The present invention relates to process for the preparation of (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoy
[r,2,:4s5]pyrazino[2,l-b][l,3]pxazin-7-ol represented by the following structural formula-1 and pharmaceutical^ acceptable salts thereof.

Field of the Invention:
The present invention provides process for the preparation of (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbam^
[r)2':4J5]pyrazino[2,l-b][l,3]oxazin-7-ol represented by the following structural formula-1
and pharmaceutically acceptable salts thereof.
i
J OH 0 CH3
F O n
i
Formula-1 Background of the Invention:
(4R|,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-638-dioxo-
i
3J4,6J8,123j2a-hexahydro-2H-pyrido[l,,2,:4,5]pyrazino[2,l-b][lJ3]oxazin-7-ol (commonly known as JDolutegravir), its salts and process for their preparation is first disclosed in US8129385B2.
i
The present invention provides an improved process for the preparation of (4R,12aS)-9-{[(2J4-difluorophenyl)methyl]carbamoyl}-4-methyl-6s8-dioxo-3J4,6,8,12,12a-hexahydro-2H-pyrido01',2,:4,5]pyrazino[2,l-b][lJ3]oxazin-7-ol and its pharmaceutically acceptable salts.

Brief description of the invention:
t
i

The first aspect of the present invention is to provide a process for the preparation of
(4R, 12aS)-J9- {[(2,4-difluorophenyl)methyl]carbamoyl} -4-methyl-6,8-dioxo-3,4,6,8,12,12a-
hexahydro-J2H-pyrido [l'^'^^JpyrazinoPJ-bltl^Joxazin-y-ol compound of formula-1 and
i its sodium salt of formula-la.
i i
!
: i

The second aspect of the present invention is to provide a process for the preparation of an intermediate compound, which is useful for the preparation of compound of formula-1 and its pharmaceutically acceptable salts.
1 Q

Detailed description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" sjuch as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene,
i
xylene andjthe like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacfetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP)
and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon
i
tetrachloride 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; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or mixture of any of the
aforementioned solvents.
I
i t i

The| term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium
t i
bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide
i i
and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium
methoxide,! potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tertbutoxide,
potassium fcert.butoxide, lithium tertbutoxide and the like; "alkali metal hydrides" such as
j sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such
as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth
metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate,
calcium ac'etate and the like; ammonia; "organic bases" like dimethylamine, diethylamine,
diisopropyl mine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine,
tributylamine, tertbutyl amine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-
i
methylimioiazole, l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-

1 ene(DBN)i N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-
lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium
diisopropylamide (LDA) and the like; "organosilicon bases" such as lithium
i
hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or their mixtures.

The first aspect of the present invention provides a process for the preparation of (4R, i 2aS)-k- {[(2,4-difluorophenyl)methyl]carbamoyl} -4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,l-b][l,3]oxazin-7-ol compound of formula-1 and
its sodium salt of formula-la, comprising of;
i

a) Reacting the beta-keto ester compound of general formula-2
i
i i
s
1 I
s i
t
with 1,2-ethanediol or 1,3-propanediol under suitable conditions to provide compound of general formula-3,
i i i
!
i i
: !
wherein, 'n' is 1 or 2; 'Rf represents C1-C6 straight/branched chain alkyl group; 'R2' represents substituted or unsubstituted alkyl, aryl, aralkyl group;
b) hydrolyzing the compound of general formula-3 in presence of a suitable base optionally
in a suitable solvent to provide compound of general formula-4,
1 i 1 »
1 1 1
i
c) reacting the compound of general formula-4 with 2,4-difluorobenzylamine in presence of
i a suitable coupling agent and/or a suitable base in a suitable solvent to provide
1 compound of general formula-5,

i
i
1 !
1
I 1
d) deprotecting the compound of general formula-5 to provide compound of general
formula-6,
j"
t
e) reacting the compound of general formula-6 with N,N-dimethylformamide dimethyl
!
acetal in a suitable solvent to provide compound of general formula-7,
0 0
I J H I
I '
| Formula-7
f) reacting the compound of general formula-7 with oxalic acid derivative represented by
below mentioned structural formula
|
i i
i
wherein, 'R3' represents alkoxy, halogen; 'R4' represents alkyl group;
in a suitable solvent optionally in presence of a suitable base followed by reacting the
i obtainejd compound with allyl amine in a suitable solvent to provide compound of general
i
formula-8,
!
■ i I
i !
i 1
I !
I

