Claims:WE CLAIM:
1. An improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (I), comprising the steps of:

Formula (I)

a) reacting the compound of Formula (IV)
Formula (IV)
with chlorinating agent in presence of a base in a solvent to produce acid chloride compound of Formula (IVa),
Formula (IVa)
b) reacting the compound of Formula (IVa) in situ with compound of Formula (III)

Formula (III)
in presence of a base in a solvent to produce mixture of compound of Formula (V) and compound of Formula (VI),

Formula (V)

Formula (VI)
c) separating the compound of Formula (V) from the mixture obtained in the above step b),
d) deprotecting the compound of Formula (V) in presence of a base in a suitable solvent to produce compound of Formula (I).

2. The process as claimed in claim 1, wherein the chlorinating agent used in step-(a) is selected from thionyl Chloride (SOCl2), Oxalyl chloride (C2O2Cl2), Cyanuric Chloride, Phosphorus oxychloride, Phosphorus trichloride, phosphorus pentachloride.

3. The process as claimed in claim 1, wherein the solvent used in step-(a) is selected from dichloromethane, dimethylformamide, dimethylsulfoxide, acetonitrile or mixture thereof.

4. The process as claimed in claim 1, wherein the base used in step (b) is selected from diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine.
5. The process as claimed in claim 1, wherein the solvent used in step-(b) is selected from dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof.

6. The process as claimed in claim 1, wherein the base used in step-(d) is 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU).

7. The process as claimed in claim 1, wherein the solvent used in step-(c) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.

8. The process as claimed in claim 1, wherein the compound of Formula (I) used in the preparation of Baloxavir morboxil compound of formula (II).

9. A process for the preparation of compound of Formula (III), comprising the step of:

Formula (III)

converting the compound of Formula (VI) to a compound of Formula (III) in presence of a base and a suitable solvent.
10. The process as claimed in claim 9, wherein the base used is 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU); and the solvent used is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c] pyrido[2,1-f] [1,2,4]triazine-6,8-dione of Formula (I).

Formula (I)
which is a key intermediate in the synthesis of Baloxavir morboxil of Formula (II).

Formula (II)
BACKGROUND OF THE INVENTION
Baloxavir morboxil is chemically known as ({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methylmethyl carbonate of Formula (II). Baloxavir morboxil is an antiviral drug developed by Shionogi Co. and Roche for the treatment of influenza A and influenza B infections. It is a prodrug that is converted (by hydrolysis) to Baloxavir, the active form that exerts anti -influenza virus activity.
US 10392406, US 10759814, US 20210093640 and CN 109503625 A disclose a process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4] oxazino[3,4-c]pyrido[2,1-f][1,2,4] triazine-6,8-dione of Formula (I) by reacting 3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyri- do[2,1-f][1,2,4]triazine-6,8-dione of Formula (III) with (R)-2-tetrahydro- furoic acid of formula (IV) in the presence of propanephosphonic acid anhydride (T3P) and pyridine in ethyl acetate and ethanol solvent to produce (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furanyl]carbonyl]-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (V) and (12aS)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furan yl]carbonyl]1H-[1,4]oxazino[3,4-c]pyrido[2,1-f]-[1,2,4]triazine-6,8-dione of Formula (VI). Further, deprotecting the compound of Formula (V) in the presence of DBU in Ethanol/ Diisopropyl ether solvent to produce compound of Formula (I).
The synthetic procedure is illustrated in Scheme-I as below:

WO 2017221869 A1 and CN 112079848 A1 also disclose a process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4] oxazino[3,4-c] pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (I) by reacting 3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]triazine-6,8-dione hemihydrate of Formula (IIIa) with (R)-2-tetrahydrofuroic acid of formula (IV) in the presence of propanephosphonic acid anhydride (T3P) and triethylamine in ethyl acetate and ethanol to produce (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furanyl]carbo nyl]-1H-[1,4]oxazino [3,4-c]pyrido[2,1-f] [1,2,4]triazine-6,8-dione of Formula (V) and (12aS)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furanyl] carbonyl]-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f]-[1,2,4]triazine-6,8-di- one of Formula (VI). Further, deprotecting the compound of Formula (V) in the presence of DBU in Methanol/ Ethyl acetate to produce compound of Formula (I).
The synthetic procedure is illustrated in Scheme-II as below:

The prior art processes suffer from the following disadvantages:
? T3P (50% in Ethyl acetate) reagent is very expensive and excess moles are required.
? Recovery of compound of Formula (III) from unwanted compound of Formula (VI) (S-isomer compound) is very poor due to presence of huge T3P as byproduct and lengthy process.

