DESC:RELATED PATENT APPLICATION(S)
This application claims the priority to and benefit of Indian Patent Application No. 201741039325 filed on November 03, 2017; the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to an improved process for the preparation of Dolutegravir sodium and its intermediates thereof.
BACKGROUND OF THE INVENTION
Dolutegravir is an integrase inhibitor being developed by Shionogi for the treatment of HIV-I (Human Immunodeficiency Virus-I) infection. Dolutegravir sodium was approved in US and marketed under the trade name Tivicay. Dolutegravir sodium chemically known as sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate, having the formula I as mentioned below:
Formula I
PCT Publication WO 2006/116764A1 assigned to Shionogi discloses a process for the preparation of dolutegravir, mentioned in scheme-1.
The PCT Publication WO2010068253A1 discloses the crystalline form of dolutegravir sodium characterized by the following powder X-ray diffraction (PXRD) pattern having peaks at 6.4, 9.2, 13.8, 19.2 and 21.8±0.2º two theta.
Besides the availability of processes for the preparation of Dolutegravir sodium, there is a need to improve the process for the preparation of Dolutegravir sodium that is commercially significant.
Scheme-1
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved process for the preparation of Dolutegravir sodium.
Another object of the present invention is to provide the process for the preparation of various Dolutegravir intermediates and the purification processes thereof.
Yet another object of the present invention is to provide the crystalline form of various Dolutegravir intermediates.
SUMMARY OF THE INVENTION
In first aspect of the present invention, there is provided an improved process for the preparation of Dolutegravir sodium, involving the steps of:
a) reacting a compound of formula XII,
Formula XII
with N,N-dimethyl formamide dimethyl acetate to obtain a compound of formula XI,
Formula XI
b) treating the compound of formula XI with amino acetaldehyde dimethyl acetal to obtain a compound of formula X,
Formula X
c) cyclizing the compound of formula X with oxalate ester in the presence of alkali alkoxide to obtain a compound of formula IX,
Formula IX
d) converting the compound of formula IX in the presence of alkali metal hydroxide to obtain a compound of formula VI,
Formula VI
e) reacting the compound of formula VI with catalytic amount of methane sulfonic acid to obtain a compound of formula V,
Formula V
f) reacting the compound of formula V with a compound of formula VII,
Formula VII
in the presence of anhydrous potassium acetate to obtain a compound of formula IV,
Formula IV
g) condensing the compound of formula IV with a compound of formula VIII,
Formula VIII
in the presence of carbonyl diimidazole in water immiscible solvent to obtain a compound of formula III,
Formula III
h) converting the compound of formula III in the presence of Lewis acid to obtain a compound of formula II,
Formula II
i) treating the compound of formula II with source of sodium in a mixture of alcoholic solvent and water to obtain a compound of formula I,
Formula I
In second aspect of the present invention, there is provided a process for preparation of Dolutegravir intermediate of formula III,
Formula III
comprising the step of:
reacting the compound of formula IV,
Formula IV
with 2,4-difluoro benzyl amine of formula VIII,
Formula VIII
in water immiscible solvent to obtain a compound of formula III.
In some embodiment, the compound of formula III is obtained by reacting a compound of formula IV with a compound of formula VIII in the presence of coupling agent selected from the group comprising isobutyl chloroformate, pivaloyl chloride, 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl-)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-yl-oxy- (pyrrolidino)phophoum (BOP), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), carbonyldiimidazole (CDI), tris(dimethylamino)phosphonumhexaflurophosphate (pyCOP).
In third aspect of the present invention, there is provided a process for the preparation of Dolutegravir sodium of formula I,
Formula I
comprising the step of:
treating the Dolutegravir free base of formula II,
Formula II
with a source of sodium in a mixture of alcoholic solvent and water.
In some embodiment, the source of sodium in the above described process of preparing formula I from formula II is selected from the group comprising sodium hydroxide, sodium methoxide or mixture thereof.
In some embodiment, the alcoholic solvent used in the conversion of compound of formula II to compound of formula I is selected from the group comprising of ethanol, methanol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-butanol, 2-propanol or mixtures thereof.
In fourth aspect of the present invention, there is provided a crystalline compound of formula IV,
Formula IV
characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 4.14, 8.19, 12.67, 19.25 and 24.65 ± 0.2 degrees.
In some embodiment, there is provided a crystalline compound of formula IV characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 4.14, 8.19, 11.79, 12.67, 12.97, 15.77, 17.53, 19.25, 20.55, 21.29, 24.65, 26.62, 27.61, and 37.31 ± 0.2 degrees.
In fifth aspect of the present invention, there is provided a crystalline compound of formula IV,
Formula IV
characterized by X-ray diffraction pattern as shown in FIG. 1.
