1-yl)-N,N,N',N'-tetramethyl uronium hexafluoro phosphate (HATU), optionally in
15 combination with HOAt, HOBt, HOCt, O-5 (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-
NHS), DMAP; optionally in presence of a organic base, inorganic base.
in step-e) the suitable potassium source selected form potassium bases comprises potassium
hydroxide, potassium carbonate, potassium bicarbonate, or potassium alkoxide. The term
20 “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 C1-4 alkyl alcohol. Suitable potassium alkoxides include, for example, potassium methoxide,
potassium ethoxide, potassium propoxide, and potassium isopropoxide.
The preferred embodiment of the present invention provides an improved process for
25 the preparation of N-[(4-Fluorophenyl) methyl]-1,6-dihydro5-
hydroxy-1-methyl-2-[1-methyl-1-
[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-4pyrimidinecarboxamide
the
compound of formula-1a,
Formula-1a
8
comprising of:
a)reacting the compound of formula-2
5 Formula-2
with 4-fluorobenzylamine in presence of triethylamine in methanol to provide compound of
formula-4,
10 Formula-4
b) N-methylating the compound of formula-4 with trimethyl sulphoxoniumiodide in presence of
magnesium oxide in N-methyl-2-pyrrolidone to provide compound of formula-5,
15
Formula-5
c)debenzylating the compound of formula-5 with sodium hydroxide, in n-butanol solvent to
provide compound of formula-6 ,
20 Formula-6
9
d)reacting the compound of formula-6 with the compound of formula-7a in presence of
oxalylchloride, triethylamine, in DMF to provide the compound of formula-1,
5 Formula-7a
e)treating the compound obtained in step-d) with KOH in acetone to give potassium salt of
raltegravir.
The other preferred aspect of the present invention is debenzylation of compound of
10 formula-5 using inroganic base in alcohol, water or mixture thereof; the suitable base is sodium
hydroxide, potassium hydroxide. The suitable solvent in methanol, ethanol, isopropanol, butanol;
suitable temperature is 10-150°C; optionally compound of formula-6 is isolated as acid addition
salt or hydrated. The suitable acids are HCl, HBr, TFA, acetic acid, phosphoric acid, sulphate
salt.
15 The other preferred aspect of the present invention is a process for preparation of
compound of formula-6
Formula-6
20
Comprising of
debenzylating the compound of formula-5 with a suitable base, solvent to provide compound of
formula-6 ,
25
10
Formula-5
Wherein in the suitable solvent is selected from chloro solvents, d 5 ioxane, polar aprotic solvents,
alcohol such as methanol, ethanol, isopropanol, butanol and water or any mixture thereof; the
suitable base is sodium hydroxide, potassium hydroxide or any mixture thereof. Suitable
temperature is 10-150°C;
The other embodiment of the present invention is a process for preparation of compound of
10 formula-6
Formula-6
15 comprising of
debenzylating the compound of formula-5 with sodium hydroxide in n-butanol to provide at
105-115°C to provide compound of formula-6,
20
Formula-5
The compound of formula-2 used in the present invention can be prepared any process
know in the art US7754731B2 and US 7169780 B2.
11
The process for the preparation of raltegravir, its salt developed by the present inventors
produces highly pure raltegravir and raltegravir potassium salt without nitroso amine
compounds with good yield. All the related substances and residual solvents are controlled well
within the limits as suggested by ICH guidelines and most of the related substances are
5 controlled in non-detectable levels.
The compound of formula-1 and 1a produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC
The compound of the formula-1 or its pharmaceutically acceptable salts produced by the
10 present invention can be further micronized or milled using conventional techniques to get the
desired particle size to achieve desired solubility profile based on different forms of
pharmaceutical composition requirements. 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.
15 The process of the present invention can be represented schematically as follows:
12
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.
5
Example-1: Preparation of benzyl 1--amino--1--(hydroxyimino)--2--methylpropan--2--yl carbamate
A round button flask was charged with 2--Hydroxy--2--methylpropanenitrile (100 g), toluene (200 mL) and stirred for 15 min. Cooled the reaction mixture to 5 ± 5°C, ammonia gas passed slowly about 2 hr and stirred for 24 hr at 20--25°C, maintained the PH value 11. The reaction mixture 10 was cooled to 5 ± 5°C, added benzylchloroformate (448 g) about 1 hr, followed by diisopropyl ethylamine (167 g) about 1 hr and stirred for 12 hr at 20--25°C. The reaction mixture was diluted with water (300 mL) and cooled to 5 ± 5°C, stirred for 1.5 hr. Filtered the obtained solid, washed with water (100 mL) to get the wet compound.