Hence, there exists a need to have simple, easy to handle and cost effective process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4] oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (I) with high chemical purity and higher yield.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and cost effective process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4] oxazino[3,4-c]pyrido[2,1-f][1,2,4] triazine-6,8-dione of Formula (I) which is a key intermediate for the preparation of Baloxavir morboxil of Formula (II) with high purity and good yield on a commercial scale.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4] triazine-6,8-dione of Formula (I), comprising the steps of:

Formula (I)

a) reacting a compound of Formula (IV);
Formula (IV)
with chlorinating agent in presence of a base in a solvent to produce acid chloride compound of Formula (IVa).
Formula (IVa)
b) reacting the compound of Formula (IVa) in situ with compound of Formula (III);

Formula (III)

in presence of a base in a solvent to produce mixture of compound of Formula (V) and compound of Formula (VI).

Formula (V)

Formula (VI)
c) separating the compound of Formula (V) from the mixture obtained in above step b);
d) deprotecting the compound of Formula (V) in presence of a base in suitable solvent to produce compound of Formula (I).
Another present invention provides a process for the preparation of 3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4] triazine-6,8-dione compound of Formula (III), comprising the step of converting the compound of Formula (VI)

Formula (VI)
to a compound of Formula (III) in presence of a base in a solvent.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4] triazine-6,8-dione of Formula (I), comprising the steps of:
a) reacting a compound of Formula (IV) with chlorinating agent in presence of a base in a solvent to produce acid chloride compound of Formula (IVa),
b) reacting the compound of Formula (IVa) in situ with compound of Formula (III) in presence of a base in a solvent to produce to produce mixture of compound of Formula (V) and compound of Formula (VI),
c) separating the compound of Formula (V) from the mixture obtained in above step b),
d) deprotecting the compound of Formula (V) in presence of a base in suitable solvent to produce compound of Formula (I).
The chlorinating agent used in step a) is selected from thionyl Chloride (SOCl2), Oxalyl chloride (C2O2Cl2), Cyanuric Chloride, Phosphorus oxychloride, Phosphorus trichloride, phosphorus pentachloride or mixtures thereof.
The solvent used in step a) is an organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof; ketone solvent comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
The reaction may be performed usually from 0° C to a boiling point of used solvent for 30 min to 48hours and then compound of formula (IVa) can be obtained by a usual procedure. The obtained compound (IVa) can be used in the next reaction directly without isolation.
The base used in step b) is an organic or inorganic base. The organic base is selected from diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine preferably triethylamine; the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, or mixture thereof or mixtures thereof.
The solvent used in step b) is an organic solvent, for example an aprotic polar solvent comprises dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or mixture thereof preferable dichloromethane; alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof.
The reaction may be performed from 0°C to 60° C for 30 min to 48hours and then compound of formula (V) can be obtained by a usual procedure.
Step c) performs in a suitable solvent selected from dichloromethane and ethylacetetate or mixture thereof.
The reaction may be performed from -30°C to 60° C for 30 min to 48hours and then compound of formula (V) can be obtained by a usual procedure.
The base used in step d) is 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
The solvent used in step d) is organic solvent, for example alcohol comprises methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof preferable methanol; ketone comprises acetone, methylisobutylketone, 2-pentanone, ethylmethylketone, diethylketone; ester comprises ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate or mixture thereof preferable ethyl acetate.
The reaction may be performed from -30°C to 60° C for 30 min to 48hours and then compound of formula (I) can be obtained by a usual procedure.
Another present invention provides a process for the preparation of 3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4] triazine-6,8-dione compound of Formula (III), comprising the step of converting compound of Formula (VI) to compound of Formula (III) in presence of base and suitable solvent.
The base used in above step is 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU)
The solvent used in above step is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutylalcohol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof preferable methanol.
The reaction may be performed from -30°C to 60° C for 30 min to 48hours and then compound of formula (III) can be obtained by a usual procedure.
(12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4] triazine-6,8-dione of Formula (I) prepared from the present invention is converted to Baloxavir morboxil of Formula (II) by reacting with isopropyl magnesium chloride in the presence of p-Toluenesulfonic acid in MTBE, hexanol in THF to produce compound of Formula (VIII), which is further reacted with compound of Formula (IX) in the presence of T3P and Methanesulfonic acid in EtOAc and cyclohexane to produce compound of Formula (X). Deprotection of obtained compound in the presence of magnesium chloride in NMP, CH3CN and water to produce Baloxavir of Formula (XI). Further, compound of Formula (XI) is reacted with chloromethyl methyl carbonate in the presence of potassium carbonate, potassium iodide in dimethyl acetatmide to produce Baloxvir morboxil of Formula (II).