In sixth aspect of the present invention, there is provided a process for the purification of compound of formula IV,
Formula IV
comprising the steps of:
a) dissolving the compound of formula IV in an organic solvent;
b) adding an anti-solvent to the solution obtained in the step (a); and
c) isolating the compound of formula IV as a solid.
In some embodiment, the organic solvent used in above described process for the purification of compound of formula IV is selected from the group comprising of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, heptane, toluene, acetone, tetrahydrofuran or mixtures thereof.
In some other embodiment, the anti-solvent used in above described process for the purification of compound of formula IV is selected form the group comprising of methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, diethyl ether, hexane, cyclohexane, n-propanol, heptane or mixtures thereof.
In seventh aspect of the present invention, there is provided a crystalline compound of formula III,
Formula III
characterized by X-ray diffraction pattern having significant peaks expressed as 2? value at about 6.97, 8.49, 10.86, 13.67, 13.91, 17.12, 19.14, 23.46, and 25.56 ± 0.2 degrees
In some embodiment, there is provided a crystalline compound of formula III characterized by X-ray diffraction pattern having significant peaks expressed as 2? value at about 5.52, 6.97, 7.24, 8.49, 10.86, 13.67, 13.91, 15.30, 17.12, 19.14, 21.70, 22.65, 23.46, 25.42, 25.56, 26.85, and 27.62 ± 0.2 degrees.
In eighth aspect of the present invention, there is provided a crystalline compound of formula III,
Formula III
characterized by X-ray diffraction pattern as shown in FIG. 2.
In ninth aspect of the present invention, there is provided a process for the purification of compound III,
Formula III
comprising the steps of:
a) dissolving the compound of formula III in an organic solvent;
b) adding an anti-solvent to the solution obtained in step (a); and
c) isolating the compound of formula III as a solid.
In some embodiment, the organic solvent used in the process for the purification of compound III is selected from the group comprising of ethyl acetoacetate, ethyl acetate, methyl acetate, methyl phenyl acetate, methyl propionate, isopropyl acetate, dichloromethane, tetrahydrofuran, dimethyl formamide, acetone, toluene or mixtures thereof.
In some embodiment, the anti-solvent used in the process for the purification of compound III is selected from the group comprising of methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, diethyl ether, hexane, cyclohexane, n-propanol, heptane or mixtures thereof.
In tenth aspect of the present invention, there is provided a crystalline compound of formula II,
. Formula II
characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 5.46, 10.80, 12.41, 15.32, 16.43, 21.84, and 24.95 ± 0.2 degrees.
In some embodiment, there is provided a crystalline compound of formula II characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 5.46, 10.80, 12.41, 12.91, 13.55, 14.39, 15.32, 16.43, 21.84, 23.34, 24.95, 25.43, 26.45, 27.91, and 45.82 ± 0.2 degrees.
In eleventh aspect of the present invention, there is provided a crystalline compound of formula II,
Formula II
characterized by X-ray diffraction pattern as shown in FIG. 3.
In twelfth aspect of the present invention, there is provided a process for the purification of compound of formula II,
Formula II
comprising the steps of:
a) dissolving the compound of formula II in mixture of alcoholic and water solvent;
b) cooling the solution obtained in step (a); and
c) isolating the compound of formula II as a solid.
In some embodiment, the alcoholic solvent used in the process for the purification of compound of formula II is selected from the group comprising of ethanol, methanol, 2-propanol or mixtures thereof.
BREIF DESCRIPTION OF FIGURES
Figure 1: Illustrates the Powder X-ray Diffractogram (PXRD) of crystalline compound of formula IV.
Figure 2: Illustrates the Powder X-ray Diffractogram (PXRD) of crystalline compound of formula III.
Figure 3: Illustrates the Powder X-ray Diffractogram (PXRD) of crystalline compound of formula II.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect of the present invention, there is provided an improved process for the preparation Dolutegravir sodium, involving the steps of:
a) reacting a compound of formula XII,
Formula XII
with N,N-dimethyl formamide dimethyl acetate to obtain a compound of formula XI;
Formula XI
b) treating the compound of formula XI with amino acetaldehyde dimethyl acetal to obtain a compound of formula X,
Formula X
c) cyclizing the compound of formula X with oxalate ester in the presence of alkali alkoxide to obtain a compound of formula IX;
Formula IX
d) converting the compound of formula IX in the presence of alkali metal hydroxide to obtain a compound of formula VI;
Formula VI
e) reacting the compound of formula VI with catalytic amount of methane sulfonic acid to obtain a compound of formula V;
Formula V
f) reacting the compound of formula V with a compound of formula VII,
Formula VII
in the presence of anhydrous potassium acetate to obtain a compound of formula IV;
Formula IV
g) condensing the compound of formula IV with a compound of formula VIII,
Formula VIII
in the presence of carbonyl diimidazole in water immiscible solvent to obtain a compound of formula III;
