[ CAS No. 1206102-11-5 ] {[proInfo.proName]}

Name: 1206102-11-5|(4R,12aS)-7-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide|95%
Brand: Ambeed
SKU: A191959
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Quality Control of [ 1206102-11-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1206102-11-5 ]

SDS Specification

Alternatived Products of [ 1206102-11-5 ]

Product Details of [ 1206102-11-5 ]

CAS No. :	1206102-11-5	MDL No. :	MFCD22741602
Formula :	C₂₇H₂₅F₂N₃O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RWEIORQEUUWOLH-ZHRRBRCNSA-N
M.W :	509.50	Pubchem ID :	66554053
Synonyms :

Calculated chemistry of [ 1206102-11-5 ]

Physicochemical Properties

Num. heavy atoms :	37
Num. arom. heavy atoms :	18
Fraction Csp3 :	0.3
Num. rotatable bonds :	7
Num. H-bond acceptors :	7.0
Num. H-bond donors :	1.0
Molar Refractivity :	133.43
TPSA :	89.87 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.29
Log Po/w (XLOGP3) :	3.71
Log Po/w (WLOGP) :	3.38
Log Po/w (MLOGP) :	2.29
Log Po/w (SILICOS-IT) :	3.83
Consensus Log Po/w :	3.3

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-5.23
Solubility :	0.00297 mg/ml ; 0.00000583 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.29
Solubility :	0.00262 mg/ml ; 0.00000515 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-7.61
Solubility :	0.0000124 mg/ml ; 0.0000000244 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.78

Safety of [ 1206102-11-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1206102-11-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1206102-11-5 ]

[ 1206102-11-5 ] Synthesis Path-Downstream 1~59

1
[ 201230-82-2 ]
[ 1206102-10-4 ]
[ 72235-52-0 ]
[ 1206102-11-5 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine;tetrakis(triphenylphosphine) palladium(0); In dimethyl sulfoxide; at 90℃; for 5.5h;Product distribution / selectivity;	Under carbon mono-oxide atmosphere, a mixture of 33.5 g of compound 10(1.0 eq.), 34.8 mL of /-Pr2NEt(2.5 eq.), 14.3 mL of <strong>[72235-52-0]2,4-difluorobenzylamine</strong>(1.5 eq.) and 4.62 g of Pd(PPh3)4(0.05 eq.) in 335 mL of DMSO was stirred at 90 0C for 5.5 h. After cooling, precipitate was filtered and washed with 50 mL of 2-propanol. After addition of 502 mL of H2O and 670 mL of AcOEt to the filtrate, the organic layer was washed with 335 mL of 0.5N HCIaq. and 335 mL of H2O and the aqueous layer was extracted with 335 mL of AcOEt. The organic layers were combined and concentrated. To the residue, 150 mL of 2-propanol was added and the mixture was concentrated. After addition of 150 mL of 2- propanol, concentration, cooling to 20 0C