[ CAS No. 23443-25-6 ]

Name: 23443-25-6|6-Methoxy-1,5-naphthyridin-4-ol|96%
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CAS No. :	23443-25-6	MDL No. :	MFCD15142684
Formula :	C₉H₈N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SSMACLPPRSQXHH-UHFFFAOYSA-N
M.W :	176.17 g/mol	Pubchem ID :	11378807
Synonyms :

Safety of [ 23443-25-6 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H302	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 23443-25-6 ]

* 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.

Upstream synthesis route of [ 23443-25-6 ]
Downstream synthetic route of [ 23443-25-6 ]

[ 23443-25-6 ] Synthesis Path-Upstream 1~5

1
[ 23443-25-6 ]
[ 10261-82-2 ]

Reference： [1] Patent: WO2010/81874, 2010, A1,

2
[ 23443-25-6 ]
[ 249889-68-7 ]

Reference： [1] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 79
[2] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0323
[3] Patent: WO2008/124083, 2008, A2, . Location in patent: Page/Page column 50
[4] Patent: WO2007/113548, 2007, A1, . Location in patent: Page/Page column 153-154

3
[ 23443-25-6 ]
[ 249889-68-7 ]

Reference： [1] Patent: EP1214314, 2005, B1, . Location in patent: Page/Page column 15

4
[ 23443-25-6 ]
[ 881658-92-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With phosphorus tribromide In N,N-dimethyl-formamide at 0 - 20℃; for 1.5 h;	6-(Methyloxy)-1,5-naphthyridin-4-ol (21.5 g) (for a synthesis see W02007016610 Preparation 2 (a)) was stirred in DMF (150 ml) at 0°C under N₂, and phosphorous tribromide (13.5 ml) was added slowly. The mixture was allowed to warm to room temperature and stirred for 90 minutes. H₂O (375 ml) was added and the pH was adjusted to pH 7 by addition of solid Na₂CO₃. The solid was isolated by filtration with suction, dried on the sinter with suction for 2h then dried under vacuum at 45°C to give the desired compound (26.0 g, 90percent). ¹H-NMR δ, ppm, DMSO-d₆): 8.59 (d, 1 H), 8.30 (d, 1 H), 8.08 (d, 1H), 7.33 (d, 1 H), 4.06 (s, 3H).
90%	Stage #1: With phosphorus tribromide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere Stage #2: With sodium carbonate In water; N,N-dimethyl-formamide	6-(Methyloxy)-1 ,5-naphthyridin-4-ol (21.5 g) (for a synthesis see WO2007016610 Preparation 2 (a)) was stirred in DMF (150 ml) at O⁰C under N₂, and phosphorous tribromide (13.5 ml) was added slowly. The mixture was allowed to warm to room temperature and stirred for 90 minutes. H₂O (375 ml) was added and the pH was adjusted to pH 7 by addition of solid Na₂CO₃. The solid was isolated by filtration with suction, dried on the sinter with suction for 2h then dried under vacuum at 45⁰C to give the desired compound (26.0 g, 90percent). ¹H-NMR (δ, ppm, DMSOd₆): 8.59 (d, 1 H), 8.30 (d, 1 H), 8.08 (d, 1 H), 7.33 (d, 1 H), 4.06 (s, 3H).
75%	Stage #1: With phosphorus tribromide In N,N-dimethyl-formamide at 45℃; for 0.333333 h; Stage #2: With sodium hydroxide In water	C. 8-Bromo-2-methoxy-[1,5]naphthyridine. To a suspension of 6-methoxy-[1,5]naphthyridin4-ol (8.8 g, 0.050 mol) in DMF (167 mL) was added PBr₃ (4.7 mL, 0.050 mol) at 45° C. The suspension became homogeneous and then a suspension formed over 20 min. The mixture was cooled to RT and the solid was filtered and washed with Et₂O (100 mL). Further solids precipitated from the filtrate and were collected. Water (50 mL) was added to the solid and the suspension was basified with 1 N NaOH (200 mL). The aqueous layer was extracted with CH₂Cl₂ (3*250 mL), washed with brine (150 mL), dried (MgSO₄) and concentrated. The resulting residue was purified on SiO₂ (0-60percent EtOAc/hexanes) to provide 8.9 g (75percent) of the title compound as a white solid. MS (ESI): exact mass calculated for C₉H₇BrN₂O, 237.97; m/z found, 239.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): 8.57 (d, J=4.7, 1H), 8.27 (d, J=9.0, 1H), 8.05 (d, J=4.7, 1H), 7.30 (d, J=9.0, 1H), 4.04 (s, 3H).

67%

Stage #1: With phosphorus tribromide In N,N-dimethyl-formamide at 20 - 90℃;

To a mixture of iV,iV-dimethylformamide (26.4 g, 0.36 mol ) in acetonitrile (350 mL) was added PBr₃ (51.0 g, 0.188 mol) at room temperature. The mixture was stirred at 9O⁰C for 30 min. Then 6-methoxy-l,5-naphthyridin-4-ol (47; 22.0 g, 0.124 mol) was added and the mixture was stirred for 30 min. After cooling to room temperature, the solvent was removed in vacuo and adjusted with saturated NaHCO₃ to pH=10. The precipitate was filtered and the filter cake was washed with water and dried in vacuo to give 8-bromo-2-methoxy-l,5-naphthyridine 48 (20.0 g, 0.083 mol, 67percent) as a white solid. MS calcd for C₉H₇BrN₂O: 239.1; found: 240 [M+l]

Reference： [1] Patent: EP2080761, 2009, A1, . Location in patent: Page/Page column 15
[2] Patent: WO2010/81874, 2010, A1, . Location in patent: Page/Page column 17-18
[3] Patent: US2006/223810, 2006, A1, . Location in patent: Page/Page column 18
[4] Patent: WO2010/101949, 2010, A1, . Location in patent: Page/Page column 125

5
[ 23443-25-6 ]
[ 881658-92-0 ]

Yield	Reaction Conditions	Operation in experiment
3.20 g	With phosphorus(V) oxybromide In N,N-dimethyl-formamide at 80℃; for 0.5 h;	0004-1 Phosphorous oxybromide (5.60 g) was added to a solution of 6-methoxy-1,5-naphthyridin-4(1H)-one (3.51 g) in N,N-dimethylformamide (20 mL), followed by stirring at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and added dropwise to a mixture solution of methanol-water (1:10). The resultant product was neutralized by the addition of a sodium hydroxide aqueous solution, and ethyl acetate was added thereto. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), thereby obtaining 8-bromo-2-methoxy-1,5-naphthyridine (3.20 g) as a yellow solid. MS m/z (M+H): 239, 241.