Formula III
h) converting the compound of formula III in the presence of Lewis acid to obtain a compound of formula II;
Formula II
i) treating the compound of formula II with source of sodium in a mixture of alcoholic solvent and water to obtain a compound of formula I;
Formula I
In some embodiment, the step (a) of the above described process for the preparation of a compound of formula I may be carried out in suitable nonpolar solvents selected from the group comprising of toluene, chloroform, dioxane or the like; alcoholic solvent such as methanol, ethanol, isopropanol, butanol or the like; chlorinated solvents such as dichloromethane, chloroform, trichloroethylene or its mixtures; preferably the solvent is dichloromethane.
In some other embodiment, the step (b) of the above described process for the preparation of a compound of formula I may be carried out in suitable nonpolar solvents selected form the group comprising of toluene, chloroform, dioxane or the like, polar aprotic solvent such as ethyl acetate, dichloromethane, tetrahydrofuran, acetone or the like, alcoholic solvent such as methanol, ethanol, isopropanol, butanol or its mixture; preferably the solvent is methanol.
In another embodiment, the step (c) of the above described process for the preparation of a compound of formula I may be carried out in the presence of alkali alkoxide selected from the group comprising of lithium methoxide, lithium ethoxide, sodium methoxide or sodium ethoxide, preferably sodium methoxide; and may be carried out in suitable ether solvent selected from the group comprising of dioxane, tetrahydrofuran or the like, alcoholic solvent such as methanol, ethanol, isopropanol, butanol or its mixture; preferably the solvent is methanol.
In some embodiment, the step (d) of the above described process for the preparation of a compound of formula I may be carried out in suitable ether solvent selected form the group comprising of dioxane, tetrahydrofuran or the like; alcoholic solvent such as methanol, ethanol, isopropanol, butanol or its mixture, preferably the solvent is methanol.
In some embodiment, the step (e) of the above described process for the preparation of a compound of formula I may be carried out in the presence of catalytic strong protic acid selected from the group comprising of methane sulfonic acid, sulphuric acid, toluene sulfonic acid and hydrochloric acid, preferably the strong protic acid is methane sulfonic acid.
In some other embodiment, the step (e) of the above described process for the preparation of a compound of formula I may be carried out in suitable solvent selected from the group comprising of polar aprotic solvent such as acetonitrile, ethyl acetate, acetone, tetrahydrofuran, dimethyl formamide or its mixture; non-polar solvent such as toluene, chloroform, dioxane or its mixture; preferably the solvent is acetonitrile.
In yet another embodiment, the step (f) of the above described process for the preparation of a compound of formula I may be carried out in suitable organic solvents selected form the group comprising of acetonitrile, ethyl acetate, acetone, tetrahydrofuran, dimethyl formamide or its mixture; non-polar solvent such as toluene, chloroform, dioxane or its mixture; preferably the solvent is acetonitrile.
In some embodiment, the step (g) of the above described process for the preparation of a compound of formula I may be carried out in suitable water immiscible solvent selected form the group comprising of dichloromethane, dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, ethyl acetate, diethyl ether, heptane, hexane, pentane, methyl tert-butyl ester, toluene, toluene or the like, preferably solvent is ethyl acetate.
In some embodiment, the step (h) of the above described process for the preparation of a compound of formula I may be carried out in the presence of Lewis acid selected from the group comprising of lithium bromide, lithium chloride, magnesium bromide, magnesium chloride, lithium iodideor the like; preferably the Lewis acid is lithium bromide.
In some other embodiment, the step (h) of the above described process for the preparation of a compound of formula I may be carried out in suitable organic solvent selected from the group comprising of acetonitrile, ethyl acetate, acetone, dimethyl formamide, tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethyl sulfoxide, ethanol, isopropanol, methanol or mixtures thereof; preferably the solvent is acetonitrile.
According to this embodiment step (i) above described process for the preparation of a compound of formula I may be carried out in suitable solvents selected from the group comprising of ethanol, methanol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-butanol, 2-propanol, and water or mixtures thereof.
In another embodiment of the present invention, there is provided a process for the preparation of Dolutegravir intermediate of formula III,
Formula III
comprising the step of:
reacting the compound of formula IV,
Formula IV
with 2,4-difluoro benzyl amine of formula VIII,
Formula VIII
in water immiscible solvent to obtain a compound of formula III.
In some embodiment, the compound of formula III is prepared by reacting the compound of formula IV with the compound of formula VIII in the presence of coupling agent selected from the group comprising isobutyl chloroformate, pivaloyl chloride, 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl-)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-yl-oxy- (pyrrolidino)phophoum (BOP), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), carbonyldiimidazole (CDI) or tris(dimethylamino)phosphonumhexaflurophosphate (pyCOP).