and filtration, crude crystal of compound 11 was obtained. After dissolution of the crude crystal in 380 mL of acetone by heating, precipitate was filtered and the filtrate was concentrated. After addition of 200 mL of EtOH, concentration, addition of 150 mL of EtOH, concentration, cooling and filtration, crude crystal of compound 11 was obtained. After dissolution of the crude crystal in 450 mL of acetone by heating, the solution was concentrated. To the residue, 150 mL of 2- propanol was added and the mixture was concentrated (twice). After cooling of the residue, filtration, washing with 2-propanol and drying provided 34.3 g of compound 11 (84% yield) as a crystal.1H NMR(300 MHz, CDCI3) delta 10.40 (t, J = 6.0 Hz, 1H), 8.35 (s, 1 H), 7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m, 2H), 5.30 (d, J = 9.9 Hz, 1 H)1 5.26 (d, J = 10.2 Hz, 1H), 5.15 (dd, J = 3.9, 5.7 Hz, 1 H)1 5.05-4.90 (m, 1 H), 4.64 (d, J = 5.4 Hz, 2H), 4.22 (dd, J = 3.9, 13.5, 1 H), 4.09 (dd, J = 6.0, 13.2 Hz, 1H), 4.02-3.88 (m, 2H), 2.24-1.86 (m, 1H), 1.50 (ddd, J = 2.4, 4.5, 14.1 Hz, 1 H)1 1.33 (d, J = 7.2 Hz1 3H).
84%	With tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; for 5.5h;	Under carbon mono-oxide atmosphere, a mixture of 33.5 g of compound 10 (1.0 eq.), 34.8 mL of i-Pr2NEt (2.5 eq.), 14.3 mL of <strong>[72235-52-0]2,4-difluorobenzylamine</strong> (1.5 eq.) and 4.62 g of Pd(PPh3)4(0.05 eq.) in 335 mL of DMSO was stirred at 90 C. for 5.5 h. After cooling, precipitate was filtered and washed with 50 mL of 2-propanol. After addition of 502 mL of H2O and 670 mL of AcOEt to the filtrate, the organic layer was washed with 335 mL of 0.5N HClaq. and 335 mL of H2O and the aqueous layer was extracted with 335 mL of AcOEt. The organic layers were combined and concentrated. To the residue, 150 mL of 2-propanol was added and the mixture was concentrated. After addition of 150 mL of 2-propanol, concentration, cooling to 20 C. and filtration, crude crystal of compound 11 was obtained. After dissolution of the crude crystal in 380 mL of acetone by heating, precipitate was filtered and the filtrate was concentrated. After addition of 200 mL of EtOH, concentration, addition of 150 mL of EtOH, concentration, cooling and filtration, crude crystal of compound 11 was obtained. After dissolution of the crude crystal in 450 mL of acetone by heating, the solution was concentrated. To the residue, 150 mL of 2-propanol was added and the mixture was concentrated (twice). After cooling of the residue, filtration, washing with 2-propanol and drying provided 34.3 g of compound 11 (84% yield) as a crystal.