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 13, p. 5692 - 5703
[2] Patent: US2015/322063, 2015, A1, . Location in patent: Paragraph 0459; 0460; 0461

[ 23443-25-6 ] Synthesis Path-Downstream 1~59

1
[ 577771-12-1 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	In diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	2.a 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 h, then evaporated and the product purified by chromatography on silica gel (DCM) followed by recrystallisation from DCM-hexane (44.6g, 48%). The unsaturated ester (10.5g, O.Oδmol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipitate was filtered to give the title compound (6.26g, 70%)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/20561, 2006, A2 Location in patent: Page/Page column 29

2
[ 25063-69-8 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	In diphenylether at 260℃;
85%	In diphenyl ether-biphenyl eutectic at 250 - 260℃; for 0.233333h;	A.B 2-(6-Methoxy-[1,5]naphthyridin-4-yl)4,5,6,7-tetrahydro-2H-indazol-5-ylamine B. 6-Methoxy-[1,5]naphthyridin-4-ol. Dowtherm A (26.5:73.5 diphenyl/diphenyl oxide) (140 mL) was added to a three-neck flask fitted with an air-condenser, thermocouple and a funnel and the solvent was heated to 260° C. To the Dowtherm A was added 5-[(6-methoxy-pyridin-3-ylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (34.8 g, 125 mmol) over a period of 10 min, keeping the temperature above 250° C. The funnel was rinsed with Dowtherm A (20 mL). The reaction mixture was heated for a further 4 min and then removed from the heat source. The resulting suspension was cooled to RT and treated with Et2O (200 mL). The-solid was filtered, washed with Et2O (300 mL), hexanes (500 mL) and dried in vacuo to provide 18.8 g (85%) of the title compound as a tan solid. 1H NMR (500 MHz, DMSO-d6): 11.88 (br s, 1H), 8.13 (br s, 2H), 7.17 (s, 1H), 6.22 (br s, 1H), 3.93 (s, 3H).
68%	With 1,3-dimethyl-2-imidazolidinone at 80 - 255℃; for 0.583333h; Inert atmosphere;	1.ii 1. ii. 6-methoxy-], 5-naph thyridin-4-ol. Dowtherm A (1300 mL) was heated to 255°C under nitrogen atmosphere with the help of an electrical heating mantle. Intermediate 1.i (161 g, 1 eq.) was dissolved in 1,3-dimethyl- imidazolidinone (500 mL) at 80°C. The solution was added to the boiling Dowtherm A over a period of about 35 mm. The reaction mixture was cooled to 20°C. The mixture was filtered and slurried in ethanol (800 mL) at 80°C. The mixture was cooled to 20°C, filtered and washed with ethanol (150 mL). The product was dried on a rotary evaporator at 50°C and below 5 mbar to yield a brown solid (69.6 g; 68% yield). 1H-NMR (d6-DMSO): δ = 11.78 (m, 1H), 7.97 (m, 2H), 7.17 (d, J = 9.0 Hz, 1H), 6.28 (m, 1H), 3.94 (s, 3H). LC-MS: tR = 0.49 min; [M+1]+ = 177; purity: 99% a/a.

68%	With 1,3-dimethyl-2-imidazolidinone; Dowtherm A at 80 - 255℃;
68%	With 1,3-dimethyl-2-imidazolidinone at 80 - 255℃; for 0.583333h; Inert atmosphere;	1.1.ii 1.ii. 6-methoxy-1,5-naphthyridin-4-ol 1.ii. 6-methoxy-1,5-naphthyridin-4-ol Dowtherm A (1300 mL) was heated to 255° C. under nitrogen atmosphere with the help of an electrical heating mantle. Intermediate 1.i (161 g, 1 eq.) was dissolved in 1,3-dimethyl-imidazolidinone (500 mL) at 80° C. The solution was added to the boiling Dowtherm A over a period of about 35 min. The reaction mixture was cooled to 20° C. The mixture was filtered and slurried in ethanol (800 mL) at 80° C. The mixture was cooled to 20° C., filtered and washed with ethanol (150 mL). The product was dried on a rotary evaporator at 50° C. and below 5 mbar to yield a brown solid (69.6 g; 68% yield). 1H-NMR (d6-DMSO): δ=11.78 (m, 1H), 7.97 (m, 2H), 7.17 (d, J=9.0 Hz, 1H), 6.28 (m, 1H), 3.94 (s, 3H). LC-MS: tR=0.49 min; [M+1]+=177; purity: 99% a/a.
60%	With diphenyl ether-biphenyl eutectic at 190℃; for 0.5h;	6-Methoxy-[1,5] naphthyridin-4-ol Diphenyl ether-biphenyl eutectic (170 mL) was heated to 190 °C,. 5-[(6-methoxy-pyridine-3-ylamino)-methylene]-2,2-dimethyl-[l,3]dioxan-4,6-dione (17 g, 61.5 mmol) was added to the above solution in batches, then the reaction solution was maintained at 190 °C and stirred for 0.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, and diethyl ether (170 mL) was added, a large amount of solid was precipitated and filtered. The filter cake was washed with diethyl ether and dried to afford a brown solid (6.5 g, yield 60%). MS (ESI): m/z = 177 [M+H]+.
	In diphenylether for 0.416667h; Heating / reflux;	46 5-[(6-Methoxypyridin-3-yl)amino]methylene}-2,2-dimethyl-l,3-dioxane-4,6-dione (23g) was added in small portions to refluxing phenyl ether and stirred for 25 minutes. The mixture was then cooled to room temperature and diethyl ether (10OmL) was added. The solids were filtered, suspended in diethyl ether, stirred at room temperature for 30 minutes and filtered again to give 4-hydroxy-6-methoxy-l,5-naphthyridine (10.4g).
	In diphenylether at 220℃; for 0.166667h;	A1.b Preparation of intermediate 2 Intermediate 1 (13.6 g, 49.6 mmol) was added portionwise to diphenyl ether (100 ml, 630 mmol) at 220°C. The solution was stirred at reflux for 10 minutes and then cooled to room temperature. The combined precipitated solid were filtered off and washed with diethyl ether (2 x 500 ml) to give 45.6 g of a pale brown solid. The solid was triturated in diethyl ether (2 x 500 ml), filtered off and dried under vacuum to give 44g (50%) of intermediate 2, that was used without further purification for the next step.
27.3 g	With diphenyl ether-biphenyl eutectic at 240℃; for 0.0833333h;	Step 2M.1 M.2M.l (54. Og) was added portionwise to Dowtherm A (320 mL) (Sigma-Aldrich, St. Louis, MO) at 240 °C for 5 minutes. After cooling, the resulting precipitates were collected by filtration and washed with diethyl ether to give M.2 (27.3 g). 1H NMR (DMSO-de): δ 3.93 (s, 3H), 6.23 (brs, 1H), 7.15 (d, J= 8.6 Hz, 1H), 7.94 (d, J= 8.6 Hz, 1H), 8.65 (d, J= 2.4 Hz, 1H), 11.72 (brs, 1H).
	In diphenylether; biphenyl