In some embodiment, the compound of formula III is prepared by reacting the compound of formula IV with the compound of formula VIII in the presence of suitable water immiscible solvent selected form the group comprising of dichloromethane, dichloroethane, cyclohexane, chloroform, carbon tetrachloride, butyl acetate, n-butanol, benzene, ethyl acetate, diethyl ether, heptane, hexane, pentane, methyl tert-butyl ester, toluene or the like; preferably the solvent is ethyl acetate.
The inventors of the present invention have done this reaction with different solvent such as dimethoxymethane and acetonitrile. After reaction completion, the workup procedure was cumbersome due to multiple steps to get the desired product. The inventors of the invention surprisingly found that when the reaction of formula IV with 2,4-difluoro benzyl amine of formula VIII is carried in the presence of water immiscible solvents the workup procedure reduces and makes easier for large scale preparation of compound of formula III.
In another aspect of the present invention, there is provided a process for the preparation of Dolutegravir sodium of formula I,
Formula I
comprising the step of:
treating the Dolutegravir free base of formula II,
Formula II
witha source of sodium in a mixture of alcoholic solvent and water.
In some embodiment of the present invention, the compound of Formula I is prepared from the compound of formula II in the presence of alcoholic solvent selected from the group comprising of ethanol, methanol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-butanol, 2-propanol or mixtures thereof.
The inventors of the present invention, carried out this reaction in alcoholic solvents in the presence of sodium hydroxide. During the reaction, sodium hydroxide is suspension in nature which affects the rate of reaction and filtration. Unexpectedly, according to the present invention, this reaction is carried out in alcoholic solvent with water, which breaks the suspension of sodium hydroxide and makes it to solution. This increases the rate of the reaction and filtration.
In another aspect of the present invention, there is provided a crystalline compound of formula IV,
Formula IV
characterized by X-ray diffraction pattern having significant peaks expressed as the 2? values at about 4.14, 8.19, 12.67, 19.25 and 24.65 ± 0.2 degrees.
In some other embodiment, there is provide a crystalline compound of formula IV characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 4.14, 8.19, 11.79, 12.67, 12.97, 15.77, 17.53, 19.25, 20.55, 21.29, 24.65, 26.62, 27.61, and 37.31 ± 0.2 degrees
In another embodiment of the present invention, there is provided a crystalline compound of formula IV,
Formula IV
characterized by X-ray diffraction pattern as shown in Figure 1.
In another aspect of the present invention, there is provided a process for the purification of compound of formula IV,
Formula IV
comprising the steps of:
a) dissolving the compound of formula IV in an organic solvent;
b) adding an anti-solvent to the solution obtained in the step (a); and
c) isolating the compound of formula IV as a solid.
In some embodiment, the organic solvent used in step (a) of the above described process for the purification of compound of formula IV is selected from the group comprising of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, heptane, toluene, acetone, tetrahydrofuran or its mixture thereof; preferably the solvent is methanol.
In some other embodiment, the anti-solvent used in step (b) of the above described process for the purification of compound of formula IV is selected from the group comprising of methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, diethyl ether, hexane, cyclohexane, n-propanol, heptane or mixtures thereof; preferably the solvent is methyl tert-butyl ether.
In yet another aspect of the present invention, there is provided a crystalline compound of formula III,
Formula III
characterized by X-ray diffraction pattern having significant peaks expressed as 2? value at about 6.97, 8.49, 10.86, 13.67, 13.91, 17.12, 19.14, 23.46, and 25.56 ± 0.2 degrees.
In some embodiment, there is provided a crystalline compound of formula III characterized by X-ray diffraction pattern having the significant peaks expressed as 2? values at about 5.52, 6.97, 7.24, 8.49, 10.86, 13.67, 13.91, 15.30, 17.12, 19.14, 21.70, 22.65, 23.46, 25.42, 25.56, 26.85, and 27.62 ± 0.2 degrees.
In some other embodiment of the present invention, there is provided a crystalline compound of formula III,
Formula III
characterized by X-ray diffraction pattern as shown in Figure 2.
In another aspect of the present invention, there is provided a process for the purification of compound III,
Formula III
comprising the steps of:
a) dissolving the compound of formula III in an organic solvent;
b) adding an anti-solvent to the solution obtained in step (a); and
c) isolating the compound of formula III as a solid