Reference： [1]Organic Process Research and Development,2019,vol. 23,p. 558 - 564
[2]Patent: WO2010/68262,2010,A1 .Location in patent: Page/Page column 19
[3]Patent: JP5848595,2016,B2 .Location in patent: Paragraph 0034
[4]Organic Process Research and Development,2019,vol. 23,p. 565 - 570

2
[ 1206102-11-5 ]
dolutegravir [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; for 2.5h;Product distribution / selectivity;	Under hydrogen atmosphere, a mixture of 28.0 g of compound 11(1.0 eq.) and 5.6 g of 10% Pd-C in 252 mL of THF and 28 mL of MeOH was stirred for 1 h. After precipitate(Pd-C) was filtered and washed with 45 mL of THF, 5.6 g of 10% Pd-C was added and the mixture was stirred for 1.5 h under hydrogen atmosphere. After Pd-C was filtered and washed with 150 mL of CHCl3/MeOH(9/1 ), the filtrate was concentrated. After dissolution of the residue in 1.38 L of EtOH by heating, the solution was gradually cooled to room temperature. After filtration, the filtrate was concentrated and cooled. Filtration, washing with EtOH and drying provided 21.2 g of compound 12 (92% yield) as a crystal.1H NMR(300 MHz, DMSO-d6) delta 12.51 (s, 1H), 10.36 (t, J = 5.7 Hz, 1 H), 8.50 (s, 1H), 7.39 (td, J = 8.7, 6.3 Hz, 1H), 7.24 (ddd, J = 2.6, 9.5, 10.8 Hz, 1H), 7.12-7.00 (m, 1H), 5.44 (dd, J = 3.9, 5.7 Hz, 1 H), 4.90-4.70 (m, 1 H), 4.65-4.50 (m, 1 H), 4.54 (d, J = 5.1 Hz, 2H), 4.35 (dd, J = 6.0, 13.8 Hz, 1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 1H), 2.10-1.94 (m, 1H), 1.60-1.48 (m, 1H), 1.33 (d, J = 6.9 Hz, 3H).
92%	With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; for 2.5h;	Under hydrogen atmosphere, a mixture of 28.0 g of compound 11 (1.0 eq.) and 5.6 g of 10% Pd-C in 252 mL of THF and 28 mL of MeOH was stirred for 1 h. After precipitate (Pd-C) was filtered and washed with 45 mL of THF, 5.6 g of 10% Pd-C was added and the mixture was stirred for 1.5 h under hydrogen atmosphere. After Pd-C was filtered and washed with 150 mL of CHCl3/MeOH (9/1), the filtrate was concentrated. After dissolution of the residue in 1.38 L of EtOH by heating, the solution was gradually cooled to room temperature. After filtration, the filtrate was concentrated and cooled. Filtration, washing with EtOH and drying provided 21.2 g of compound 12 (92% yield) as a crystal.
85%	With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; for 15.0h;	A 2 L round bottom flask was charged with 68.0 g of 4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-4-methyl-6,8-dioxo-7- (phenylmethoxy)-2H-Pyrido [ Gamma,2' : 4,5]pyrazino [2, 1 -b] [ 1 ,3 ] oxazine-9-carboxamide (DTG- 1)(0.13 mol, 1.00 eq.), 68 ml methanol and 610 ml tetrahydrofuran. The flask was flushed with argon, and 2.40 g 10% palladium on activated charcoal (2.2 mmol, 0.017 eq.) were added. The resulting mixture was stirred at RT, under hydrogen atmosphere, for 15 h. The flask was again flushed with argon, the solid was filtered off and the filtrate was concentrated. Pd/C filter cake was suspended in recovered solvents (600 ml), filtered and the filtrate was concentrated. The combined residues were dissolved in 370 ml absolute ethanol by heating to reflux; the solution was gradually cooled down in air to RT then with an ice-bath. The precipitate was collected by filtration, washed with ethanol (300 ml) and dried at room temperature under vacuum to give 47.6 g of Dolutegravir (85.0%> yield) ("Form I") as off-white solid. Chemical purity: 99.7% (HPLC, peak area at lambda=254 nm). LC-MS: m/z = 420.1 , ([M+H-Na]+); 1H NMR (400 MHz, DMSO-d6, delta ppm): 1.31 (d, 3H, J = 6.8 Hz), 1.53 (d, 1H, J = 13.6 Hz), 1.9-2.1 (m, 1H), 3.88 (d, 1H, J = 8.0 Hz), 4.01 (pseudo t, 1H, J = 11.8 Hz), 4.33 (dd, 1H, J = 13.2, 5.6 Hz), 4.5 - 4.6 (m, 3H), 4.7 - 4.8 (m, 1H), 5.43 (s, 1H), 7.04 (pseudo t, 1H, J = 8.6 Hz), 7.22 (pseudo t, 1H, J = 10.0 Hz), 7.37 (dd, 1H, J = 16.0, 8.0 Hz), 8.47 (s, 1H), 10.33 (s, 1H), 12.47 (s, 1H). IR [cm-1] : 3186, 3070, 2979, 2888, 1658, 1628, 1575, 1538, 1498, 1449, 1429, 1415, 1370, 1355, 1310, 1264, 1238, 1207, 1189, 1168, 1132, 1090, 1081 , 1066, 1056, 1024, 958, 930, 885, 837, 802, 781, 764, 723, 714, 662, 603

0.06 g

With palladium 10% on activated carbon; hydrogen; In ethanol; ethyl acetate; for 0.5h;