!
g) oxidizing the compound of general formula-8 with a suitable oxidizing agent in a suitable solvent to provide compound of general formula-9,
i
i i i
h) reacting the compound of general formula-9 with (R)-3-amino-butanol in a suitable
i i
solvent! optionally in presence of a suitable acid to provide compound of general formula-10,
!
! |
|
! I
J M
I f
i) deproteeting the compound of general formula-10 under suitable conditions to provide
compoiiind of formula-1, j) optionally purifying the compound of formula-1 from a suitable solvent or mixture of
solvents to provide pure compound of formula-1, k) treating the compound of formula-1 with a suitable sodium source in a suitable solvent to
provide sodium (4R, 12aS)-9- {[(2,4-difluorophenyl)methyl] carbamoyl} -4-methyl-6,8-
i
dioxo-3,4,6,8s12,12a-hexahydro-2H-pyrido[l,,2,:4,5]pyrazino[2,l-b][l,3]oxazin-7-olate compound of formula-la, 1) purifying the compound of formula-la from a suitable solvent or mixture of solvents to provide pure compound of formula-la.
i i
i Wherein, in step-a) the reaction is carried out in presence of p-toluenesulfonic acid,
HC1, sulfuric acid, oxalic acid, trimethylsilyl trifluoromethanesulfonate (TMSOTf),
BF3/etherate, FeCl3, pyridinium p-toluenesulfonate (PPTS), trialkyl orthoformate in presence
of catalytic! amount of tetrabutylammonium tribromide (TBATB) and the like;
In s;tep-b) the suitable base is selected from but not limited to alkali metal hydroxides,
i
alkali metal alkoxides and the like;

I
I
I In step-c) the suitable coupling agent is selected from but not limited to 1,1'-
carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide
(DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), 1-
[bis(dimethylamino)methylene]-1H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafluoro phosphate (HATU), 2-( 1 H-benzotriazol-1 -yl)-1,1,3,3 -tetramethyluronium
hexafluorophosphate (HBTU), lH-benzotriazolium l-[bis(dimethylamino)methylene]-
i
Schloro-hexafluorophosphate (1-) 3-oxide (HCTU), alkyl or aryl chloroformates such as
ethyl chloroformate, isobutyl chloroformate, benzylchloroformate, diphenylphosphoroazidate
(DPPA), thionyl chloride, oxalyl chloride, pivaloyl chloride, phosphorous oxychloride,
phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl),
(benzotriaz:ol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate % (BOP),
i benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane
sulfonyl chloride and the like optionally in combination with l-hydroxy-7-azatriazole
(HO At), jl -hydroxybenzotriazole (HOBt), 1 -hydroxy-1H-1,2,3 -triazole-4-carboxylate
(HOCt), Ol-Oenzotriazol-l-yy-N^^^N'-tetramethyluronium tetrafluoroborate (TBTU), N-
i ■
hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS) and the like; the suitable base is selected from but not limited to organic bases, organolithium bases, organosilicpn base or their mixtures;

In step-d) the deprotection is carried out by using HC1, H2SO4, acetic acid, formic acid, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), p-toluenesulfonic acid and the like;

In jstep-f) the suitable base is selected from inorganic bases, organic bases, organolithium bases, organosilicon bases or their mixtures;

In ^tep-g) the suitable oxidizing agent is selected from but not limited to osmium tetraoxide, I alkali metal osmium tetraoxide such as potassium osmate, Ruthenium (III) chloride, permanganates and the reaction is carried out in presence of sodium/potassium metaperioaate or periodic acid or lead tetraacetate Pb(OAc)4;
j

In s|tep-h) the suitable acid is selected from acetic acid, formic acid, HC1 and the like;
i

In step-i) the suitable reagent for deprotection is selected based on the type of protecting group employed; for example when 'IV represents methyl group, then Lewis
1
acids such; as A1C13, Magnesium halides, lithium halides, Boron trihalides, trialkylsilyl
!
1
1
1 I

halides can be used as deprotecting agents; when 'R2' represents aralkyl group such as benzyl, then Pd-C, trifluoroacetic acid can be used as deprotecting agents;

In step-k) the suitable sodium source is selected from sodium hydroxide, sodium alkoxides and the like.