In some embodiment, the organic solvent used in the step (a) of the above described process for the purification of compound III is selected from the group comprising of ethyl acetoacetate, ethyl acetate, methyl acetate, methyl phenyl acetate, methyl propionate, isopropyl acetate, dichloromethane, tetrahydrofuran, dimethyl formamide, acetone, toluene or mixtures thereof; preferably the solvent is ethyl acetate.
In some embodiment, the anti-solvent used in the step (b) of the above described process for the purification of compound III is selected from the group comprising of methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, diethyl ether, hexane, cyclohexane, n-propanol, heptane or mixtures thereof; preferably the solvent is methyl tert-butyl ether.
In yet another aspect, there is provided a crystalline compound of formula II characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 5.46, 10.80, 12.41, 15.32, 16.43, 21.84, and 24.95 ± 0.2 degrees.
Formula II
In some embodiment of the present invention, there is provided a crystalline compound of formula II characterized by X-ray diffraction pattern having significant peaks expressed as the 2? values at about 5.46, 10.80, 12.41, 12.91, 13.55, 14.39, 15.32, 16.43, 21.84, 23.34, 24.95, 25.43, 26.45, 27.91, and 45.82 ± 0.2º.
In another embodiment of the present invention, there is provided a crystalline compound of formula II,
. Formula II
characterized by X-ray diffraction pattern as shown in Figure 3.
In another aspect of the present invention, there is provided a process for the purification of compound of formula II,
Formula II
comprising the steps of:
a) dissolving the compound of formula II in mixture of alcoholic and water solvent;
b) cooling the solution obtained in step (a); and
c) isolating the compound of formula II as a solid.
In some embodiment, the alcoholic solvent used in the step (a) of the process for the purification of compound of formula II is selected from the group comprising of methanol, ethanol, isopropanol or mixture thereof; preferably the solvent is methanol.
The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
EXAMPLES
Example-1
Preparation of formula VI:
To a mixture of formula XII (100 gm) and dichloromethane (500 ml), dimethyl formamide dimethyl acetal (97.85 gm) was slowly added at 30°C and maintained for two hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent in the reaction mixture was distilled under reduced pressure.
The resultant oily mass containing the compound of formula XI was mixed with methanol (400 ml) at 30°C to obtain a solution. Amino acetaldehyde dimethyl acetal (86.34 gm) was added to the obtained solution at 30°C and maintained for two hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the methanol in the reaction mixture was distilled under vacuum.
The resultant oily mass containing the compound of formula X was mixed with methanol (300 ml) and dimethyl oxalate (161.62 gm) at 30°C and cooled to 0°C. A solution of sodium methoxide in methanol (246.43 gm) was slowly added to the cooled reaction mixture, heated to 12.5°C and maintained for two hours at the same temperature. The reaction was then heated to 30°C and maintained for seven hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0°C and the pH was adjusted to 2 by adding 2N hydrochloric acid solution. The contents of the reaction mass was extracted by dichloromethane (1000 ml). The dichloromethane layer was washed with water (500 ml) and then distilled to remove the dichloromethane at 35°C under vacuum.
The resultant oily mass containing the compound of formula IX was mixed with methanol (675 ml) and cooled to 0°C. Lithium hydroxide monohydrate (28.71 gm) was added to the cooled mass in four equal lots, then heated to 25°C and maintained for 30 minutes. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0°C and the pH was adjusted to 2 by adding 1N hydrochloric acid solution. The contents of the cooled reaction mass was extracted by ethyl acetate (1500 ml). The ethyl acetate layer was washed with 10% sodium chloride solution (500 ml) followed by treatment with activated carbon (20 gm). The resulted filtrate was distilled under vacuum at 45°C to obtain a residue. The residue was mixed with water (600 ml) and stirred for one hour at 25°C. The resultant solid was filtered and washed with water (1000 ml). Wet solid was mixed with isopropanol (500 ml) at 25°C and heated to 55°C to obtain a solution. The resulted solution was maintained for one hour at 55°C and cooled to 25°C. The solution was further cooled to 0°C and maintained for one hour at the same temperature. The contents were then filtered, washed with isopropanol (50 ml) and dried. Yield: 110 gm.
Example-2
Preparation of formula IV: To a mixture of formula VI (obtained from example-1)(300 gm) and acetonitrile (2700 ml), methane sulfonic acid (27.43 gm) and acetic acid (285 gm) was added at 30°C and heated to 85°C. The reaction mixture was then maintained for 4 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass containing the compound of formula V was cooled to 30°C.