Example 19: Preparation of Dolutegravir (4R,12aS)-7-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a- hexahydro-2H-[l ,3]oxazino[3,2-d]pyrido[l ,2-a]pyrazine-9-carboxamide (0.4 gm) was dissolved in a mixture of ethyl acetate and ethanol (10: 1, 4.2 ml) and 10% palladium on carbon (0.042 gm) was then added. To the reaction mass was applied hydrogen gas via a balloon for 30 minutes. The resultant reaction mass was filtered through celite bed arid concentrated to obtain a residual solid. The residual solid was purified by silica gel column chromatography with a mixture of chloroform and methanol (99: 1) to obtain 0.06 gm of dolutegravir. 1H NMR (300 MHz, DMSO): delta 12.5 (s, I H), 10.35 (t, J- 5.7 Hz, IH), 8.5 (s, IH), 7.42-7.34 (m, IH), 7.27-7.21 (m, IH), 7.1-7.03 (m, IH), 5.45 (t, J= 4.8 Hz, IH), 4.81-4.77 (m, IH), 4.6- 4.5 (m, 3H), 4.34 (dd, J= 5.7, 13.8 Hz, IH), 4.07-3.99 (m, IH), 3.9-3.88 (m, IH), 2.05-1.96 (m, IH), 1.56-1.52 (m, IH), 1.33 (d, J= 6.9 Hz, 3H).

Reference： [1]Patent: WO2010/68262,2010,A1 .Location in patent: Page/Page column 19-20
[2]Patent: JP5848595,2016,B2 .Location in patent: Paragraph 0035
[3]Patent: WO2015/9927,2015,A1 .Location in patent: Page/Page column 24; 25
[4]Patent: WO2015/1572,2015,A2 .Location in patent: Page/Page column 27
[5]Organic Process Research and Development,2016,vol. 20,p. 1461 - 1468
[6]Organic Process Research and Development,2019,vol. 23,p. 558 - 564

3
[ 1206102-11-5 ]
[ 1339879-91-2 ]

Reference： [1]Patent: US2013/96109,2013,A1

4
[ 1206102-11-5 ]
[ 1339879-93-4 ]

Reference： [1]Patent: US2013/96109,2013,A1

5
[ 1206102-11-5 ]
[ 1339877-65-4 ]

Reference： [1]Patent: US2013/96109,2013,A1

6
[ 1206102-11-5 ]
[ 1339879-96-7 ]

Reference： [1]Patent: US2013/96109,2013,A1

7
[ 1206102-11-5 ]
[ 1339877-45-0 ]

Reference： [1]Patent: US2013/96109,2013,A1

8
[ 24424-99-5 ]
[ 1206102-11-5 ]
[ 1339879-88-7 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; In acetonitrile; at 80℃;	(1) To an acetonitrile solution (80 mL) of amide 1 (8.00 g, 14.5 mmol) was added Boc2O (10.0 g, 45.8 mmol) and DMAP (7.07 g, 57.8 mmol) at room temperature. The reaction mixture was then stirred under heating to 80 C., and Boc2O (10.0 g, 45.8 mmol) was added thereto every 10 minutes. After the raw material disappeared, aqueous 2 N sodium hydroxide solution (578 mL, 1.15 mol) and ethanol (80 mL) were added thereto, the reaction mixture was then stirred under heating to 60 C. for 5 hours. The reaction solution was evaporated off under reduced pressure, and then ethyl acetate was added to the resulting residue, followed by extraction with aqueous saturated sodium hydrogen carbonate solution. After aqueous 2 N hydrochloric acid solution was added to the aqueous layer to acidify it, it was extracted with chloroform, and then the organic layer was dried over sodium sulfate. The solvent was evaporated off under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (chloroform:methanol=95:5). Solidifying from the solution of the resulting residue in a mixture of methylene chloride-diethyl ether yielded carboxylic acid 3 as a white solid (3.58 g, 64%). 1H NMR (CDCl3, 300 MHz) delta 1.35 (d, J=7.1 Hz, 3H), 1.46-1.56 (m, 1H), 2.08-2.24 (m, 1H), 3.95 (d, J=2.5 Hz, 1H), 3.98 (dd, J=3.3, 1.9 Hz, 1H), 4.15 (dd, J=13.5, 5.8 Hz, 1H), 4.28 (dd, J=13.5, 3.8 Hz, 1H), 4.93-5.06 (m, 1H), 5.19 (dd, J=5.8, 3.8 Hz, 1H), 5.37 (d, J=10.2 Hz, 1H), 5.42 (d, J=10.2 Hz, 1H), 7.28-7.40 (m, 3H), 7.56-7.62 (m, 2H), 8.32 (s, 1H); ESI-MS [M+H+] calculated: 385, observed: 385.