From step-a) to step-1) the suitable solvent wherever required is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.

The aldehyde compound of general formula-9 can also be synthesized by reacting the compound 'of general formula-7 with the above mentioned oxalic acid derivative followed by reacting the obtained compound with 2-aminoethanol to provide an alcohol compound which can be further oxidized with a suitable oxidizing agent to provide compound of general
i i
formula-9.!
i
i i
i
i , *

Alternatively, compound of general formula-9 can also be synthesized by replacing 2-aminoetHanol with (2,2-dimethyl-l,3-dioxolan-4-yl)methanamine of following formula
i |
I
i
i |
and then subsequent deprotection of obtained compound under suitable conditions for example in presence of an acid such as p-toluenesulfonic acid, acetic acid to provide diol compound land then oxidation of diol with a suitable oxidizing agent as mentioned in step-g) of above aspect to provide compound of general formula-9.
i i
i

The beta-keto ester compound of general formula-2 utilized in the above aspect can be synthesized by any of the known process.

The second aspect of the present invention provides a process for the preparation of an intermediate compound, which is useful for the preparation of compound of formula-1 and its pharmaceutically acceptable salts.

I
1 '
1
I
■I
I
I
One embodiment of the second aspect of the present invention provides a process for the preparation of compound represented by the general formula-8, which is an useful intermediate in the synthesis of compound of formula-1
!
i i i
i t
i
!
wherein, 'R2' represents alkyl, aryl, aralkyl and 'IV represents alkyl group; comprising of, reacting the compound of general formula-7
I
i [ I
I t (
i
i
i
with oxalic- acid derivative represented by below mentioned structural formula
i
i
[ i
!
J
i
i wherein, 'R3' represents alkoxy, halogen; 'IV represents alkyl group;
in a suitable solvent optionally in presence of a suitable base followed by reacting the
obtained compound with allyl amine in a suitable solvent to provide compound of general
formula-8.
i
Wherein, the suitable base is selected from inorganic bases, organic bases, organolithiiim bases, organosilicon bases or their mixtures and the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
i i
i

The' compound represented by the following structural formula is formed as an intermediate by reacting compound of general formula-7 with oxalic acid derivative.


wherein, 'R^' & 'R4' have the same meaning as defined above.

A preferred embodiment of the present invention provides a process for the preparation of methyl l-allyl-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-l,4-dihydropyridine-2-carboxylate compound of formula-8a
i !
I I
i
!
wherein, 'Bn' means benzyl group (-CH2PI1);
1 comprising! of reacting the (E)-4-(benzyloxy)-N-(2,4-difluorobenzyl)-2-((dimethylamino)
i methylene)|-3-oxobutanamide compound of formula-7a
Formula-7a
i with dimethyl oxalate represented by the below structural formula
1
1 in a suitable solvent in presence of a suitable base followed by reacting the obtained
compound represented by the below structural formula

with allyl amine in a suitable solvent to provide compound of formula-8a.

I
i
Wherein, the suitable base and the suitable solvent are same as defined above in the
second aspect.
i i i

A more preferred embodiment of the present invention provides a process for the preparation of methyl l-allyl-3-(benzyloxy)-5-((2,4-difluorobenzyl) carbamoyl)-4-oxo-l,4-dihydropyridine-2-carboxylate compound of formula-8a, comprising of reacting the compound of formula-7a with dimethyl oxalate in dimethyl sulfoxide in presence of sodium methoxide solution in methanol followed by reacting the obtained compound with allyl amine in tetrahydrofuran in presence of acetic acid to provide compound of formula-8a.

i
The present invention is schematically represented as follows.