Anhydrous potassium acetate (46.69 gm) was added to the reaction mixture and maintained for 30 minutes at 30°C, then the reaction mixture was further cooled to 10°C. (R) 3-aminobutan-1-ol (RABO solution) of formula VII was slowly added to the cooled reaction mass (RABO solution prepared by dissolving the R-amino butanol (89.07 gm) in acetonitrile (300 ml)) and heated to 30°C and maintained the same for one hour. The reaction mixture was further heated to 85°C and maintained for 5 hours at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was distilled at 50°C under vacuum and cooled to 30°C. Dichloromethane (1500 ml) was added to the reaction mixture at 30°C and then cooled to 10°C. Diluted hydrochloric acid solution (1500 ml) was slowly added to the cooled reaction mass and maintained for 20 minutes. Then the temperature of the reaction mass was raised to 30°C. The contents of the reaction mass was extracted with dichloromethane (600 ml). The extracted layer was washed with 10% of sodium chloride solution (600 ml) and distilled under vacuum to obtain a residue. Methanol (900 ml) was added to the obtained residue and heated to 50°C and maintained the temperature for 1 hour at the same temperature. The reaction mass was then cooled to 30°C. Methyl tertiary butyl ether (1800 ml) was added to the reaction mass and stirred for 1 hour. The resultant solid was filtered, washed with methyl tertiary butyl ether (900 ml) and dried. Yield: 204 gm.
Example-3
Preparation of methoxy Dolutegravir of formula III:
To a mixture of formula IV (obtained from example-2) (170 gm) and ethyl acetate (1700 ml), carbonyldiimidazole (CDI) (82.79 g) was added at 30°C and stirred for 10 minutes. The reaction was then heated to 75°C and maintained for 2 hours at the same temperature. The resulted reaction mixture was cooled to 10°C. A solution of 2,4-difluorobenzyl amine of formula VIII in ethylacetate was added to the cooled reaction mixture (2,4-difluorobenzyl amine solution was prepared by dissolving of 102.68 gm of 2,4-difluorobenzyl amine in 170 ml of ethyl acetate). The reaction mixture was heated to 30°C and maintained for 1 hour at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, water (1530 ml) was added to the reaction mass at the 30°C to form biphasic mixture. The organic layer was separated, washed with (i) 1.5% of dilute hydrochloric acid (510 ml), (ii) 5% of sodium carbonate solution (510 ml) and (iii) 20% of sodium chloride solution (510 ml) respectively then concentrated at 50°C under vacuum. The resulted residue was mixed with methyl tertiary butyl ether (1190 ml) and heated to 55°C. The reaction mass was maintained at 55°C for one hour then cooled to 30°C and maintained for 2 hours. The resultant solid was filtered, washed with methyl tertiary butyl ether (340 ml) and dried. Yield: 209 gm.
Example-4
Preparation of Dolutegravir free base of formula II:
To a mixture of methoxy Dolutegravir of formula III (obtained from example-3) (170 gm) and acetonitrile (1700 ml) was heated to 60°C, then lithium bromide solution (850 ml) (dissolved the lithium bromide 68 gm in 850 ml of acetonitrile) was added at 60°C and maintained the temperature for 4 hours. The reaction mixture was then cooled to 30°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was distilled at 50°C under vacuum and then cooled to 20°C. The resultant residue was mixed with water (680 ml) followed by 5N hydrochloric acid solution (142 ml) and water (2550 ml) was added to the reaction mixture at 20°C respectively then maintained for 2 hours. The resultant solid was filtered and washed with water (850 ml). The wet solid was heated with methanol (1190 ml) and water (85 ml) to 65°C and maintained for 4 hours. The content were then cooled to 10°C and maintained for 2 hours. The resultant solid was filtered, washed with pre chilled methanol (170 ml) and dried. Yield: 124 gm.
Example-5
Preparation of Dolutegravir sodium of formula I:
To a mixture of isopropanol (1280 ml) and water (320 ml), Dolutegravir sodium of formula I (obtained from the example-4)(100 gm) was added and stirred for 10 minutes at 30°C. The mixture was then heated to 75°C and maintained the temperature for 30 minutes to obtain a clear solution. A 20% of sodium hydroxide solution (50 ml) was added to the obtained solution and maintained for 1 hour at 75°C. The reaction mass was then cooled to 30°C and maintained for 1 hour. The resultant solid was filtered, washed with isopropyl alcohol (200 ml) and dried. Yield: 99 gm.
Example-6
Preparation of Dolutegravir free base of formula II:
To a mixture of methoxy dolutegravir of formula III (obtaining from the example-3) (170 gm) and dimethyl formamide (500 ml), anhydrous magnesium chloride (44 gm) was added at 10°C. The reaction mixture was heated to 55°C and maintained for 5 hours. The progress of the reaction mixture was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 15°C, then water (500 ml) was added to the cooled reaction mass and maintained for 20 minutes at 15°C. Dilute acetic acid (41.5 gm of acetic acid in 1000 ml of water) was added slowly to the cooled reaction mass. Then the temperature was raised to 30°C and maintained the same for 4 hours. The reaction mass was cooled to 15°C and maintained the same for 4 hours. The reaction mass was filtered and washed with water (1000 ml).
The resulted wet material was mixed with methanol (700 ml) and heated to 70°C and maintained the temperature for 4 hours. The content were then cooled to 10°C and maintained for 2 hours. The resultant mass was filtered, washed with methanol (100 ml) and dried. Yield: 136 gm.
,CLAIMS:
1. A process for preparation of Dolutegravir intermediate of formula III:
Formula III
comprising the step of:
reacting the compound of formula IV
Formula IV
with 2,4-difluoro benzyl amine of formula VIII
Formula VIII
in water immiscible solvent to obtain a compound of formula III.