Reference： [1]Gomez, Laurent; Hack, Michael D.; Wu, Jiejun; Wiener, John J.M.; Venkatesan, Hari; Santillan Jr., Alejandro; Pippel, Daniel J.; Mani, Neelakandha; Morrow, Brian J.; Motley, S. Timothy; Shaw, Karen Joy; Wolin, Ronald; Grice, Cheryl A.; Jones, Todd K. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2723 - 2727]
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2006/223810, 2006, A1 Location in patent: Page/Page column 17-18
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2013/118086, 2013, A1 Location in patent: Page/Page column 18; 19
[4]Abele, Stefan; Schmidt, Gunther; Fleming, Matthew J.; Steiner, Heinz [Organic Process Research and Development, 2014, vol. 18, # 8, p. 993 - 1001]
[5]Current Patent Assignee: JOHNSON & JOHNSON INC - US2015/25244, 2015, A1 Location in patent: Paragraph 0113-0115
[6]Current Patent Assignee: SHANGHAI ENNOVABIO PHARMACEUTICALS - EP3882247, 2021, A1 Location in patent: Paragraph 0106; 0110-0112
[7]Current Patent Assignee: ASTRAZENECA PLC - WO2006/125974, 2006, A1 Location in patent: Page/Page column 85
[8]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2013/61077, 2013, A1 Location in patent: Page/Page column 138
[9]Current Patent Assignee: KYORIN HOLDINGS, INC. - WO2013/3383, 2013, A1 Location in patent: Page/Page column 84-85
[10]Current Patent Assignee: SCORPION THERAPEUTICS - WO2022/98992, 2022, A1 Location in patent: Page/Page column 216-217

3
[ 23443-25-6 ]
[ 911485-68-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine In 1-methyl-pyrrolidin-2-one at 140℃;

4
[ 23443-25-6 ]
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NH₂NH₂ / 1-methyl-pyrrolidin-2-one / 140 °C

5
[ 23443-25-6 ]
C₂₆H₂₄N₆O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: NH₂NH₂ / 1-methyl-pyrrolidin-2-one / 140 °C

6
[ 23443-25-6 ]
[ 911485-69-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: NH₂NH₂ / 1-methyl-pyrrolidin-2-one / 140 °C 2.1: tetrahydrofuran 2.2: p-TsOH / tetrahydrofuran

7
[ 23443-25-6 ]
C₂₁H₂₅N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: NH₂NH₂ / 1-methyl-pyrrolidin-2-one / 140 °C 2.1: tetrahydrofuran 2.2: p-TsOH / tetrahydrofuran

8
[ 358-23-6 ]
[ 23443-25-6 ]
[ 394223-86-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	With 2,6-dimethylpyridine; dmap In dichloromethane at 0℃; for 2.5h;	1.b 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine (10g, 0.057mol) in DCM (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g, 0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml, 0.063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified via column chromatography (silica, dichloromethane (DCM)) to generate the title compound as an off-white solid (13.2g, 77%): MS (APCI+) m/z 309 (M+H)+.
77%	With 2,6-dimethylpyridine; dmap In dichloromethane at 0℃; for 2.5h;	1.b b) 6-(methyloxy)-1,5-naphthyridin-4-yl trifluoromethanesulfonate; 4-Hydroxy-6-methoxy-[1,5]-naphthyridine (10g, 0.057mol) in DCM (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g, 0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml, 0.063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified via column chromatography (silica, dichloromethane (DCM)) to generate the title compound as an off-white solid (13.2g, 77%): MS (APCI+) m/z 309 (M+H)+.
75%	With 2,6-dimethylpyridine In dichloromethane at 0℃; for 2.5h;	1.b 4-Hydroxy-6-methoxy-[1,5]naphthyridine (10 g, 0.057 mole) in dichloromethane (200 mL) containing 2,6-lutidine (9.94 mL, 0.086 mole) and 4-dimethylaminopyridine (0.07 g, 0.0057 mole) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5 mL, 0.063 mole). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica gel (dichloromethane) to give a light yellow solid (13.2 g, 75%). LC-MS (ES) m/e 309 (M+H)+.

	With 2,6-dimethylpyridine; dmap In dichloromethane for 2.5h;	2.b b) 6-(methyloxy)-1 ,5-naphthyridin-4-yl trifluoromethanesulfonate; 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine (10g, 0.057mol) in dichloromethane (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g,0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml,0.063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane).
	With 2,6-dimethylpyridine; dmap In dichloromethane at 0℃; for 2.5h;	1.A.b 4-Hydroxy-6-methoxy-[1,5]-naphthyridine (1a Method A) (10 g, 0.057 mol) indichloromethane (200 mL) containing 2,6-lutidine (9.94 mL, 0.086 mol) and 4-dimethylaminopyridine (0.07 g, 0.0057 mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5 mL, 0.063 mol). After stirring for 2.5 h the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica gel (dichloromethane) to give a solid (13.2 g).
	With 2,6-dimethylpyridine In dichloromethane at 0℃; for 2.5h;	1.b Pyridone (la) (lOg, 0. 057mol) in dichloromethane (200mL) containing 2,6- lutidine (9.94mL, 0. 086mol) and 4-dimethylaminopyridine (0.07g, 0. 0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5mL, 0. 063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica gel (dichloromethane) to give a solid (13.2g).
	With 2,6-dimethylpyridine; dmap In dichloromethane at 0℃; for 2.5h;	8.b b) Bromomethyl-(6-methoxy-[1 ,5]-naphthyridin-4-yl)-ketone; 4-Hydroxy-6-methoxy-[1,5]-naphthyridine (10g, 0.057mol) in dichloromethane (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g, 0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml, 0.063mol). After stirring for 2.5 hours the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (dichloromethane). The triflate (13.2g, 0.044mol) in DMF (200ml) with triethylamine (12ml, 0.086mol) butyl vinyl ether (22ml, 0.17mol), palladium (II) acetate (0.97g, 0.0044mol) and 1 ,3- bis(diphenylphosphino)propane (1.77g, 0.0044mol) was heated at 6O0C for 3 hours then evaporated and chromatographed on silica gel (dichloromethane) to give a yellow solid (10.7g, 95%). This was dissolved in THF (250ml), water (40ml) and treated with N- bromosuccinimide (7.4g.0.042 mol) for 1 hour, then evaporated and chromatographed on silica gel (dichloromethane) to give the ketone (10.42g, 98%).
	With 2,6-dimethylpyridine In dichloromethane at 0℃; for 2.5h;	2.b (b) Bromomethyl-(6-methoxy-[1,5]-naphthyridin-4-yl)-ketone; 4-Hydroxy-6-methoxy-[1,5]-naphthyridine (10g, 0.057mol) in DCM (200ml)containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g,0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml,0.063mol). After stirring for 2.5 h the mixture was washed with saturated ammoniumchloride solution, dried, evaporated and purified on silica (DCM). The triflate (13.2g,0.044mol) in DMF (200ml) with TEA (12ml, 0.086mol), butyl vinyl ether (22ml, 0.17mol),1,3-bis(diphenylphosphino)propane (1.77g, 0.0044mol) and palladium (II) acetate (0.97g,0.0044mol) was heated at 60°C for 3 h then evaporated and chromatographed on silicagel (DCM) to give a yellow solid (10.7g, 95%). This was dissolved in THF (250ml), water(40ml) and treated with N-bromosuccinimide (7.4g.0.042 mol) for 1 h, then evaporatedand chromatographed on silica gel (DCM) to give the ketone (10.42g, 98%).
	With 2,6-dimethylpyridine; dmap In dichloromethane at 0℃; for 2.5h;	2.b 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine (10g, 0.057mol) in DCM (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g, 0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml, 0.063mol). After stirring for 2.5 h the mixture was washed with saturated ammonium chloride solution, dried, evaporated and purified on silica (DCM). The triflate (13.2g, 0.044mol) in DMF (200ml) with TEA (12ml, 0.086mol), butyl vinyl ether (22ml, 0.17mol), 1 ,3-bis(diphenylphosphino)propane (1.77g, 0.0044mol) and palladium (II) acetate (0.97g, 0.0044mol) was heated at 6O0C for 3 h then evaporated and chromatographed on silica gel (DCM) to give a yellow solid (10.7g, 95%). This was dissolved in THF (250ml), water (40ml) and treated with /V-bromosuccinimide (7.4g.0.042 mol) for 1 h, then evaporated and chromatographed on silica gel (DCM) to give the ketone (10.42g, 98%).
	With 2,6-dimethylpyridine; dmap In dichloromethane at 0℃; for 2.5h;	2.b 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine (10g, 0.057mol) in DCM (200ml) containing 2,6-lutidine (9.94ml, 0.086mol) and 4-dimethylaminopyridine (0.07g, 0.0057mol) was cooled in ice and treated with trifluoromethanesulfonic anhydride (10.5ml, 0.063mol). After stirring for 2.5 hr the mixture was washed with saturated ammonium EPO chloride solution, dried, evaporated and purified on silica (DCM). The triflate (13.2g, 0.044mol) in DMF (200ml) with TEA (12ml, 0.086mol), butyl vinyl ether (22ml, 0.17mol), 1 ,3-bis(diphenylphosphino)propane (1.77g, 0.0044mol) and palladium (II) acetate (0.97g, 0.0044mol) was heated at 6O0C for 3 hr then evaporated and chromatographed on silica gel (DCM) to give a yellow solid (10.7g, 95%). This was dissolved in THF (250ml), water (40ml) and treated with N-bromosuccinimide (7.4g.0.042 mol) for 1 h, then evaporated and chromatographed on silica gel (DCM) to give the title product (10.42g, 98%): LC/MS(ES) m/z 287 [M+H]+