Another round button flask was charged with hydroxylamine hydrochloride (79.6 g), methanol 15 (400 mL) and slowly added a solution of sodium hydroxide (45.8 g in 400 mL of methanol), stirred for 20 min at 25--35°C. The above obtained wet compound was charged to the reaction mixture, heated to 60--65°C and stirred for 6 hr. The reaction mixture was evaporated completely, and cooled to 25--35°C added a mixture of methanol (25 mL ) and water (600 mL) and stirred for 1.5 hr. The obtained solid was filtered and washed with water (200 mL) and dried to get the title 20 compound.
Yield: 203.5 g
Example--2: Preparation of methyl--2--(2--(benzyloxycarbonylamino)propan--2--yl) --5--hydroxy -- 6--oxo--1,6--dihydropyrimidine--4--carboxylate.
A round bottom flask was charged with benzyl 1--amino--1--(hydroxyimino)--2--methylpropan--2--yl 25 carbamate (500 g), methanol (1000 mL) and stirred for 10 min. Cooled the reaction mixture to 5--15°C, added dimethyl acetylenedicarboxylate (305.5 g) and stirred for 2 hr at 25--35°C. The reaction mixture was distilled off completely, charged o--xylene (1250 mL) and heated to 130--140 °C stirred for 22 hr. Evaporated the solvent completely and cooled to 40--50°C, added methanol (1000 mL) and heated to 55--65°C stirred for 45 min. Cooled the reaction mixture to 15--25°C, 30 and stirred for 1.5 hr. Filtered the obtained solid and washed with methanol (500 mL), dried to get the title compound.
13
Yield: 313.8 g.
Example--3: Preparation of compound of formula--5
A round bottom flask was charged with compound of formula--2 (100 g), methanol (200 mL), stirred for 15 min. Triethylamine (42 g), compound of formula--3 (51.92 g) were charged simultaneously and heated to 55--65°C stirred for 10 hr. The reaction mixture was charged with 5 acetic acid solution (41.54 g in 34 ml of water) and water (130 mL) stirred for 1 hr at 55--65°C. Cooled the reaction mixture to 15--25°C, stirred for 1 hr, filtered the obtained solid and washed with methanol (50 mL) to get the wet compound of formula--4.
Another round bottom flask was charged with compound of formula--4, N--methyl--2--pyrrlidone (175 mL), trimethylsulfoxonium iodide (139.35 g) and magnesiumoxide (25.5 g) are heated to 10 100--110°C and stirred for 8 hr. Cooled the reaction mixture to 25--35°C, charged with methanol (217 mL) and diluted hydrochloric acid (67.5 mL in 67.5 mL of water) and stirred for 1 hr.
A solution of sodium metabisulphate (2.75 g in 6 mL) was added to the reaction mixture stirred for 2 hr, charged with dil. hydrochloric acid (67.5 mL in 67.5 mL of water), methanol solution (250 mL in 250 mL water ) and stirred for 2 hr at 25--35°C. Filtered the precipitate solid washed 15 with a mixture of methanol, water (50 mL: 50 mL) to obtained wet compound. The wet compound was stirred in methanol (300 mL) for 30 min at 55--65°C, filtered the obtained solid and washed with methanol (50 mL) and dried to get the title compound.
Yield: 108 g.
Example--4: Preparation of compound of formula--6 20
A round bottom flask was charged with compound of formula--5 (100 g), n--butanol (500 mL), stirred for 15 min. To the solution charged sodium hydroxide (32.44 g) and heated to 105--115°C stirred for 5 hr. Cooled the reaction mixture to 20--30°C, charged with water (700 mL) and adjusted the pH to 7.5 with hydrochloric acid solution stirred for 90 min. Filtered the obtained solid, washed with water (100 mL) to get the wet compound. The obtained wet compound was 25 suspended in toluene (300 mL) and heated to 105--115°C, collected the water (15 mL) by azeotropic distillation. Cooled the reaction mixture to 15--25°C, filtered the obtained solid and washed with toluene (50 mL) and dried to get the title compound.
Yield: 66 g.
Purity by HPLC: 99.2 % 30
Example--5: Preparation of compound of formula--6
14
An auto clave vessel was charged with compound of formula--5 (300 g), methanol (3000 mL), palladium carbon (18 g) and methane sulfonic acid (61.54 g), the solution was hydrogenated at 3 kg/ cm2 for about 1.5 hr at 25--35°C. The reaction mixture was filtered through hyflow bed, washed with methanol (300 mL). The filtrate solution diluted with water (450 mL) and cooled to 0--10°C, adjusted the pH to 7.5 with sodium hydroxide solution (30 g in 300 mL) stirred for 1.5 5 hr. Filtered the obtained solid and washed with water (300 mL) and dried to get the title compound.