Reference： [1]Patent: US2013/96109,2013,A1 .Location in patent: Paragraph 0193

9
[ 1246616-83-0 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1

10
[ 1246616-84-1 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1

11
[ 1246616-87-4 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1

12
[ 1357289-04-3 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1
[2]Patent: WO2015/9927,2015,A1

13
[ 1339879-91-2 ]
[ 72235-52-0 ]
[ 1206102-11-5 ]

Yield	Reaction Conditions	Operation in experiment
93.3%	With 1,1'-carbonyldiimidazole; In dichloromethane; for 36h;	A 3 L round bottom flask was charged with 180.0 g of (4R, 12aS)- 3 ,4,6,8, 12, 12a-hexahydro-4-methyl-6, 8-dioxo-7-(phenylmethoxy)-2H- Pyrido[l',2':4,5]pyrazino[2,l-b][l ,3]oxazine-9-carboxylic acid (DTG-2) (0.47 mol, 1.00 eq.) and 1.0 L dichloromethane. To this solution, at room temperature, a slurry of 98.6 g N.N'-carbonyldiimidazole (0.61 mol, 1.30 eq.) in 500 ml dichloromethane was added in portions. The mixture was stirred at RT until complete consumption of starting material (approx. 7 h). Then 2,4 difluorobenzyl amine was added dropwise three times, i.e. initially 67.0 g (0.47 mol, 1.00 eq.) in 160 ml dichloromethane, secondly after 15 h stirring at RT another portion of 13.4 g (93.6 mmol, 0.20 eq.) and, finally, after 6 h stirring, 3.80 g 2,4 difluorobenzyl amine (26.6 mmol, 0.05 eq.). After the third portion, the mixture was stirred for another 15 h at RT. The reaction mixture was washed with 10% HC1 solution (620 ml), 10% sodium carbonate (400 ml), water (3 x 675 ml). The organic phase was dried and concentrated under reduced pressure. The residue was crystallized in 800 ml isopropanol, collected by filtration, washed with isopropanol (400 ml) and dried at room temperature under vacuum to give 222.5 g of 4R,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a- hexahydro-4-methyl-6,8-dioxo-7-(phenylmethoxy)-2H-Pyrido[l ',2':4,5]pyrazino[2,l- b][l,3]oxazine-9-carboxamide (93.3% yield) as off-white solid. Chemical purity: 96.6% (HPLC, peak area at lambda=254 nm). 1H NMR (400 MHz, CDCl3, 5 ppm): 1.32 (d, 3H, J = 7.0 Hz), 1.49 (dd, 1H, J = 13.9, 1.8 Hz), 2.0 - 2.2 (m, 1H), 3.8 - 4.0 (m, 2H), 4.09 (dd, 1H, J = 13.5, 5.7 Hz), 4.22 (dd, 1H, J = 13.3, 3.5 Hz), 4.32 (s, 1H), 4.63 (d, 2H, J = 5.9 Hz), 4.9 - 5.1 (m, 1H), 5.13 (dd, 1H, J = 5.5, 3.9 Hz), 5.2 - 5.3 (m, 2H), 6.7 - 6.9 (m, 3H), 7.2 - 7.4 (m, 4H), 7.61 (d, 2H, J = 6.7 Hz), 8.36 (br. s., 1H), 10.40 (br. s., 1H)
73%	With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20℃; for 32h;	Compound 8E (50 mg, 0.13 mmol) and <strong>[72235-52-0]2,4-difluorobenzylamine</strong> (20.5 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (1 ml). To the solution, N,N,N',N'-tetramethyl-O-(7-aza-benzotriazol-1-yl)uronium hexafluorophosphate (HATU) (64 mg, 0.17 mmol) and N-methylmorpholine (0.037 ml, 0.34 mmol) were added, and the mixture was stirred at room temperature for 16 hours. HATU (64 mg, 0.17 mmol) and N-methylmorpholine (0.037 ml, 0.34 mmol) were further added thereto, and the mixture was stirred at room temperature for additional 16 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layers were combined, washed with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol: 100:0 ? 95:5) to obtain 48.4 mg (yield: 73%) of compound 8F as a yellow oil. 1H-NMR (CDCl3) delta: 1.36 (4H, d, J = 7.1 Hz), 1.50-1.55 (1H, m), 2.16-2.18 (1H, m), 3.98-3.99 (2H, m), 4.11 (1H, dd, J = 13.4, 6.0 Hz), 4.24 (1H, dd, J = 13.5, 3.9 Hz), 4.66 (2H, d, J = 5.9 Hz), 5.01-5.04 (1H, m), 5.19 (1H, dd, J = 6.0, 3.9 Hz), 5.29 (1H, d, J = 10.2 Hz), 5.33 (1H, d, J = 9.9 Hz), 6.79-6.87 (2H, m), 7.31-7.43 (4H, m), 7.63-7.65 (2H, m), 8.36 (1H, s), 10.42 (1H, s).