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/81182, 2006, A2 Location in patent: Page/Page column 18
[2]Current Patent Assignee: HONDA MOTOR CO., LTD. - WO2006/17326, 2006, A1 Location in patent: Page/Page column 22
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2006/166977, 2006, A1 Location in patent: Page/Page column 8-9
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/81264, 2006, A1 Location in patent: Page/Page column 23; 24
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/14361, 2004, A1 Location in patent: Page/Page column 30
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2003/87098, 2003, A1 Location in patent: Page/Page column 37
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/2047, 2006, A2 Location in patent: Page/Page column 72-73
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/14580, 2006, A1 Location in patent: Page/Page column 33
[9]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/20561, 2006, A2 Location in patent: Page/Page column 29
[10]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/16610, 2007, A2 Location in patent: Page/Page column 23; 24

9
[ 53241-85-3 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
	In quinoline for 2h; Heating / reflux;	8.c (c) 4-Chloro-6-methoxy-[1,5]naphthyridine The acid (8b) (6.82 g) was heated in quinoline (20ml) at reflux for 2 hours, the mixture was cooled and poured into ether (200ml) and the orange solid was filtered and washed with ether (5 x 200ml). A sample (3.87g) of the dried solid was treated with phosphorus oxychloride (30ml) at room temp for 3 hours, the solvent was removed in vacuo and the residue quenched with crushed ice (200g). The mixture was basified with ammonia solution and filtered. The solid was washed with dichloromethane (10 x 100ml), which was evaporated and chromatographed on silica gel (dichloromethane as eluent) to give a yellow solid (3.0g). MS (+ve ion electrospray) m/z 195, 197 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - EP1214314, 2005, B1 Location in patent: Page/Page column 15

10
[ 23443-25-6 ]
[ 249889-68-7 ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; at 20℃; for 3.0h;	(c) 4-Chloro-6-methoxy-[1,5]naphthyridine The acid (8b) (6.82 g) was heated in quinoline (20ml) at reflux for 2 hours, the mixture was cooled and poured into ether (200ml) and the orange solid was filtered and washed with ether (5 x 200ml). A sample (3.87g) of the dried solid was treated with phosphorus oxychloride (30ml) at room temp for 3 hours, the solvent was removed in vacuo and the residue quenched with crushed ice (200g). The mixture was basified with ammonia solution and filtered. The solid was washed with dichloromethane (10 x 100ml), which was evaporated and chromatographed on silica gel (dichloromethane as eluent) to give a yellow solid (3.0g). MS (+ve ion electrospray) m/z 195, 197 (MH+).

Reference： [1]Patent: EP1214314,2005,B1 .Location in patent: Page/Page column 15

11
[ 405937-76-0 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	1.a 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6g, 48%). The unsaturated ester (10.5g, O.Oδmol) in warm Dowtherm A (50ml) was added over 3 minutes to ref luxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26g, 70%)
70%	With dowtherm A for 0.383333h; Heating / reflux;	1.A.a 5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000 mL) with methylpropiolate (40 mL, 0.44 mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6 g, 48%). The unsaturated ester (10.5g, 0.05 mol) in warm Dowtherm A (50 mL) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipitate was filtered to give a solid (6.26 g, 70%).
70%	In diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	1.a The unsaturated ester (10. 5g, 0. 05mol) in warm Dowtherm A (50mL) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipitate was filtered to give a solid (6.26g, 70%).

70%	In diphenyl ether-biphenyl eutectic for 0.333333h; Heating / reflux;	8.a Preparation 8; Preparation of (S)-2-(6-Methoxy-H ,51-naphthyridin-4-yl)oxirane; a) 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine; 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6g, 48%). The unsaturated ester (10.5g, O.Oδmol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26g, 70%)
70%	In diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	2.a Preparation 2; Preparation of (S)-2-(6-Methoxv-ri ,51-naphthvridin-4-vl)oxirane; (a) 4-Hydroxy-6-methoxy-[1,5]-naphthyridine; 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methylpropiolate (40ml, 0.44mol) was stirred for 48 h, then evaporated and the product purifiedby chromatography on silica gel (DCM) followed by recrystallisation from DCM-hexane(44.6g, 48%).The unsaturated ester (10.5g, O.OSmol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipitate was filtered to give the title compound (6.26g, 70%)
70%	In diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	1.a Preparation 1; Preparation of 6-(methvloxv)-1,5-naphthvridin-4-yl trifluoromethanesulfonate; (a) 4-Hydroxy-6-methoxy-[1,5]-naphthyridine; 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6g, 48%).The unsaturated ester (10.5g, 0.05mol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26g, 70%).
70%	In diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	2.a 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hr, then evaporated and the product purified by chromatography on silica gel (DCM) followed by recrystallisation from DCM-hexane (44.6g, 48%).The unsaturated ester (10.5g, O.Oδmol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26g, 70%): LC/MS (ES) m/z 177 [M+H]+