Yield: 214 g.
Example--6: Preparation of compound of formula--1
A round bottom flask was charged with potassium 5--methyl--1,3,4--oxadiazole --2--carboxylic acid 10 (99.4 g), dichloromethane (500 ml) and dimethyl formamide (4 ml) stirred for 15 min. Cooled the reaction mixture to --5 to 5°C, added oxalyl chloride (80 g) and stirred for 4 hr.
In another round bottom flask charged with compound of formula--6 (100 g), dichloromethane (500 mL), triethylamine (121 g) and stirred for 15 min. The reaction mixture was cooled to --10 to 20°C, charged with the above reaction mixture and stirred for 3 hr. The reaction mixture was 15 quenched with water (400 mL) and separated both layers. The aqueous layer was extracted with dichloromethane (2 x 100 mL), the combined organic layer pH was adjusted to 11.0 using with potassium hydroxide (23.6 g in 472 mL of water) stirred for 1 hr. Again adjusted the solution pH to 1.5 with dil HCl (50 mL: 50 mL of water) and separated both layers, the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layer was washed with 5% 20 sodium bicarbonate solution (5 gr in 100 mL of water) and brine solution. The total combined organic layer was evaporated completely and co--distilled with a mixture of ethyl acetate, isopropanol (25 mL: 25 mL). The obtained compound was charged with ethyl acetate (300 mL) and isopropanol (300 mL) heated to 65--75°C stirred for 45 min. Cooled the reaction mixture to 25--35°C, filtered the obtained solid, washed with a mixture of ethyl acetate (50 mL), isopropanol 25 (50 mL) and stirred in methanol for 2 hr to get the title compound.
Yield: 94.9 g.
Purity by HPLC: 99.6 %
Example--7: Preparation of the compound of formula--1a (Form--1):
A round bottom flask was charged with a mixture of the compound of formula--1 (50 gm), 30 acetone (600 mL) and carbon (2.0 g) and heated to 35--45°C and stirred for 30 min. The solution
15
was filtered through hyflow bed and washed with acetone (25 mL). The obtained filtrate solution was cooled to 20--30°C, charged with potassium hydroxide solution (6.3 g in 75 mL of water) and stirred for 2 hr. Filtered the obtain solid, washed with acetone (25 mL) and dried to get the title compound.
Yield: 47.2 g 5
Purity by HPLC: 99.7 % ,CLAIMS:1. A process for preparation of compound of formula-6
5
Formula-6
10 Comprising of
debenzylating the compound of formula-5 with suitable base, solvent to provide compound of
formula-6 ,
15
Formula-5
2.The process according to claim 1 wherein in the suitable solvent is selected from chloro solvents,
dioxane, polar aprotic solvents, alcohol such as methanol, ethanol, isopropanol, butanol and water
20 or any mixture thereof; the suitable base is sodium hydroxide, potassium hydroxide and lithium
hydroxide; suitable temperature is 10-150°C;
3. A process for preparation of compound of formula-6
Formula-6
17
comprising of
debenzylating the compound of formula-5 with sodium hydroxide in n-butanol at 105-115°C to
provide compound of formula-6,
5
Formula-5
10 4. A process for the preparation of N-[(4-Fluorophenyl) methyl]-1,6-dihydro5-
hydroxy-1-
methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-
4pyrimidine
carboxamide the compound of formula-1a,
15 Formula-1a
comprising of:
a)reacting the compound of formula-2
20 Formula-2
with 4-fluorobenzylamine in presence of triethylamine in methanol to provide compound of
formula-4,
18
Formula-4
b) N-methylating the compound of formula-4 with trimethyl sulphoxoniumiodide in presence of
magnesium 5 oxide in N-methyl-2-pyrrolidone to provide compound of formula-5,
Formula-5
c)debenzylating the compound of formula-5 with sodium hydroxide, in n-butanol to provide
10 compound of formula-6 ,
Formula-6
d)reacting the compound of formula-6 with the compound of formula-7a in presence of
oxalylchloride, triethylamine, in DMF to provide the compound of formula-1,
15
Formula-7a
e)treating the compound obtain in step-d) with KOH in acetone to give potassium salt of
raltegravir.
20
19
5. Raltegravir or raltegravir potassium obtained according to any preceding claims having chemical purity by HPLC >99%;