53241-92-2|Ethyl 4-hydroxy-6-methoxy-1,5-naphthyridine-3-carboxylate| Ambeed

Structure of 53241-92-2

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Quality Control of [ 53241-92-2 ] Purity: 95% SDS Specification

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Product Details of [ 53241-92-2 ]

CAS No. :	53241-92-2
Formula :	C₁₂H₁₂N₂O₄
M.W :	248.23
SMILES Code :	O=C(C1=C(O)C2=NC(OC)=CC=C2N=C1)OCC
MDL No. :	MFCD18800826
InChI Key :	UQVDJAIJPVHGER-UHFFFAOYSA-N
Pubchem ID :	600736

Safety of [ 53241-92-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P264-P270-P301+P312-P330

Computational Chemistry of [ 53241-92-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	10
Fraction Csp3	0.25
Num. rotatable bonds	4
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	64.14
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	81.54 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.45
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.93
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.52
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.63
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.66
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.64

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.74
Solubility	0.45 mg/ml ; 0.00181 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.27
Solubility	0.134 mg/ml ; 0.000542 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.37
Solubility	0.106 mg/ml ; 0.000429 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.44 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.33

Application In Synthesis of [ 53241-92-2 ]

* 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 [ 53241-92-2 ]

[ 53241-92-2 ] Synthesis Path-Downstream 1~35

1
[ 53241-90-0 ]
[ 53241-92-2 ]

Yield	Reaction Conditions	Operation in experiment
73%	With diphenyl ether-biphenyl eutectic; for 0.333333h;Heating / reflux;	Dowtherm A (Fluka, 500 mL) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portion-wise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to room temperature and diluted with hexane (750 mL). The mixture was cooled in ice for 1 h, then the brown solid was filtered off, washed with hexane, and dried under vacuum to afford the title compound (61.72g, 73%).
73%	In diphenyl ether-biphenyl eutectic; at 250℃; for 0.333333h;Heating / reflux;	b) 6-Methoxy-4-oxo-1 ,4-dihvdro-ϖ ,51naphthyridine-3-carboxylic acid ethyl ester; b) _Dowthemn A (Fluka, 500 ml_) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distill over. The resulting solution was cooled to RT and diluted with hexanes (750 ml_). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g, 73%).
73%	In diphenyl ether-biphenyl eutectic; at 250℃; for 0.333333h;Heating / reflux;	(b) 6-Methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester; Dowtherm A (Fluka, 500 ml_) was brought to boiling (250 C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portion-wise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to room temperature and diluted with hexane (750 ml_). The mixture was cooled in ice for 1 h, then the brown solid was filtered off, washed with hexane, and dried under vacuum to afford the title compound (61.72g, 73%).