The best mode of carrying out the present invention is illustrated by the below
!
mentioned jexamples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:
Example-1: Preparation of ethyl 4-(benzyloxy)-3-oxobutanoate (Formula-2a)
i
A solution of benzyl alcohol (30 gm) in tetrahydrofuran (180 ml) was added to a mixture ofj sodium tert.butoxide (66.2 gm) and tetrahydrofuran (135 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 40-45°C and stirred for 2 hrs at the same temperature. A solution of ethyl-4-chloro-3-oxobutanoate (50 gm) in tetrahydrofuran (135
t
ml) was ajdded to the reaction mixture at 40-45 °C and stirred for 2 hrs at the same
i
temperature. Cooled the reaction mixture to 0-5°C and 2N hydrochloric acid solution was slowly added to it. Raised the temperature of the reaction mixture to 25-30°C, ethyl acetate was added! and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 6% aqueous sodium
t
bicarbonate solution followed by with 10% aqueous sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to j get the title compound. Yield: 60.Q gm.
i i
Example-i: Preparation of ethyl 2-(2-((benzyloxy)methyl)-l,3-dioxolan-2-yl)acetate
j ,
(Formula-3a)
p-Toluenesulfonic acid (2.2 gm) and ethylene glycol (48.5 ml) were added to a mixture of'ethyl 4-(benzyloxy)-3-oxobutanoate compound of formula-2a (30 gm) and toluene
i
(300 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 100-105°C under azeotrope condition and stirred for 5 hrs at the same temperature. Cooled the reaction mixture toJ25-30°C, 5% aqueous potassium carbonate solution was added and stirred the
reaction mixture for 15 min at the same temperature. Both the organic and aqueous layers
i
were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic
i
layers and jvashed with water followed by with 10% aqueous sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to!get the title compound. Yield: 23.1 gm.
!

Example-3f: Preparation of 2-(2-((benzyloxy)methyl)-l,3-dioxolan-2-yl)acetic acid (Formula-4a)
16°/|o Aqueous sodium hydroxide solution (38.6 ml) was drop wise added to a mixture of ethyl 2-(2-((benzyloxy)memyl)-l,3-dioxolan-2-yl)acetate compound of formula-3a (23 gm) and ethanol (230 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction
i
mixture fot 16 hrs at the same temperature. Distilled off the solvent completely from the
i
reaction rriixture under reduced pressure and ethyl acetate was added to the obtained
j
compound.! Cooled the reaction mixture to 10-15°C and 5% citric acid solution was added. Raised the jtemperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and dried the organic layer over sodium sulfate. Distilled off solvent completely from the organic layer under reduced
i
pressure to j get title compound. Yield: 12.4 gm.
i
i
t
Example-4: Preparation of 2-(2-((benzyIoxy)methyl)-l,3-dioxoIan-2-yl)-N-(2,4-difluoro benzyl)ace|tamide (Formula-5a)
Hydroxybenzotriazole (8.2 gm), dicyclohexylcarbodiimide (10.6 gm) and dichloromdthane (62 ml) were added to a mixture of 2-(2-((benzyloxy)methyl)-l,3-dioxolan-2-yl)acetic!acid compound of formula-4a (12.4 gm) and dichloromethane (124 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 30 min at the same
i
temperaturk To the obtained reaction mixture, 2,4-difluorobenzylamine (8.4 gm) was added at 25-30°Ci and stirred for 15 hrs at the same temperature. Filtered the reaction mixture and washed the filtrate with 5% citric acid solution followed by with 7% aqueous sodium bicarbonate solution and then finally with 10% aqueous sodium chloride solution. Dried the
organic layer over sodium sulfate and distilled off the solvent completely under reduced
i pressure to j get the title compound.
Yield: 18.6: gm.
i i
Example-5: Preparation of 4-(benzyloxy)-N-(2,4-difluorobenzyl)-3-oxobutanamide
i (Formula-jSa)
62% Sulfuric acid solution (10 ml) was slowly added drop wise to a mixture of 2-(2-
((benzyloxy)methyl)-1,3-dioxolan-2-yl)-N-(2,4-difluorobenzyl)acetamide compound of
i
i
i