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/81182, 2006, A2 Location in patent: Page/Page column 18
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2004/14361, 2004, A1 Location in patent: Page/Page column 30
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2003/87098, 2003, A1 Location in patent: Page/Page column 37
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/2047, 2006, A2 Location in patent: Page/Page column 72
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/14580, 2006, A1 Location in patent: Page/Page column 33
[6]Current Patent Assignee: HONDA MOTOR CO., LTD. - WO2006/17326, 2006, A1 Location in patent: Page/Page column 21-22
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2007/16610, 2007, A2 Location in patent: Page/Page column 23

12
C₁₀H₁₂N₂O₃ [ No CAS ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	In diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	2.a Preparation 2; Preparation of 6-(methyloxy)-1 ,5-naphthyridin-4-yl trifluoromethanesulfonate; a) 4-Hydroxy-6-methoxy-[1 ,5]-naphthyridine; 5-Amino-2-methoxypyridine (55g, 0.44mol) in methanol (1000ml) with methyl propiolate (40ml, 0.44mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6g, 48%).The unsaturated ester (10.5g, O.Oδmol) in warm Dowtherm A (50ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26g, 70%).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/81264, 2006, A1 Location in patent: Page/Page column 24

13
[ 6628-77-9 ]
[ 922-67-8 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	In methanol	18.b (b) (b) 4-Hydroxy-6-methoxy-[1,5]-naphthyridine 5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000 ml) with methyl propiolate (40 ml, 0.44 mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6 g, 48%). The unsaturated ester (10.5 g, 0.05 mol) in warm Dowtherm A (50 ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26 g, 70%)
70%	In methanol	31.a (a) (a) 4-Hydroxy-6-methoxy-[1,5]-naphthyridine 5-Amino-2-methoxypyridine (55 g, 0.44 mol) in methanol (1000 ml) with methyl propiolate (40 ml, 0.44 mol) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallisation from dichloromethane-hexane (44.6 g, 48%). The unsaturated ester (10.5 g, 0.05 mol) in warm Dowtherm A (50 ml) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into ether. The precipate was filtered to give the title compound (6.26 g, 70%)
	Stage #1: 6-methoxy-pyridin-3-ylamine; propynoic acid methyl ester In methanol for 48h; Stage #2: In diphenyl ether-biphenyl eutectic for 0.383333h; Heating / reflux;	1.a 5-Amino-2-methoxypyridine (55.0 g, 0.44 mole) in methanol (1000 mL) with methyl propiolate (40 mL, 0.44 mole) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallization from dichloromethane-hexane (44.6 g, 48%). The unsaturated ester (10.5 g, 0.05 mole) in warm Dowtherm A (50 mL) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipitate was filtered to give a solid (6.26 g, 70%).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2004/38998, 2004, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2004/53928, 2004, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2006/166977, 2006, A1 Location in patent: Page/Page column 8

14
[ 1025373-45-8 ]
[ 23443-25-6 ]
[ 394223-86-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: trifluoromethanesulfonic acid anhydride; 6-methoxy-1,5-naphthyridin-4-ol With 2,6-dimethylpyridine; dmap In dichloromethane at 0℃; for 4h; Stage #2: With ammonium chloride In dichloromethane; water	1b Ib) Trifluoro-methanesulfonic acid 6-methoxy- [1, 5] -naphthyridin-4-yl esterNaphthyridin-4-ol (la) (4.83 g) was suspended in dichloromethane(111 ml), cooled to 0°C and treated with 2,6-lutidine (4.8 ml),DMAP (0.50 g) and trifluoromethanesulfonic anhydride (5.1 ml).The mixture was stirred at this temperature for 4 hours, thendiluted with saturated ammonium chloride solution and extractedtwice with dichloromethane. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and evaporated.The residue was purified by flash chromatography (silica gel,dichloromethane) to give the desired product (6.14 g).XH NMR (300 MHz, CDC13) : 5: 8.85 (d, 1H) , 8.18 (d, 1H) , 7.35 (d,1H), 7.17 (d, 1H), 4.06 (s, 3H)

Reference： [1]Current Patent Assignee: DEINOVE SA - WO2006/21448, 2006, A1 Location in patent: Page/Page column 29

15
[ 23443-25-6 ]
[ 724787-12-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-chloro-succinimide In acetic acid at 35℃; for 24h;	1.a A solution of 6-(methyloxy)-l,5-naphthyridin-4-ol (6-methoxy-lH- [l,5]naphthyridin-4-one, for a synthesis see WO2002096907 Example 1) (50 g; 0.2841 mol) in glacial acetic acid (750 niL) was treated with N-chlorosuccinimide (42.5 g; 0.3185 mol) and the mixture was heated under argon at 350C for 24 hours. It was cooled and the precipitated solid filtered off and washed with a little cold acetic acid, then ether and finally hexane. It was dried at 5O0C overnight in vacuo to give an off-white solid 48g (80%). LC/MS (+ve ion electrospray): m/z 209/211 (M+η)+
43%	With N-chloro-succinimide; acetic acid at 30℃; for 16h;	3-chloro-6-methoxy-l,5-naphthyridin-4-ol To a mixture of 6-Methoxy-[1,5]naphthyridin-4-ol (19.4 g, 110.23 mmol) in acetic acid (330 mL)N-chlorosuccinimide (16.87 g, 126.76 mmol) was added, and the reaction solution was stirred at 30 °C for 16 h. After the reaction solution was cooled to room temperature, and a large amount of solid was precipitated and filtered. The filter cake was washed with diethyl ether and n-heptane, and dried to obtain an off-white solid (10 g, yield 43%). MS (ESI): m/z = 211 [M+H]+.
	With N-chloro-succinimide In acetic acid at 65℃; for 1.5h;	46 4-Hydroxy-6-methoxy-l,5-naphthyridine (10.4g) and N-chlorosuccinimide (8.7g) were combined and heated at 65 °C in acetic acid (12OmL) for 1.5 hours. The mixture was cooled to room temperature, filtered, washed with water, saturated sodium bicarbonate solution, then with water again, and dried in vacuo to give product 3-chloro-4-hydroxy-6-methoxy-l,5-naphthyridine (12g).

