FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Sodium (2RJ5S;13aR)-7]9-dioxo-10-((254J6-trifluorobenzyl)carbamoyl)-2,334J5;739J3I13a-octahydro-2:5-Methanopyrido[r,2':4,5]pyrazino[2,l -b][l ,3] oxazepin-8-olate compound of formula- 1 . represented by the following structural formula:
BACKGROUND OF THE INVENTION
Sodium(2R,5S, 13aR)-7:9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[l\2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate is known to be Bictegravir sodium, which has been approved as the combination drug in US as Bictegravir;Emtricitabine;Tenofoviralafenamide under the trade name of BIKTARVY® for treating HIV.
(2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9, 13,13a-octahydro-2,5-Methanopyrido[ 1 ',2':4,5]pyrazino[2, 1 -b] [ 1,3]oxazepin-8-olate (compound of formula-la), as well as its pharmaceutically acceptable salts are first known in US 9,216,996 (US'996).
US'996 has disclosed the following process for the preparation of (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a- octahydro-2,5-methano pyrido[r32':4,5]pyrazino[2,l-b][l,3] oxazepin-8-olate of formula-la is as follows:

US 9,708,342 (US'342) discloses Sodium (2R, 5S, 13aR) -7,9-dioxo-10- ((2,4,6-trifluoro benzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro- 2,5-Methanopyrido [l',2':4,5] pyrazino [2,1-b] [1,3] oxazepin-8-olate.
US'342 has disclosed the following process for the preparation of Form-Ill of (2R,5S,13aR)- 7,9-dioxo- 10-((2,4,6-trifluorobenzyl) carbamoyl) -2,3,4,5,7,9,13,13a octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate and is as follows:
US 201500368264 has disclosed the following process for the preparation of (2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzy l)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate and is as
~h\~ ! ! i t C T—l! C i-""rr_! (.I'M—A T il T 7—.-.—r. . ^« , .

Further this patent discloses that "deprotection of methoxy group in presence of metal salt to obtain (2R,5S, 13aR)-7,9-dioxo-10-((2,4,64rifluorobeiizyl)carbarnoyl)-2,3=4,5,7,9, 13J 3a-octahydro-2,5-Methanopyrido [ 1 ',2':4,5]pyrazino[2,1 -b][ 1,3] oxazepin-8-olate.The metal salt is selected from the group consisting of magnesium bromide, lithium chloride, lithium bromide and lithium iodide. In still further embodiments, the metal salt is lithium chloride".
As per the present invention, the prior art process yielded sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9, 13,13a-octahydro-2,5-Methanopyrido [l':2':4,5]pyrazino[2,l-b][l,3] oxazepin-8-olate product,which has low purity and yield. Hence, there is a need for an improved and commercially viable process for preparing compound of Formula-1, which is suitable industrially.
OBJECTIVES OF THE INVENTION
An objective of the present invention is to prepare Sodium (2R,5S,13aR)-7,9-dioxo-10-
((2,4,6-trifluorobenzyl) carbamoyO^SAS^^JSjDa-octahydro^.S-Melhanopyrido
nr[r#'i:4£]Tpyrazmo^

Another objective of the present invention is to provide a process for the preparation of Sodium(2R,5S, 13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[l \2':4,5]pyrazino[2.1-b][l,3]oxazepin-8-olate, which is economically and industrially feasible process.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-tjifluorobenzyl)carbamoyl)-2,3 ,4,5,7,9,13,13a-octahydro-2,5-Methanopyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepin-8-olate of compound Formula-I,

e) treating the compound of formula la with sodium base in presence of suitable solvent
to provide compound of formula I. wherein compound of formula-V is optionally isolated or insitu reacted with compound of formula VI.
The present invention also relates to a Lithium (2Rs5S,13aR)-7s9-dioxo-10-((2s4,6-trifluorobenzylcarbamoyl) -2,3,4,5,7:9,13.13a- octahydro-2,5- Methanopyrido [l',2':4.5]
$k-&— J3--P' **" ' '" " f-' f" H" (- (\f ixi /* r 'j
pyrazlno[%T-r5][n3]l3Yazepin^