formula-5a| (18.6 gm) and formic acid (93 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 16 hrs at the same temperature. Water and dichloromethane
i i
were slowljy added to the reaction mixture at 0-5 °C and stirred for 15 min. Both the organic
i
i
and aqueous layers were separated and washed the organic layer with 10% aqueous sodium
i chloride so'lution. Dried the organic layer over sodium sulfate and distilled off the solvent
completely! from the organic layer under reduced pressure. The obtained compound was
■
purified byj column chromatography using 30% ethyl acetate in cyclohexane as eluent to get pure title compound.
Yield: 7.5 gm.
I
| Example-6: Preparation of (E)-4-(benzyloxy)-N-(2,4-difluorobenzyl)-2-((dimethyl
amino)methylene)-3-oxobutanamide (Formula-7a)
N,N-dimethylformamide dimethyl acetal (4 gm) was added to a mixture of 4-
(ben2yloxyi)-N-(2,4-difluorobenzyl)-3-oxobutanamide compound of formula-6a (7.5 gm) and
i
i
toluene (37.5 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for
i
12 hrs at the same temperature. 10% Aqueous sodium chloride solution was added to the
reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic
and aqueous layers were separated and dried the organic layer over sodium sulfate. Distilled
off the soljvent completely from the organic layer under reduced pressure to get the title
j compound.;
Yield: 7.0 gm.
I
t i
Example-^: Preparation of methyl l-allyl-3-(benzyloxy)-5-((2,4-
l
difluorobenzyl)carbamoyl)-4-oxo-l,4-dihydropyridine-2-carboxylate (Formula-8a)
Dimethyl oxalate (4.3 gm) was added to a mixture of. (E)-4-(benzyloxy)-N-(2,4-difluorobenzyl)-2-((dimethylamino)methylene)-3-oxobutanamide compound of formula-7a (7 gm) andjdimethylsulfoxide (25.2 ml) at 25-30°C under nitrogen atmosphere and stirred the " reaction mixture for 5 min at the same temperature. Cooled the reaction mixture to 15-20°C, 28% sodiuin methoxide solution in methanol (4.2 ml) was slowly added drop wise to the reaction mixture at 15-20°C and stirred the reaction mixture for 2 hrs at 25-30°C. A mixture of allyl amine (1.54 gm), acetic acid (5.2 ml) and tetrahydrofuran (10 ml) was slowly added

drop wise to the reaction mixture at 15-20°C. Heated the reaction mixture to 45-50°C and
stirred for 5 hrs at the same temperature. Water and ethyl acetate were added to the reaction
mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and
aqueous layers were separated and washed the organic layer with IN HC1 solution followed
! by with 20% sodium chloride solution. Dried the organic layer over sodium sulfate and
i i
distilled off the solvent completely from the organic layer under reduced pressure. The obtained cbmpound was purified by column chromatography using 50% ethyl acetate in
i t
cyclohexarie as eluent to get the pure title compound. Yield: 2.0 £m.
i
Example-8: Preparation of methyl 3-(benzyIoxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-2-carboxylate(Formula-9a)
Methyl l-allyl-3-(benzyloxy)-5-((2s4-difluorobenzyl)carbamoyl)-4-oxo-l,4-dihydro
pyridine-2-jcarboxylate compound of formula-8a (10 gm) was added to a mixture of
RuCl3.2H2p (0.18 gm), acetonitrile (215 ml) and water (35 ml) at 25-30°C and stirred the
reaction mixture for 15 min at the same temperature. Sodium meta periodate (8.5 gm) was
j added portion wise to the reaction mixture at 25-30°C and stirred the reaction mixture for 2
hrs at the same temperature. Ethyl acetate and 10% aqueous sodium thiosulfate solution were
added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature.
i
Both the organic and aqueous layers were separated and dried the organic layer over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to^ get the title, compound. Yield: 6.0 gm.
i
i i
Example-9: Preparation of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-2-carboxylate(Formula-9a)
A solution of potassium osmate dihydrate (0.4 gm) in water (50 ml) was added to a mixture of methyl l-allyl-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-l,4-dihydropyridine-2-carboxylate compound of formula-8a (10 gm) and 1,4-dioxane (300 ml) at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Sodium meta
t i
periodate (19.4 gm) was added portion wise to the reaction mixture at 25-30°C and stirred for
i