Advantages of present invention:
? Thionyl chloride is less expensive compared to T3P (50% in Ethyl acetate) reagent.
? Chiral purity of compound of formula (I) achieved more than 99.5% with high yield by the improved process in the present invention.
? Compound of formula (III) has been recovered multiple times from racemization process and increased the overall yield up to 80 %.

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES:
Example-1: Preparation of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furanyl]carbonyl]1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]triazine-6,8-dione of Formula (V).
To a solution of (R)-2- tetrahydro furoic acid of formula (IV) (106.4 g), DMF (3.3 g) and DCM (1000 ml), was added Thionyl chloride (SOCl2) (136.2 g) at 0-5°C under nitrogen atmosphere. The reaction mixture was stirred at 0-5°C for 1h, followed by at 25-30°C for 2h. After completion of reaction, the reaction mixture was concentrated at 35-45°C under vacuum and obtained (2R)-Tetrahydrofuran-2-carbonylchloride residue of Formula (IVa) was diluted with dichloromethane (600 ml).
To a suspension of 3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino[3, 4-c] pyrido [2,1-f][1,2,4]triazine-6,8-dione (III) (200g), dichloromethane (5400 ml) and Triethylamine (92.7g), was added above obtained (2R)-Tetrahydrofuran-2-carbonylchloride residue of Formula (IVa) in dichloromethane (600ml) at 0-5°C. The reaction mass was stirred for 1 h at 0-10 °C. After completion of reaction, reaction mixture was washed with water (2000 ml), separated the organic layer and concentrated at below 40°C, resulting residue was purified in mixture of dichloromethane and ethyl acetate to produce compound of Formula (V) (118 g, wet) as a solid. Also, the filtrate and the washing solutions were combined to obtain as ethyl acetate solution of compound of formula (V), which was used for isolation of compound of Formula (VI) and preparation of compound (III).
Yield: 89.6% by theory, Purity by HPLC: 99.48%.