	With N-chloro-succinimide; acetic acid at 35℃;	25a 25a) 3-Chloro-6-methoxy-[1,5]-naphthyridin-4-ol6-Methoxy-[1,5]-naphthyridin-4-ol (la) (12 g) was suspended inacetic acid (200 ml) and warmed until all had dissolved, thenNCS (10 g) was added and the mixture stirred at 35°C over night.The mixture was cooled, the solid collected by filtration,washed with acetic acid and dried under vacuum to give thedesired product (13.1 g).XH NMR (300 MHz, d6-DMSO) : 8: 12.30 (bs, 1H) , 8.40 (s, 1H) , 7.98(d, 1H), 7.20 (d, 1H), 3.95 (s, 3H)
	With N-chloro-succinimide In acetic acid at 35℃; for 18h;	4.a 6-Methoxy-[1 ,5]naphthyridin-4-ol (12 g) in acetic acid (200 mL) was sonicated and warmed until all had dissolved, and then it was treated with N-chlorosuccinimide (10.01 g) and the mixture was heated at 350C for 18 hr, cooled, and the solid collected and washed with acetic acid and dried in vacuo at 4O0C overnight, to give a white solid (9.5 g); MS (ES) m/z211/213 (M + H)+.
55.4 g	With N-chloro-succinimide; acetic acid at 35 - 40℃; for 4h;	Step 3To a solution of M.2 (50.0 g) in acetic acid (heating was needed to dissolve) was added N-chlorosuccinimide (41.7 g), the mixture was stirred at 35-40 °C for 4 hours. The resulting precipitates were collected by filtration. A suspension of the crude product in water was stirred at 80 °C for 1 hour. The precipitates were collected by filtration and washed with water to give M.3 (55.4 g).1H NMR (DMSO-dg): δ 4.07 (s, 3H), 7.47 (d, J= 9.2 Hz, 1H), 8.45 (d, J= 9.2 Hz, 1H), 8.65 (d, J= 2.4 Hz, 1H), 9.08 (s, 1H).
	With N-chloro-succinimide; acetic acid at 60℃; for 3h; Inert atmosphere;	2.1 Stepl: 3-Chloro-6-methoxy-l,5-naphthyridin-4-ol (Xlla) To a stirred solution of 6-methoxy-l,5-naphthyridin-4-ol (10.0 g, 56.76 mmol) in glacial acetic acid (150 mL) at room temperature under nitrogen atmosphere was added N- chlorosuccinimide (8.48 g, 63.57 mmol). The reaction mixture was heated to 60 °C and stirred for 3 hour. After that, the reaction mixture was cold to room temperature and solid precipitated was filtered, washed with n-hexane and dried under vacuo to get compound Xlla as a white solid, which was used as such for the next step without any further purification. Yield: 10.0 g (crude), 85.03 %.LC_MS Calc for C9H7CIN2O2, 210.62; Obs: 211.0 [M++H]; -NMII (300 MHz, DMSO- d6): d 8.40 (s, 1H) 7.99 (d, J = 11.60 Hz, 1H), 7.20 (d, J = 12.0 Hz, 1H), 3.95 (s, 3H), 3.33 (brs, 1H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/6648, 2008, A1 Location in patent: Page/Page column 23
[2]Current Patent Assignee: SHANGHAI ENNOVABIO PHARMACEUTICALS - EP3882247, 2021, A1 Location in patent: Paragraph 0106; 0113-0115
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2006/125974, 2006, A1 Location in patent: Page/Page column 86
[4]Current Patent Assignee: DEINOVE SA - WO2006/21448, 2006, A1 Location in patent: Page/Page column 63
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/20561, 2006, A2 Location in patent: Page/Page column 30
[6]Current Patent Assignee: KYORIN HOLDINGS, INC. - WO2013/3383, 2013, A1 Location in patent: Page/Page column 85
[7]Current Patent Assignee: BUGWORKS RESEARCH - WO2019/106693, 2019, A1 Location in patent: Paragraph 000170; 000228; 000229

16
[ 23443-25-6 ]
[ 249889-68-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 100℃; for 1.0h;	The residue was suspended in diisopropylethylamine (7 ml), phosphorus oxychloride (1.5 ml) was added to the suspension, and the mixture was stirred at 100C for one hr. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give 8-chloro-2-methoxy-[1,5]naphthyridine (572 mg, yield 29%) (3 steps). 8-Chloro-2-methoxy-[1,5]naphthyridine (50 mg), 5,6-dimethyl-[2,2']bipyridinyl-3-ol (51 mg), and 4-dimethylaminopyridine (94 mg) were dissolved in dimethylsulfoxide (1.5 ml), cesium carbonate (251 mg) was added to the solution, and the mixture was stirred at 130C overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (70 mg, yield 75%). 1H-NMR (CDCl3, 400 MHz): delta 2.34 (s, 3H), 2.66 (s, 3H), 3.92 (s, 3H), 6.92 (d, J = 5.4 Hz, 1H), 7.17 - 7.26 (m, 3H), 7.65 (dd, J = 7.6, 7.6 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.36 (s, 1H), 8.53 (d, J = 5.9 Hz, 1H), 8.58 (m, 1H) Mass spectrometric value (ESI-MS, m/z): 381 (M+Na)+
	With trichlorophosphate; at 110℃; for 12.0h;Inert atmosphere;	Step 3: 8-Chloro-2-methoxy-1,5-naphthyridine To the intermediate 6-methoxy-1,5-naphthyridin-4(1H)-one (15.0 g, 0.085 mumol) was added POCl3 (300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110 C. with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pH of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4100 mL). The combined organic extracts were washed with water (2*100 mL), saturated NaCl solution (100 mL), dried (Na2SO4), filtered and concentrated in vacuo.
		Step 3: 8-Chloro-2-methoxy-1.5-naphthyridine; To the intermediate 6-methoxy-l,5-naphthyridin-4(lH)-one (15.0 g, 0.085mol) was added POCI3 (300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110 C with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2 * 100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pW of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4 x 100 mL). The combined organic extracts were washed with water (2 x 100 mL), saturated NaCl solution ( 100 mL), dried (Na2SO4), filtered and concentrated in vacuo.

With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In chlorobenzene; at 70℃; for 1.5h;

Under an atmosphere of argon, a solution of phosphorus oxychloride (0.128 ml) in chlorobenzene (0.15 ml) was added dropwise to a stirred mixture of 6-methoxy-4-oxo- l,4-dihydro-l,5-naphthyridine (0.176 g), diisopropylethylamine (0.261 ml) and chlorobenzene (5 ml). The resultant mixture was heated to 700C for 1.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and a saturated aqueous sodium 0 bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. There was thus obtained 4-chloro-6-methoxy-l,5-naphthyridine (0.15 g); 1H NMR Spectrum: <n="155"/>(DMSOd6) 4.07 (s, 3H), 7.37 (d, IH)5 7.92 (d, IH), 8.34 (d, IH), 8.72 (d, IH); Mass Spectrum: M+H+ 195.