Reference： [1]Patent: WO2015/9927,2015,A1 .Location in patent: Page/Page column 23; 24
[2]Patent: EP2602260,2013,A1 .Location in patent: Paragraph 0165

14
[ 1229006-21-6 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1
[2]Organic Process Research and Development,2016,vol. 20,p. 1461 - 1468

15
[ 1357289-08-7 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1
[2]Patent: EP2602260,2013,A1
[3]Organic Process Research and Development,2016,vol. 20,p. 1461 - 1468
[4]Organic Process Research and Development,2019,vol. 23,p. 565 - 570

16
[ 1357289-10-1 ]
[ 72235-52-0 ]
[ 1206102-11-5 ]

Yield	Reaction Conditions	Operation in experiment
69%	With acetic acid; In toluene; at 100℃; for 7h;	<strong>[72235-52-0]2,4-difluorobenzylamine</strong> (75 mg, 0.52 mmol) and acetic acid (31 mg, 0.52 mmol) were added dropwise to a toluene (3.4 mL) slurry solution of compound 12C (171 mg, 0.43 mmol) at room temperature, and the mixture was then heated to 100C and stirred for 7 hours. After the completion of reaction, the solvent was distilled off under reduced pressure, and the obtained residue was then purified by silica gel chromatography (chloroform:methanol = 97:3 (v/v)) to obtain 150 mg (yield: 69%) of compound 12D as yellow crystals.

Reference： [1]Patent: EP2602260,2013,A1 .Location in patent: Paragraph 0181

17
[ 82961-76-0 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1
[2]Patent: EP2602260,2013,A1
[3]Organic Process Research and Development,2019,vol. 23,p. 565 - 570

18
[ 100-51-6 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1
[2]Patent: EP2602260,2013,A1
[3]Patent: EP2602260,2013,A1
[4]Organic Process Research and Development,2019,vol. 23,p. 565 - 570

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[ 1246616-65-8 ]
[ 1206102-11-5 ]

Reference： [1]Patent: EP2602260,2013,A1
[2]Patent: EP2602260,2013,A1
[3]Organic Process Research and Development,2019,vol. 23,p. 565 - 570