2 hrs at the same temperature. Ethyl acetate and water were added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the organic layer was washed with 5% sodium hydrogen sulfite solution followed by with 10% aqueous sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent under reduced pressure to get the title compound.
i
Yield: 7.0 gm.
i
i
I I
Example-10: Preparation of (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[lf,2':4,5]pyrazino[2,l-b][l,3]oxazine-9-
i I
carboxamide (Formula-10)
i i
(R)f3-amino-butanol (13.8 gm) and methanol (15.3 ml) were added to a mixture of methyl 3-i(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydro
pyridine-2-;carboxylate compound of formula-9a (50 gm) and toluene (500 ml) at 25-30°C
i
under nitro'gen atmosphere. Glacial acetic acid (7.8 ml) was slowly added portion wise to the
reaction mixture at 25-30°C. Heated the reaction mixture to 85-90°C and stirred for 8 hrs at
I
the same temperature. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 9% aqueous sodium bicarbonate solution followed by with 10% aqueous sodium chloride solution. Dried the organic layer over
i i
sodium sulfate, distilled off the solvent under reduced pressure and co-distilled with
I
methanol. 50 ml of methanol was added to the obtained compound at 25-30°C and stirred for
i 1
30 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and
i
!
dried to get the title compound. Yield: 27.0 gm.
!
Example-11: Preparation of compound of formula-1
5%| Pd/C (1.4 gm) was added to a solution of (4R,12aS)-7-(benzyloxy)-N-(2,4-
difluoroberkyl)-4-methyl-658-dioxo-3,4}6s8,12512a-hexahydro-2H-pyrido[1^2,:4J5]pyrazine
i
[2,l-b][l,3]oxazine-9-carboxamide compound of formula-10a (20 gm) in tetrahydrofuran (180 ml) and methanol (20 ml) in an autoclave vessel at 25-30°C under nitrogen atmosphere. Flushed the reaction mixture with nitrogen gas followed by with hydrogen gas. 2.5-3.0
i

Kg/cm of hydrogen gas pressure was applied to the reaction mixture and stirred the reaction
mixture for 15 hrs at 25-30°C. Released the hydrogen gas from autoclave vessel, filtered the
i reaction mixture through hyflow bed and washed with tetrahydrofuran. Distilled off the
solvent completely from the filtrate under reduced pressure. Ethanol (580 ml) was added to
the obtainejd compound at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 30
i
min at the jsame temperature. Filtered the reaction mixture through hyflow bed, cooled the filtrate to 2|5-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with ethanol and then dried to get the title compound.
Yield: 14.2 gm.
i
l
Example-12: Preparation of compound of formula-la
A mixture of compound of formula-1 (13.4 gm) and ethanol (469 ml) was heated to
V
90-95°C and stirred the reaction mixture for 15 min at the same temperature. Filtered the
i
reaction mixture through hyflow bed, heated the filtrate to 90-95°C and stirred for 15 min at the same temperature. 2N aqueous sodium hydroxide solution (16 ml) was added drop wise to the reaction mixture and stirred for 10 min. Cooled the reaction mixture to 25-30°C and stirred for j 45 min at the same temperature. Filtered the precipitated solid, washed with ethanol and then dried the material to get the title compound.
Yield: 12.0 gm.
i i
Example-1!3: Purification of compound of formula-la
i
A jmixture of sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8fdioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[r,2':4,5]pyrazino[2,1 -b] [ 1,3]oxazin-7-olate compound of formula-la (10 gm) and ethanol (300 ml) was heated to 90-95°C and stirred the reaction mixture for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C arid stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with ethanol and the dried the material to get pure title compound. Yield: 8.0 gm.