73%	With diphenyl ether-biphenyl eutectic; for 0.333333h;Heating / reflux;	_Dowtherm A (Fluka, 500 ml_) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distill over. The resulting solution was cooled to RT and diluted with hexanes (750 ml_). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g, 73%).
73%	In diphenyl ether-biphenyl eutectic; at 250℃; for 0.333333h;	b) 6-Methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester; Dowtherm A (Fluka, 500 mL) was brought to boiling (250 C.) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72 g, 73%).
73%	In diphenyl ether-biphenyl eutectic; at 250℃; for 0.333333h;	b) 6-Methoxy-4-oxo-1 ,4-dihvdro-ri ,51naphthyridine-3-carboxylic acid ethyl ester; Dowtherm A (Fluka, 500 mL) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g, 73%).
73%	In diphenyl ether-biphenyl eutectic; at 250℃; for 0.333333h;Heating / reflux;	(b) 6-Methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester; Dowtherm A (Fluka, 500 mL) was brought to boiling (250 C) in a 2 L 3-neck flaskfitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portion-wiseover 5 min. The solution was heated at reflux for an additional 15 min, allowing somesolvent to distil over. The resulting solution was cooled to room temperature and dilutedwith hexane (750 mL). The mixture was cooled in ice for 1 h, then the brown solid wasun, wctsiitju wiin HCACUIC, and dried under vacuum to afford the title compound(61.72g, 73%).; b) 6-Methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester; Dowtherm A (Fluka, 500 ml) was brought to boiling (250 C) in a 2 L 3-neck flaskfitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3-ylamino)methylene]malonib acid diethyl ester (100 g, 0.34 mole) was added portion-wiseover 5 min. The solution was heated at reflux for an additional 15 min, allowing somesolvent to distil over. The resulting solution was cooled to RT and diluted with hexanes(750 ml_). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off,washed with hexanes, and dried under vacuum to afford the title compound (61.72g,73%).
73%	With dowtherm A; for 0.25h;Heating / reflux;	b) 6-Methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester Dowtherm A (Fluka, 500 mL) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g, 73%).
73%	In diphenyl ether-biphenyl eutectic; at 250℃; for 0.333333h;Heating / reflux;Product distribution / selectivity;	Dowtherm A (Fluka, 500 mL) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portion-wise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to RT and diluted with hexanes (750 mL). The mixture was cooled in ice for 1 hr, then the brown solid was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g,73%) b. 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester Dowtherm A (Fluka, 500 mL) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distill over. The resulting solution was cooled to RT and diluted with hexanes (750 ml_). The mixture was cooled in ice for 1 hr, and the resulting brown precipitate was filtered off, washed with hexanes, and dried under vacuum to afford the title compound (61.72g, 73%).
73%	In diphenyl ether-biphenyl eutectic; for 0.333333h;Heating / reflux;	Dowtherm A (Fluka, 500 mL) was brought to boiling (250 0C) in a 2 L 3-neck flask fitted with a still-head and a reflux condenser. 2-[(6-Methoxypyridin-3- ylamino)methylene]malonic acid diethyl ester (100 g, 0.34 mole) was added portionwise over 5 min. The solution was heated at reflux for an additional 15 min, allowing some solvent to distil over. The resulting solution was cooled to room temperature and diluted with hexane (750 mL). The mixture was cooled in ice for 1 h, then the brown solid was EPO <DP n="22"/>filtered off, washed with hexane, and dried under vacuum to afford the title compound (61.7g, 73%) as a grey solid which was used without further purification: LC/MS (ES) m/z249 [M+H]+
32%	In diphenylether; at 245℃;Inert atmosphere;	Preparation of 6-methoxy-4-oxo-l,4-dihvdro-ri,51naphthyridine-3-carboxylic acid ethyl ester: A solution of 2-[(6-methoxy-pyridin-3-ylamino)-methylene]-malonic acid diethyl ester (260.0 g, 1.365 mol, 1.0 eq) in diphenyl ether (500 mL) is heated to reflux. While the ethanol formed is removed by azeotropic distillation the reflux temperature reached 245 0C. The reaction mixture is kept at 2450C for 3 hours, then it is cooled to 28 0C, a brown solid precipitated and is collected by filtration and washed with hexane (500 mL). The solid is dried under vacuum to afford 6-methoxy-4-oxo-l,4-dihydro-[l,5]naphthyridine-3- carboxylic acid ethyl ester as a brown powder (74.2 g, 32% yield).1H-NMR (400 MHz, DMSO-t/6) δ ppm: 12.28 (s, IH), 8.47 (s, IH), 7.98 (d, J = 9.2 Hz,IH), 7.18 (d, IH, J = 9.2 Hz), 4.20 (d, J = 7.2 Hz, 2H). 3.93 (s, 3H), 1.27 (t, J = 7.2 Hz,3H).MS m/z (+ESI): 249.1 [M+H]+.
1.04 g	With Dowtherm A; at -20 - 250℃;	Dowtherm A (10 mL) was brought to boiling (250) in a 50 mL 3-necked flask fitted with a still-head and a reflux condenser. Diethyl [(6- methoxypyridin-3-yl)amino]methylidene}propanedioate (2.1 g, 7.2 mmol) was added portion-wise. The mixture was boiled for 15' then it was cooled to room temperature, diluted with Cy (15 mL) and cooled at -20C overnight. The brown precipitate was filtered and washed with Cy to obtain a brown solid that was triturated with EtOAc. The suspension was filtered to give ethyl 6-methoxy-4-oxo-1 ,4-dihydro-1 ,5-naphthyridine-3-carboxylate as a grey solid (1 .04 g, 4.2 mmol, 58% yield). LC-MS (M-H+) = 249.2

References: [1]Patent: WO2006/81178,2006,A2 .Location in patent: Page/Page column 18.
[2]Patent: WO2006/81264,2006,A1 .Location in patent: Page/Page column 21.
[3]Patent: WO2006/81179,2006,A1 .Location in patent: Page/Page column 19.
[4]Patent: WO2006/81182,2006,A2 .Location in patent: Page/Page column 19.
[5]Patent: US2008/194547,2008,A1 .Location in patent: Page/Page column 9.
[6]Patent: WO2006/2047,2006,A2 .Location in patent: Page/Page column 63-64; 67.
[7]Patent: WO2006/14580,2006,A1 .Location in patent: Page/Page column 30-31; 48.
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2
[ 53241-92-2 ]
[ 724788-64-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 0.75h;	A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately room temperature - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmol) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 0.75h;	c) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester; A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 ml_) under argon was stirred efficiently* EPO <DP n="23"/>in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 0.75h;	A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately room temperature - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmol) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).