BRIEF DESCRIPTION OF THE DRAWINGS
Figure.! is a X-ray Powder Diffraction of crystalline Lithium(2R,5S,13aR)-7,9-dioxo-IO-((2,4,6-trifluorobenzyl) carbamoyl)- 2,3,4,5,7,9,13,13a-octahydro-235-methanopyrido [r,2':435]pyrazino [2,l-b][1.3] oxazepin-8-olate (formula-ll).
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment of the present invention provides an improved process for the
preparation of Sodium (2R,5S313aR)-739-dioxo-10-((23436-trifluorobenzyl)carbamoyl)-
2,3,4,5,7,9,13,13a-octahydro-2s5-Methanopyrido[l',2':4s5]pyrazino[2,l-b][l,3] oxazepin-
8-olate of compound formula-I, which comprises: reacting(2R,5S,13aR)-8-methoxy-7,9-
dioxo-233:4,5,739,13,13a-octahydro-2,5-methanopyrido [l',2':4,5]pyrazino[2,l-b][l,3]
oxazepin-10-carboxylic acid of formula-IN with compound of formula-IV in presence of suitable base and solvent to provide a compound of formula-V, wherein compound of formula-V is optionally isolated or insitu reacting with (2,4,6-trifluorophenyl) methanamine compound of formula VI to provide a compound of formula VII. Demethylating the compound of formula-VII with lithium bromide in a suitable solvent to provide compound of formula II. Treating the compound of formula-II with an acid in presence of solvent to provide compound of formula la. Treating the compound of formula la with sodium base to provide compound of formula I.
In another embodiment of the present invention, reacting(2R,5S,13aR)-8-methoxy-7,9-
dioxo-2,3,4,5,7s9,13,13a-octahydro-2!5-methanopyrido[r,2':4,5] pyrazino[2,l-b][l,3]
oxazepin-10-carboxylic acid of formula-Ill with compound of formula-IV in presence of suitable base and solvent to provide a compound of formula-V.

In another embodiment of the present invention, suitable base is selected from organic or inorganic base; inorganic base is selected from the group comprising of "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the tike; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and ammonia; organic base is selected from the group comprising of triethy! amine, methyl amine, ethyl amine, lithium diisopropyl amide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropyl amine, diisopropylethylamine, N-methylmorphoiine, N-ethylmorpholine, piperidine, dimethyl aminopyridine, morpholine, pyridine, 2,6-lutidine or mixtures thereof.
In another embodiment of the present invention, reacting(2R,5S,13aR)-8-methoxy-7,9-dioxo-2,3,4!5,7,9,13,13a-octahydro-2,5-methanopyrido[r,2':4s5]pyrazino[2,l-b][l,3] oxazepin-10-carboxylic acid of formula-Ill with compound of formula-IV at a temperature of 0°C to-15°C, preferably -15°C to-10°C.
In another embodiment of the present invention, compound of formula-V is optionally isolated or insitu reacting with (2,4,6-trifluorophenyl) methanamine compound of formula VI to provide a compound of formula VII.
. In another embodiment of the present invention, crystallizing the compound formula-VII in a suitable solvent or mixtures thereof.
In another embodiment of the present invention, suitable solvent is selected from the group comprising of "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, toluene, pentane, cycloheptane, methylcyclohexane, xylene; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-. nitroethanol, ethylene glycol, propylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol. pentanol, neo-pentyl alcohol, t-pentyl alcohol or mixture thereof.

In another embodiment of the present invention, demethylating the compound of formula-VII with lithium bromide in a suitable solvent to provide compound of formula II.
In another embodiment of the present invention, suitable solvent for demethylation step is selected from the group comprising of "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile or mixture thereof.
In another embodiment of the present invention, Lithium bromide is added lot wise or in one lot.
In another embodiment of the present invention, the demethylation reaction proceeds at about 50°C to about 70°C for period of 2-5 hours; preferably 60-65°C for a period of 2-3 hours.
In another embodiment of the present invention, Lithium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzylcarbamoyl) -2,3,4,5,7,9,13,13a- octahydro-2,5- methanopyrido [l'^'^SJpyrazinollJ-bin^Joxazepin-S-olate of formula-11 is isolated in crystalline form.
In another embodiment of the present invention, compound of formuta-II reacts with an acid in presence of suitable solvent to provide compound of formula la; where in acid is selected from the group comprising of hydrochloric acid, aqueous hydrochloric acid, methanolic-HCI, ethanolic-HCI, IPA-HC1, hydrochloric acid gas, sulphuric acid and acetic acid.
In another embodiment of the present invention, optionally purifying the compound of formula-la with a suitable solvent.
In another embodiment of the present invention, suitable solvent for acidification and purification for compound of formula-la is selected from the group comprising of "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, propylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol. diethylene glycol, pentanol, neo-pentyl alcohol, t-pentyl alcohol,
cyclohexanol, benzyl alcohol; "polar solvents" such as water or mixtures thereof.
~nrc"c."T i—n. i—irri—M-».-I—A—r .,—. ,—. .

In another embodiment of the present invention, the purification of compound of formula-■ la is carried out at temperature ranging from 50°C to 70°C, preferably at 60-65°C, for a period of 1-2 hours.
In another embodiment of the present invention, the compound of formula la treating with a sodium base in presence of suitable solvent to provide compound of formula I, where in suitable solvent is selected from the group comprising of "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like.
In another embodiment of the present invention, wherein sodium base is selected from the group comprising of sodium hydroxide, sodium alkoxide, sodium-2-ethylhexanoate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium lactate, sodium dihydrogen phosphate, preferably NaOH.
In another embodiment of the present invention, Sodium hydroxide solution is preparing by dissolving sodium hydroxide in alcohol.
In another embodiment of the present invention, Sodium hydroxide solution is added slowly in a period of 1 hour at room temperature, room temperature is considered as 25-30°C.
In another embodiment of the present invention, sodium(2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzylcarbamoyl)- 2,3,4,5,7,9,13,13a-octahydro- 2,5-methanopyrido [r,2':4,5] pyrazino[2,l-b][l,3] oxazepin-8-olate is in crystalline form.
In another embodiment of the present invention, the following mentioned impurities were formed during the process for preparing the sodium(2R:5S)13aR)-7)9-dioxo-10-((2!4,6-trifluorobenzylcarbamoyl)-2,3,4,5,7I9,13,13a-octahydro-2,5-methanopyrido[r,2':4,5] pyrazino[2,l-b][l,3] oxazepin-8-olate compound of formula I.