Reference： [1]Patent: EP1724268,2006,A1 .Location in patent: Page/Page column 79
[2]Patent: US2014/336182,2014,A1 .Location in patent: Paragraph 0323
[3]Patent: WO2008/124083,2008,A2 .Location in patent: Page/Page column 50
[4]Patent: WO2007/113548,2007,A1 .Location in patent: Page/Page column 153-154

17
[ 23443-25-6 ]
[ 881658-92-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With phosphorus tribromide; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h;	6-(Methyloxy)-1,5-naphthyridin-4-ol (21.5 g) (for a synthesis see W02007016610 Preparation 2 (a)) was stirred in DMF (150 ml) at 0C under N2, and phosphorous tribromide (13.5 ml) was added slowly. The mixture was allowed to warm to room temperature and stirred for 90 minutes. H2O (375 ml) was added and the pH was adjusted to pH 7 by addition of solid Na2CO3. The solid was isolated by filtration with suction, dried on the sinter with suction for 2h then dried under vacuum at 45C to give the desired compound (26.0 g, 90%). 1H-NMR delta, ppm, DMSO-d6): 8.59 (d, 1 H), 8.30 (d, 1 H), 8.08 (d, 1H), 7.33 (d, 1 H), 4.06 (s, 3H).
90%		6-(Methyloxy)-1 ,5-naphthyridin-4-ol (21.5 g) (for a synthesis see WO2007016610 Preparation 2 (a)) was stirred in DMF (150 ml) at O0C under N2, and phosphorous tribromide (13.5 ml) was added slowly. The mixture was allowed to warm to room temperature and stirred for 90 minutes. H2O (375 ml) was added and the pH was adjusted to pH 7 by addition of solid Na2CO3. The solid was isolated by filtration with suction, dried on the sinter with suction for 2h then dried under vacuum at 450C to give the desired compound (26.0 g, 90%). 1H-NMR (delta, ppm, DMSOd6): 8.59 (d, 1 H), 8.30 (d, 1 H), 8.08 (d, 1 H), 7.33 (d, 1 H), 4.06 (s, 3H).
75%		C. 8-Bromo-2-methoxy-[1,5]naphthyridine. To a suspension of 6-methoxy-[1,5]naphthyridin4-ol (8.8 g, 0.050 mol) in DMF (167 mL) was added PBr3 (4.7 mL, 0.050 mol) at 45 C. The suspension became homogeneous and then a suspension formed over 20 min. The mixture was cooled to RT and the solid was filtered and washed with Et2O (100 mL). Further solids precipitated from the filtrate and were collected. Water (50 mL) was added to the solid and the suspension was basified with 1 N NaOH (200 mL). The aqueous layer was extracted with CH2Cl2 (3*250 mL), washed with brine (150 mL), dried (MgSO4) and concentrated. The resulting residue was purified on SiO2 (0-60% EtOAc/hexanes) to provide 8.9 g (75%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H7BrN2O, 237.97; m/z found, 239.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.57 (d, J=4.7, 1H), 8.27 (d, J=9.0, 1H), 8.05 (d, J=4.7, 1H), 7.30 (d, J=9.0, 1H), 4.04 (s, 3H).

67%

To a mixture of iV,iV-dimethylformamide (26.4 g, 0.36 mol ) in acetonitrile (350 mL) was added PBr3 (51.0 g, 0.188 mol) at room temperature. The mixture was stirred at 9O0C for 30 min. Then 6-methoxy-l,5-naphthyridin-4-ol (47; 22.0 g, 0.124 mol) was added and the mixture was stirred for 30 min. After cooling to room temperature, the solvent was removed in vacuo and adjusted with saturated NaHCO3 to pH=10. The precipitate was filtered and the filter cake was washed with water and dried in vacuo to give 8-bromo-2-methoxy-l,5-naphthyridine 48 (20.0 g, 0.083 mol, 67%) as a white solid. MS calcd for C9H7BrN2O: 239.1; found: 240 [M+l]

Reference： [1]Patent: EP2080761,2009,A1 .Location in patent: Page/Page column 15
[2]Patent: WO2010/81874,2010,A1 .Location in patent: Page/Page column 17-18
[3]Patent: US2006/223810,2006,A1 .Location in patent: Page/Page column 18
[4]Patent: WO2010/101949,2010,A1 .Location in patent: Page/Page column 125

18
[ 23443-25-6 ]
[ 1075259-68-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With N-Bromosuccinimide; acetic acid at 15℃; for 0.5h; Inert atmosphere;	77 Example 77: 3-oxo-3.,4-dihvdro-2H-benzo[l,41thiazine-6-carboxylic acid {l-[2-(4- ethoxy-6-methoxy-[l,51naphthyridin-3-yloxy)-ethyll-piperidin-4-yl}-amide: Preparation of 3-bromo-6-methoxy-r 1 ,51naphthyridin-4-ol: N-Bromosuccinimide (263 mg, 1.48 mmol, 1.3 eq) is added at 15 0C to a stirred solution of 6-methoxy-[l,5]naphthyridin-4-ol (200 mg, 1.14 mmol, 1.0 eq) in acetic acid (3 mL). After 30 minutes stirring at 15 0C, the reaction mixture is allowed to come at room temperature and the resulting cake is filtered, washed with acetic acid and dried to afford 3-bromo-6- methoxy-[l,5]naphthyridin-4-ol as an off-white solid (280 mg, 97% yield).1H-NMR (400 MHz, DMSO-t/6) δ ppm: 12.90 (br, IH), 8.45 (s, IH), 7.97 (d, J = 9.2 Hz, IH), 7.20 (d, J = 9.2 Hz, IH), 3.93 (s, 3H). MS m/z (+ESI): 255.0 [M+H]+.
90%	Stage #1: 6-methoxy-1,5-naphthyridin-4-ol With N-Bromosuccinimide; acetic acid at 20℃; for 3.16667h; Stage #2: With water; sodium hydrogencarbonate	7.a Example 7; (6R)-3-Bromo-6-({4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7- ylmethyl)amino] -1-piperidinyl} methyl)-5,6-dihydro-8H-[l,4] oxazino [2,3,4-de] - 1 ,5-naphthyridin-8-one dihydrochloride; (a) 3-Bromo-6-methoxy- 1 ,5-naphthyridin-4-ol; 6-Methoxy-l,5-naphthyridin-4-ol ( for method of preparation see GB patent1147760 , 1965) ( 17.6g, 10 mmol) was dissolved in glacial acetic acid ( 500ml) and treated with N-bromosuccinimide (17.8g, 10 mmol) over a period of 10 min. A yellow precipitate was observed, and the reaction mixture stirred at room temperature for a further 3h. The mixture was concentrated under reduced pressure to a volume of 20ml. This mixture was neutralised with half-saturated aqueous sodium hydrogen carbonate solution ( strong effervescence) . The resultant precipitate was collected by filtration, washed with water , and dried in vacuo at room temperature for 18h , followed by 4h at 5O0C. The product was obtained as a buff-coloured solid (23.02g, 90%). MS (ES+), m/z 257, 259 (MH+, 100%).
	With N-Bromosuccinimide; acetic acid at 20℃; for 2h;	A1.c Preparation of intermediate 3 N-bromosuccinimide (57.8 g, 325 mmol) was added to a solution of intermediate 2 (44 g, 250 mmol) in acetic acid (800 ml) at room temperature. The mixture was stirred for 2 hours, was filtered off and washed successively with acetic acid (100 ml) and diethyl ether (2x500 ml), then dried to give 58.2 g (91 %, beige solid) of intermediate 3, that was used without further purification for the next step.