90%		(c) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester; A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid . ethyl ester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately room temperature - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmol) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 0.75h;	A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%		c) 4-Bromo-6-methoxy-[1.5]naphthyridine-3-carboxylic acid ethyl ester; A suspension of <strong>[53241-92-2]6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester</strong> (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT-may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%		c) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester; A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%		(c) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester; A suspension of 6-methoxy-4~oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acidethyl ester (74.57 g, 300 mmol) in dry DMF (260 ml) under argon was stirred efficiently* ina water bath (to maintain approximately room temperature - may need slight ice-coolingon a large scale). Phosphorus tribromide (30.0 mL, 316 mmol) was added dropwise over15 min and stirring was continued for an additional 30 min. Water (1 L) was added,followed by saturated sodium carbonate solution to pH 7. The solid was collected bysuction filtration, washed with water and dried under vacuum over phosphorus pentoxideto give the title compound (83.56 g, 90%).; c) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester; A suspension of 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acidethyl ester (74.57 g, 300 mmole) in dry DMF (260 ml_) under argon was stirred efficiently*in a water bath (to maintain approximately RT - may need slight ice-cooling on a largescale). Phosphorus tribromide (30.0 ml_, 316 mmole) was added dropwise over 15 minand stirring was continued for an additional 30 min. Water (1 L) was added, followed bysaturated sodium carbonate solution to pH 7. The solid was collected by suction filtration,washed with water and dried under vacuum over phosphorus pentoxide to give the titlecompound (83.56 g, 90%).
90%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 0.75h;	c) 4-Bromo-6-methoxy-[1 ,5]naphthyridine-3-carboxylic acid ethyl esterA suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%	With phosphorus tribromide; In N,N-dimethyl-formamide; for 0.75h;Product distribution / selectivity;	A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxyIic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%). c. 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmole) in dry DMF (260 ml_) under argon was stirred efficiently* in a water bath (to maintain approximately RT - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 ml_, 316 mmole) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.56 g, 90%).
90%		A suspension of 6-methoxy-4-oxo-1 ,4-dihydro-[1 ,5]naphthyridine-3-carboxylic acid ethyl ester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirred efficiently* in a water bath (to maintain approximately room temperature - may need slight ice-cooling on a large scale). Phosphorus tribromide (30.0 mL, 316 mmol) was added dropwise over 15 min and stirring was continued for an additional 30 min. Water (1 L) was added, followed by saturated sodium carbonate solution to pH 7. The solid was collected by suction filtration, washed with water and dried under vacuum over phosphorus pentoxide to give the title compound (83.6 g, 90%) as an off-white solid which was used without further purification: LC/MS (ES) m/z 312 [MH-H]+
83%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere;	A suspension of ethyl 6-methoxy-4-oxo-1 ,4-dihydro-1 ,5-naphthyridine-3- carboxylate (6.3 g, 25.4 mmol) in DMF (20 mL) was stirred under N2 at room temperature. Phosphorus tribromide (2.5 mL, 26.7 mmol) was added drop- wise and the reaction mixture was stirred for additional 30'. The mixture was put in an ice-bath and water (120 mL) was added, followed by sat. Na2C03 to pH 7. The solid was filtered under vacuum, washed with water and dried under vacuum. The crude product was purified by NH cartridge (eluent from Cy 100% to Cy/EtOAc 95/5%) to obtain ethyl 4-bromo-6-methoxy-1 ,5- naphthyridine-3-carboxylate (6.6 g, 21 mmol, 83% yield). LC-MS (M-H+) = 31 1 .1

References: [1]Patent: WO2006/81178,2006,A2 .Location in patent: Page/Page column 18.
[2]Patent: WO2006/81264,2006,A1 .Location in patent: Page/Page column 21-22.
[3]Patent: WO2006/81289,2006,A2 .Location in patent: Page/Page column 15.
[4]Patent: WO2006/81179,2006,A1 .Location in patent: Page/Page column 19.
[5]Patent: WO2006/81182,2006,A2 .Location in patent: Page/Page column 19.
[6]Patent: US2008/194547,2008,A1 .Location in patent: Page/Page column 9.
[7]Patent: WO2006/2047,2006,A2 .Location in patent: Page/Page column 64; 67.
[8]Patent: WO2006/14580,2006,A1 .Location in patent: Page/Page column 31; 48.
[9]Patent: WO2006/17468,2006,A2 .Location in patent: Page/Page column 21.
[10]Patent: WO2006/20561,2006,A2 .Location in patent: Page/Page column 26; 40.
[11]Patent: WO2007/16610,2007,A2 .Location in patent: Page/Page column 21; 25; 26.
[12]Patent: WO2016/96686,2016,A1 .Location in patent: Page/Page column 129-130.
[13]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7489 - 7495.