2. The process as claimed in claim 1, wherein the reaction is carried in the presence of coupling agent selected from the group comprising isobutyl chloroformate, pivaloyl chloride, 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl-)-1,1,3,3-tetramethyluronium (HBTU), benzotriazole-1-yl-oxy- (pyrrolidino)phophoum (BOP), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonum (PyBOP), bromo-tris-pyrrolidino-phosphoniumhexaflurophosphate (PyBrOP), carbonyldiimidazole (CDI) or tris(dimethylamino)phosphonumhexaflurophosphate (pyCOP).

3. A process for the preparation of Dolutegravir sodium of formula I:
Formula I
comprising the step of:
treating the Dolutegravir free base of formula II,
Formula II
with a source of sodium in a mixture of alcoholic solvent and water.

4. The process as claimed in claim 3, wherein the source of sodium is selected from the group comprising sodium hydroxide, sodium methoxide or mixture thereof.

5. The process as claimed in claim 3, wherein the alcoholic solvent is selected from the group comprising of ethanol, methanol, isobutyl alcohol, 1-pentanol, 1-propanol, 2-butanol, 2-propanol or mixtures thereof.

6. A crystalline compound of formula IV characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 4.14, 8.19, 12.67, 19.25 and 24.65 ± 0.2 degrees.
Formula IV