Reference： [1]Current Patent Assignee: BASILEA PHARMACEUTICA - WO2010/84152, 2010, A1 Location in patent: Page/Page column 124
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/128953, 2008, A1 Location in patent: Page/Page column 36
[3]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2013/61077, 2013, A1 Location in patent: Page/Page column 138

19
[ 23443-25-6 ]
[ 141699-55-0 ]
[ 1163127-73-8 ]

Yield	Reaction Conditions	Operation in experiment
62%	With bis(1,1-dimethylethyl)-1,2-diazenedicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;	1.1.i DIAD (0.69 mL, 3.45 mmol) was added dropwise to a suspension of 6-methoxy- [l,5]naphthyridin-4-ol (507 mg, 2.88 mmol), 3-hydroxy-azetidine-l-carboxylic acid tert-bvXy ester (commercial, 500 mg, 2.88 mmol) and PPh3 (906 mg, 3.45 mmol) in TηF (5 mL). A clear solution formed which was stirred at rt overnight. The mixture was concentrated under reduced pressure and purified by CC (ηex/EA 1 :1) to afford the title intermediate as a yellow solid (590 mg, 62% yield). MS (ESI, m/z): 332.4 [M+η+].

Reference： [1]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - WO2009/77989, 2009, A1 Location in patent: Page/Page column 58

20
[ 1242446-41-8 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
35%	In diphenylether at 250℃;	13.2 To a hot solvent (25O0C) of diphenyl ether (150 mL) was added 3-(6- methoxypyridin-3-ylamino)acrylate (46; 20.0 g, 96 mmol) portionwise and the mixture stirred for 10-20 min. to give 6-methoxy-l,5-naphthyridin-4-ol 47 (6.0 g, 33.9 mmol, 35%) as a grey solid. MS calcd for C9H8N2O2: 176.2; found: 177 [M+l].

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2010/101949, 2010, A1 Location in patent: Page/Page column 125

21
[ 6628-77-9 ]
[ 2033-24-1 ]
[ 101-84-8 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-methoxy-pyridin-3-ylamine; cycl-isopropylidene malonate With orthoformic acid triethyl ester In ethanol for 3h; Heating / reflux; Stage #2: diphenylether at 260℃; for 0.05h; Heating / reflux;	1a la) 6-Methoxy-[1,5]-naphthyridin-4-ol5-Amino-2-methoxypyridine (12.29 g) was dissolved in ethanol (41ml) and treated with 2,2-dimethyl-[1,3]dioxane-4,6-dione (17 g)and triethyl orthoformate (17 ml). The mixture was refluxed for3 hours and then cooled to room temperature. The precipitate wasfiltered off, washed with ethanol and dried under vacuum for 1hour to give 25.24 g of the intermediate.The intermediate was added to refluxing diphenyl ether (292 g)(260°C) slowly in portions. The mixture was stirred at 260°Cuntil the gas evolution had ceased (ca. 3 minutes) and thencooled in an ice bath. The precipitated solid was suspended indiethyl ether and filtered. The solid was washed with colddiethyl ether and ethyl acetate to give the desired product(13.2 g).XH NMR (300MHz, d6-DMSO) : 5: 11.90 (bs, 1H) , 7.96-7.89 (m, 2H) ,7.16 (d, 1H), 6.20 (bs, 1H), 3.93 (s, 3H)

Reference： [1]Current Patent Assignee: DEINOVE SA - WO2006/21448, 2006, A1 Location in patent: Page/Page column 28

22
[ 1184302-69-9 ]
[ 23443-25-6 ]
C₁₈H₂₅N₃O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis(1,1-dimethylethyl)-1,2-diazenedicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 6h;	F.F.ii F.ii. (2RS)-(4-oxo-2,3-dihydro-4H-1-oxa-3a,7-diaza-phenalen-2-ylmethyl)-carbamic acid tent-butyl esterA mixture of intermediate F.i (2.54 g) and 6-methoxy-[1,5]naphthyridin-4-ol (1.76 g, 10 mmol) in THF (100 mL) was treated with PPh3 (2.89 g, 11 mmol) and DIAD (2.18 mL, 11 mmol). The solution was stirred at rt for 6 h, concentrated in vacuo and purified by CC (EA). The intermediate mesylate, which was contaminated with PPh3O was dissolved in toluene (100 mL) and heated at reflux overnight. The mixture was cooled to rt and the solvents were removed under reduced pressure. The residue was dissolved in EA, washed with water and brine, dried over MgSO4 and concentrated. The product was purified by CC (Hep/EA 1:1, EA, EA/MeOH 9:1) to give the desired cyclised product as a colourless solid (0.625 g, 20% yield).1H NMR (d6-DMSO) δ: 8.32 (d, J=5.3 Hz, 1H), 7.90 (d, J=10.0 Hz, 1H), 7.21 (m, 1H), 7.09 (d, J=5.3 Hz, 1H), 6.84 (d, J=10.0 Hz, 1H), 4.53 (m, 1H), 4.35 (m, 1H), 3.55 (m, 1H), 3.37 (m, 2H), 1.38 (s, 9H).MS (ESI, m/z): 318.1 [M+H+].

Reference： [1]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - US2010/331318, 2010, A1 Location in patent: Page/Page column 30

23
[ 6628-77-9 ]
[ 23443-25-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: ethanol / 3 h / 80 °C / Inert atmosphere 2: diphenylether / 0.17 h / 220 °C
	Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux; Large scale 2: 1,3-dimethyl-2-imidazolidinone / 0.58 h / 80 - 255 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: cycl-isopropylidene malonate / ethanol / 1 h / Reflux 2: diphenyl ether-biphenyl eutectic / 0.08 h / 240 °C

	Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux; Large scale 2: 1,3-dimethyl-2-imidazolidinone; Dowtherm A / 80 - 255 °C
	Multi-step reaction with 2 steps 1: ethanol / 5 h / Reflux 2: diphenyl ether-biphenyl eutectic / 0.5 h / 190 °C

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2013/61077, 2013, A1
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2013/118086, 2013, A1
[3]Current Patent Assignee: KYORIN HOLDINGS, INC. - WO2013/3383, 2013, A1
[4]Abele, Stefan; Schmidt, Gunther; Fleming, Matthew J.; Steiner, Heinz [Organic Process Research and Development, 2014, vol. 18, # 8, p. 993 - 1001]
[5]Current Patent Assignee: SHANGHAI ENNOVABIO PHARMACEUTICALS - EP3882247, 2021, A1

24
[ 23443-25-6 ]
[ 1431984-61-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: acetic acid; N-Bromosuccinimide / 2 h / 20 °C 2.1: trichlorophosphate / chloroform / 3 h / Reflux 3.1: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / water; 1,4-dioxane / 16 h / 110 °C / Inert atmosphere 4.1: sodium hydroxide; hydrogen / ethanol; water; tetrahydrofuran / 40 h / 50 °C / 750.08 Torr 5.1: hydrogenchloride / water; 1,4-dioxane / 3 h / 80 °C 5.2: pH 9 6.1: trichlorophosphate / chloroform / 3 h / Reflux 7.1: propan-1-ol / 16 h / Reflux 8.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / Inert atmosphere 8.2: 20 °C