3
3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]octan-6-amine [ No CAS ]
[ 53241-92-2 ]
(+/-)-6-[((1R,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one [ No CAS ]
(+/-)-6-[((1R,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.2%; 2.7%		To a solution of 3-{2-[3-f luoro-6-(methyloxy)-1 ,5-naphthyridn-4-yl]ethyl}-8-oxa-3- azabicyclo[3.2.1]octan-6-amine (240 mg, 0.72 mmol) in EtOH:DCM (8 mL, 1 :1) were added Na2SO4 (154 mg, 1.1 mmol) followed by 3-oxo-3,4-dihydro-2/-/-pyrido[3,2- b][ ,4]thiazine-6-carbaldehyde (141 mg, 0.72 mmol). After 12h at 25 C, NaBH4 (43 mg, 1.1 mmol) was added. After an additional 1 h, the reaction was concentrated and the residue was partitioned between DCM/H2O. The combined organic fractions were dried over MgSO4, concentrated and the diastereomers separated via column chromatography (silica, 1-4% MeOH in DCM (1 % NH4OH)) yielding the title compounds as yellow solids: (β-amine, 10 mg, 2.7%); LC/MS (ES) m/e 511 (M+H)+; 1H NMR (CD3OD, 400 Hz) δ 8.40 (s, 1 H), 8.02 (d, J = 9.0 Hz, 1 H), 7.51 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 9.0 Hz, 1 H), 6.71 (d, J = 7.8 Hz, 1 H), 4.16-4.18 (m, 1 H), 3.96-3.98 (m, 1 H), 3.94 (s, 3H), 3.37-3.48 (m, 5H), 3.25 (s, 2H), 2.95-2.98 (m, 1 H), 2.81 -2.85 (m, 2H), 2.75-2.80 (m, 1 H), 2.34-2.38 (m, 1 H), 2.25-2.29 (m, 1 H), 2.12-2.18 (m, 1 H), 1.23-1.27 (m, 1 H).(α-amine, 30 mg, 8.2%); LC/MS (ES) m/e 511 (M+H)+; 1H NMR (CDCI3, 400 Hz) δ 8.57 (s, 1 H), 8.20 (d, J = 9.0 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.16 (d, J = 9.1 Hz, 1 H), 6.96 (d, J = 7.8 Hz, 1 H)1 4.32-4.34 (m, 1 H), 4.09 (s, 3H), 4.04-4.06 (m, 1 H), 3.65 (s, 2H), 3.52-3.61 EPO <DP n="28"/>(m, 2H), 3.35-3.38 (m, 2H), 2.96-2.99 (m, 1 H), 2.72-2.80 (m, 3H), 2.64-2.67 (m, 1 H), 2.31 (d, J = 10.9 Hz, 2H), 1.84-1.89 (m, 1 H), 1.54-1.55 (m, 1 H).

References: [1]Patent: WO2006/81178,2006,A2 .Location in patent: Page/Page column 26-27.

4
[ 53241-92-2 ]
[ 162220-96-4 ]

Yield	Reaction Conditions	Operation in experiment
62%		Preparation of 4-chloro-6-methoxy-ri,51naphthyridine-3-carboxyric acid ethyl ester: A solution of 6-methoxy-4-oxo-l,4-dihydro-[l,5]naphthyridine-3-carboxylic acid ethyl ester (110.0 g, 407.67 mmol, 1.0 eq) in phosphorus oxychloride (650 mL) is refluxed for 4 hours. Then the reaction mixture is cooled to room temperature and the solvent is evaporated. The residue is poured into ice water and the resulting mixture is basified with 25% ammonium hydroxide to pH = 8~9 and extracted with ethyl acetate (3 x 500 mL). The combined organic layers are dried over sodium sulfate, filtered and evaporated to give a brown solid as crude product, which is then purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1 :4, v/v) to afford 4-chloro-6-methoxy- [l,5]naphthyridine-3-carboxylic acid ethyl ester as a light yellow solid (78 g, 62% yield).1H-NMR (400 MHz, CDCl3) δ ppm: 9.05 (s, IH), 8.27 (d, J = 9.2 Hz,lH), 7.25 (d, J = 9.2 Hz, IH), 4.52 (q, J = 6.8 Hz, 2H), 4.17 (s, 3H), 1.47 (t, J = 6.8 Hz, 3H). MS m/z (+ESI): 267.1 [M+H]+.

References: [1]Patent: WO2010/84152,2010,A1 .Location in patent: Page/Page column 46-47.

5
[ 89-93-0 ]
[ 53241-92-2 ]
[ 1345869-45-5 ]