Example-2: Isolation of (12aS)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furanyl]carbonyl]-1H-[1,4]oxazino[3,4-c]pyrido[2,1] [1,2,4]triazine-6,8-dione of Formula (VI).
A mixture of filtrate and washing solutions having compound of Formula (VI) was concentrated to about half volume under vacuum then added water (35 ml, w.r.t batch size). The mixture was stirred for 30 min. Then resulting solid was collected by filtration and dried to obtain compound of Formula (VI) (21.4 g).
Yield: 94.2% by theory, Purity by HPLC: 98.20%.
Example-3: Preparation of (12aR)-3,4, 12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4] oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (I).
To a suspension of (12aR)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furanyl]carbonyl]1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione compound of Formula (V) (118 g, wet), methanol (26.6 g) and ethyl acetate (590 ml) was added DBU (4.2 g). The reaction mixture was stirred for 3-3.5 h, after completion of reaction, resulting solid was collected by filtration. The resulting solid washed with ethyl acetate (236 ml) and dried to obtain compound of Formula (I) (84.1 g).
Yield: 84.1% by theory, Purity by HPLC: 99.81%, Chiral purity by HPLC: 99.96%.
Example-4: Preparation of (12aS)-3, 4, 12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (VII).
To a suspension of (12aS)-3,4,12,12a-tetrahydro-7-(phenylmethoxy)-12-[[(2R)-tetrahydro-2-furanyl]carbonyl]1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (V) (45 g), methanol (10 g) and ethyl acetate (225 ml) was added DBU (1.6 g). The reaction mixture was stirred for 3-3.5 h, after completion of reaction, resulting solid was collected by filtration. The resulting solid washed with ethyl acetate (90 ml) and dried to obtain compound of Formula (VII) (26.8 g).
Yield: 77.4% by theory, Purity by HPLC: 99.91%, Chiral purity by HPLC: 99.70%.
Example-5: Preparation of 3,4,12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4]oxazino [3, 4-c] pyrido [2,1-f][1,2,4]triazine-6,8-dione of formula (III).
A mixture of filtrate and washing solutions having compound of formula (VI) was concentrated under vacuum followed by methanol (200ml, w.r.t batch size) and DBU (93.11 g) were added to the reaction mixture. Further, the mixture was stirred at 60-65°C for 15h. After completion of reaction, cooled to RT and resulting solid was collected by filtration. The resulting solid washed with ethyl acetate (200 ml) and dried to obtain compound of Formula (III) (91.6 g).
Yield: 91.6% by theory, Purity by HPLC: 99.44%. Chiral purity by HPLC: 49.16% (R-isomer), 50.84 (S-isomer).
Example-6: Preparation of 7-(hexyloxy)-3, 4, 12, 12a-tetrahydro-(12aR)-1H-[1,4]Oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione Tosylate (VIII).
To a solution of 1-Heaxanol (561.6 g) in Tetrahydrofuran (300 ml) was added Isopropyl magnesium chloride in tetrahydrofuran solution (343.6 ml) at 0-5°C over period of 60 min under nitrogen atmosphere followed by reaction mixture was maintained temperature at 20-30°C for 90 min then cooled to 0-5°C and compound of Formula (I) (150g) was added to above resulting solution at 0-10°C and stirred for 14h, after completion reaction by HPLC, aqueous citric acid solution (600 ml) was added to the reaction mixture followed by extracted with ethyl acetate twice (1200 ml). Combined organic layer was concentrated under reduced pressure at below 55°C, resulting syrup treated with Para toluene sulfonic acid monohydrate (95.9 g) and stirred for about 20 min.to obtain clear solution.
After, heptane solvent (6000 ml) was added to the above solution for about 20min then cooled 0-5°C and maintained for 120 min. There after resulting solid was filtered and suck dried under nitrogen atmosphere for about 30 min, unloaded the wet material and dried under vacuum at 50°C for 300 min to obtain compound of Formula (VIII) (186g)
Yield: 82.6% by theory, Purity by HPLC: 95.12%.
Example-7: Preparation of 1H-[1,4]Oxazino[3,4-c]pyrido[2,1-f][1,2,4] triazine-6,8-dione,12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-7-(hexyloxy)-3,4,12,12a-tetrahydro-(12aR)-,methanesulfonate (X).
To a mixture of ethyl acetate (788 ml) and cyclohexane (263 ml) was added compound of Formula (IX) (104.4 g) followed by compound of Formula (VIII) (175 g) and the reaction mass was stirred for about 10 min. at 20-30°C followed by Propyl phosphoric anhydride (338.41 g) and methane sulfonic acid (51.1 g) were added to the above reaction mass at 20-30°C. After that resulting clear solution was stirred for 14 h at 60-65°C. After completion of reaction by HPLC, reaction mixture in aqueous sodium carbonate solution was cooled to 0-10°C. An organic layer and aqueous layer were separated and extracted with ethyl acetate then combined organic layers were concentrated under reduced pressure at 50°C, resulting crude was dissolved in acetone (700 ml) and methane sulfonic acid (37.46g) at 40-45°C, was added to reaction mixture. After that resulting solution was cooled 0-5°C, precipitating solid was collected by filtration. The resulting solid was washed with acetone (175 ml) and dried to obtain compound of Formula (X) (191.6 g).
Yield: 81.2% by theory, Purity by HPLC: 90.57%.
Example-8: Preparation of 12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e] thiepin-11-yl]-3,4,12,12a-tetrahydro-7-hydroxy-(12aR)1H-[1,4]Oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (XI) (Baloxavir)
To a solution of compound of Formula (X) (175 g) in N-methylpyrrolidine (525 ml) was added lithium chloride- over two lots (2x67.16 g) at 0-5°C, after that maintained for 16h at 70-75°C. After completion of reaction by HPLC, reaction mixture was cooled to 20-30°C. And cold water (5000 l) was added to reaction mass, then precipitating solid was collected by filtration and washed with water (700 ml) followed by isopropyl alcohol was added (350 ml) and recrystallized in acetone to obtain compound of Formula (XI) (105g).
Yield: 82.4% by theory, Purity by HPLC: 97.0%.
Example-9: Preparation ({(12aR)-12-[(11s)-7,8-difluoro-6,11-dihydro dibenzo-[B,E]-thiepin11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1h-[1,4]-oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate of Formula (II) (Baloxavir morboxil):
To a suspension of potassium carbonate (45.73 g) and potassium iodide (30.21 g) in N-Methyl-2-pyrrolidinone (400 ml) was added compound of Formula (XI), followed by chloromethyl methyl carbonate (51.5 g) was added to reaction mixture then stirred for 8h at 40-45°C. After completion of reaction by HPLC, reaction mass was cooled to 25-30°C and water (2400 ml) was added followed by resulting solid was filtered and washed with water twice (160ml) and unloaded the material. There after resulting mass was recrystallized in dichloromethane and methanol mixture to obtain compound of Formula (II) (77.7g).
Yield: 82.2% by theory, Purity by HPLC: 99.8%.

Route of synthesis-I of (12aR)-3,4, 12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4] oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (I) in the present invention:

Route of synthesis- II of (12aR)-3,4, 12,12a-tetrahydro-7-(phenylmethoxy)-1H-[1,4] oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of Formula (III) from the compound of Formula (VI) in the present invention:

Route of synthesis-III of Baloxavir morboxil of Formula-(II) in the present invention.