As per the comparison, it is to be noted that as per the current patent application process the impurities, which were not controlled in prior art process, were controlled with in the ICH limits i.e < 0.15%, and doing so the compound of formula I obtained with high yield and high purity as well as avoid the column chromatography which is cumbersome industrially.
The process described in the present invention has been 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:
Preparation of (2R,5S,13aR)-8-methoxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-
2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [r,2':4,5]pyrazino[2,l-b][l,3]
oxazepine-10-carboxamide (compound of formuIa-VII):
Charged (2R,5S,13aR) -8-methoxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5- methano pyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazepine-10-carboxy!icacid, (60gm,0.1874 moles) in methylene chloride (390 ml)at25-30°C under nitrogen. Cooled the reaction mixture to

-15 to -10°C. N-methylmorpholine (20.7gm, 0.2047moles) was added to the reaction mixture at -15 to -10°C. Isobutylchloroformate (28gm, 0.205moles) in methylene chloride (60ml) was added for 1 hr to the cold reaction mass. (2,4,6- trifluorophenyl) methanamine (33gm, 0.204 moles) in methylene chloride (60 ml) was added to the above reaction mixture for 45 minutes at-20 to -15°C. Raised the temperature to 25-30°C and stirred for 2.30 hrs. After completion of reaction, the reaction mass was washed with sodiumbicarbonate (120ml), 1NHC1 (120ml) water (120ml) and concentrated. The Concentrated mass diluted with IPA (60 ml) and stirred for 20 minutes, n-heptane was added to the reaction mass for 30 minutes at 25-30°C and stirred for 3 hours to crystallize the product. The product was filtered and dried to yield the title compound.
Preparation of Lithium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-mcthanopyrido[l',2':4,5]pyrazino[2,l-b] [1,3] oxazepin-8-olate (compound of formula-II):
Charged (2R,5S,13aR)-8-methoxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-
2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[r,2,:4,5]pyrazino[2,l-b] [l,3]oxazepine-10-carboxamide (80gm) in acetonitrile (960 ml) at 20-30°C. Lithium bromide (52.5gm, 0.6045 moles) were added to the reaction mass in 4 lots for 30-40 minutes at 20-30°C. Heated the reaction mass to 60-65°C and stirred for 3 hours .The reaction mass was Cooled to 20-30°C and stirred for 3 hours. Filtered the obtained solid and washed with acetonitrile to yield the title compound.
Preparation of (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido|r,2':4,5]pyrazino|2,l-b] [1,3] oxazepin-8-olate (compound of formula-la):
Charged Lithium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyl) carbamoyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[ 1 ',2':4J5]pyrazino[2,1 -b] [1,3] oxazepin-8-olate and Methanol(160 ml). Reaction mass pH was adjusted to 2.0 to 3.0 with Cone HC1 at 20-30°C, stirred for 1 hour and concentrated. Concentrated mass was diluted with methanol (160 ml) and heated to 60-65°C, stirred for 1 hour, cooled to 0-5°C and stirred for 4 hours to crystallize the product. The product was filtered, washed with chilled methanol and dried to yield the title compound.

Preparation of Sodium (2R,5S,13aR)-7,9-dioxo-10-((2,4,6-trifluorobenzyi) carbamoyl)-2,3,4,5,7,9,]3,13a-octahydro-2,5-methanopyrido[r,2':4,5]pyrazino[2,l-b| [1,3] oxazcpin-8-oIate (compound of formula-I):
Dissolving (2R,5S)13aR)-7,9-dioxo-10-((2J456-trifluorobenzyl) carbamoyl)- 2,3,4,5,7,9,13, ]3a-octahydro-2,5-methanopyrido[r,2':4,5]pyrazino[25l-b] [1,3] oxazepin-8-olate (50g) in methylene dichloride at 25-30°C. Water was added to the above clear reaction mass and organic layer was separated. Organic layer was treated with carbon and passed through hyflow. Sodium hydroxide solution has been prepared by addition of ethanol (90ml) and NaOH (4.9gms) and stirred for 30 minutes. To the organic layer ethanolic sodium hydroxide solution was added for 45 minutes at 25-30°C and stirred for 2 hrs to crystallize the product. The obtained product was filtered and dried to yield the title compound.