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[ 1229006-25-0 ]
[ 61477-40-5 ]
[ 1206102-11-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With acetic acid; In methanol; toluene; at 90℃; for 2h;	A 62% aqueous sulfuric acid solution (306 mg, 1.9 mmol) was added to a toluene (2.7 mL)-formic acid (6.7 mL) solution of compound 13C (666 mg, 1.3 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. After the completion of reaction, the solution was cooled to 5C and neutralized by the addition of a saturated aqueous solution of sodium bicarbonate (37.0 g), followed by extraction with ethyl acetate (10 mL x 2). The solvent was distilled off under reduced pressure. Then, toluene (6.7 mL) was added to the obtained residue, and methanol (124 mg, 3.9 mmol), <strong>[61477-40-5](R)-3-amino-butan-1-ol</strong> (138 mg, 1.6 mmol), and acetic acid (85 mg, 1.4 mmol) were further added dropwise thereto in this order at room temperature. The mixture was heated to 90C, stirred for 2 hours, and then allowed to cool to room temperature. Then, water (7 mL) was added thereto, followed by extraction with ethyl acetate (10 mL x 2). The solvent was distilled off under reduced pressure, and toluene was added to the residue. Then, the solvent was distilled off under reduced pressure to bring the contents to approximately 4.0 g. The residue was concentrated and crystalized. The obtained yellow slurry solution was filtered to obtain 429 mg (yield: 65%) of compound 12D as pale yellow crystals.
0.2 g	With acetic acid; In methanol; toluene; at 120℃; for 4h;	Example 18: Preparation of (4R J2aS)-7-(benzyloxy)-N-(2,4-difluorobenzvO-4-methyI- 6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[l,31oxazino[3<2-dlpyrido[l<2-alpyrazine-9- carboxamide Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo- 1 -(2-oxoethyl)- 1 ,4- dihydropyridine-2-carboxylate (0.5 gm) was dissolved in toluene (5 ml) and methanol (0.5 ml). (R)-3-Aminobutane-l-ol (0.17 gm) and acetic acid (0.5 ml) were added to the solution at room temperature. The contents were heated to 120 C and stirred for 4 hours. The reaction mass was cooled to 0C, and then quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain a residual solid. The residual solid was purified by silica gel column chromatography with a mixture of ethyl acetate and -hexane (1 :3) to obtain 0.2 gm of (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8, 12,12a- hexahydro-2H-[ 1 ,3]oxazino[3,2-d]pyrido[ 1 ,2-a]pyrazine-9-carboxamide. 1H NMR (300 MHz, CDC13): delta 10.41 (bs, IH), 8.35 (s, IH), 7.63-7.61 (m, 2H), 7.38-7.33 (m, 5H), 6.86-6.78 (m, 2H), 5.33-5.25 (m, 2H), 5.17 (t, J = 5.7 Hz, IH), 5.03-4.99 (m, IH), 4.64 (d, J = 5.7 Hz, 2H), 4.25-4.19 (m, IH), 4.16-4.07 (m, IH), 3.97-3.95 (m, 2H), 2.29-2.12 (m, IH), 1.54-1.49 (m, IH), 1.34 (d, J = 7.2 Hz, 3H).

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5901 - 5916
[2]Patent: EP2602260,2013,A1 .Location in patent: Paragraph 0185
[3]Patent: WO2015/1572,2015,A2 .Location in patent: Page/Page column 26; 27

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[ 1246616-66-9 ]
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[ 67354-34-1 ]
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Reference： [1]Patent: EP2602260,2013,A1

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[ 1246616-86-3 ]
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Reference： [1]Patent: EP2602260,2013,A1

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[ 19810-31-2 ]
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Reference： [1]Patent: EP2602260,2013,A1

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[ 727382-68-5 ]
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Reference： [1]Patent: EP2602260,2013,A1
[2]Patent: WO2015/9927,2015,A1

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[ 1246617-67-3 ]
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Reference： [1]Patent: EP2602260,2013,A1

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3-(benzyloxy)-2-(dimethoxymethyl)pyridin-4(1H)-one [ No CAS ]
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Reference： [1]Patent: WO2015/1572,2015,A2
[2]Patent: WO2015/1572,2015,A2

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3-(benzyloxy)-5-bromo-2-(dimethoxymethyl)pyridin-4(1H)-one [ No CAS ]
[ 1206102-11-5 ]

Reference： [1]Patent: WO2015/1572,2015,A2
[2]Patent: WO2015/1572,2015,A2

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5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carbaldehyde [ No CAS ]
[ 1206102-11-5 ]

Reference： [1]Patent: WO2015/1572,2015,A2
[2]Patent: WO2015/1572,2015,A2

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5-(benzyloxy)-6-(dimethoxymethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid [ No CAS ]
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