7. A crystalline compound of formula IV as claimed in claim 6, characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 4.14, 8.19, 11.79, 12.67, 12.97, 15.77, 17.53, 19.25, 20.55, 21.29, 24.65, 26.62, 27.61, and 37.31 ± 0.2 degrees.

8. A crystalline compound of formula IV characterized by X-ray diffraction pattern as shown in Figure 1.

9. A process for the purification of compound of formula IV:
Formula IV

comprising the steps of:
a. dissolving the compound of formula IV in an organic solvent;
b. adding an anti-solvent to the solution obtained in the step (a); and
c. isolating the compound of formula IV as a solid.

10. The process as claimed in claim 9, wherein the organic solvent is selected from the group comprising of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, heptane, toluene, acetone, tetrahydrofuran or mixtures thereof.

11. The process as claimed in claim 9, wherein the anti-solvent is selected form the group comprising of methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, diethyl ether, hexane, cyclohexane, n-propanol, heptane or mixtures thereof.

12. A crystalline compound of formula III characterized by X-ray diffraction pattern having significant peaks expressed as 2? value at about 6.97, 8.49, 10.86, 13.67, 13.91, 17.12, 19.14, 23.46, and 25.56 ± 0.2 degrees.
Formula III

13. A crystalline compound of formula III as claimed in claim 12, characterized by X-ray diffraction pattern having significant peaks expressed as 2? value at about 5.52, 6.97, 7.24, 8.49, 10.86, 13.67, 13.91, 15.30, 17.12, 19.14, 21.70, 22.65, 23.46, 25.42, 25.56 26.85, and 27.62 ± 0.2 degrees.

14. A crystalline compound of formula III characterized by X-ray diffraction pattern as shown in Figure 2.
Formula III

15. A process for the purification of compound III:
Formula III
comprising the steps of:
a. dissolving the compound of formula III in an organic solvent;
b. adding an anti-solvent to the solution obtained in step (a); and
c. isolating the compound of formula III as a solid.

16. The process as claimed in claim 15, wherein the organic solvent is selected from the group comprising of ethyl acetoacetate, ethyl acetate, methyl acetate, methyl phenyl acetate, methyl propionate, isopropyl acetate, dichloromethane, tetrahydrofuran, dimethyl formamide, acetone, toluene or mixtures thereof.

17. The process as claimed in claim 15, wherein the anti-solvent is selected from the group comprising of methyl tert-butyl ether, ethyl tert-butyl ether, diisopropyl ether, diethyl ether, hexane, cyclohexane, n-propanol, heptane or mixtures thereof.

18. A crystalline compound of formula II characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 5.46, 10.80, 12.41, 15.32, 16.43, 21.84, and 24.95 ± 0.2 degrees.
Formula II

19. A crystalline compound of formula II as claimed in claim 18, characterized by X-ray diffraction pattern having significant peaks expressed as 2? values at about 5.46, 10.80, 12.41, 12.91, 13.55, 14.39, 15.32, 16.43, 21.84, 23.34, 24.95, 25.43, 26.45, 27.91, and 45.82 ± 0.2 degrees.

20. A crystalline compound of formula II characterized by X-ray diffraction pattern as shown in Figure 3.
Formula II

21. A process for the purification of compound of formula II
Formula II
comprising the steps of:
a. dissolving the compound of formula II in mixture of alcoholic and water solvent;
b. cooling the solution obtained in step (a); and
c. isolating the compound of formula II as a solid.

22. The process as claimed in claim 21, wherein the alcoholic solvent is selected from the group comprising of ethanol, methanol, 2-propanol or mixtures thereof.