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Product Details of [ 61049-69-2 ]

CAS No. :	61049-69-2	MDL No. :	MFCD00207271
Formula :	C₁₃H₁₂O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	216.23	Pubchem ID :	-
Synonyms :

Safety of [ 61049-69-2 ]

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

Application In Synthesis of [ 61049-69-2 ]

* 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.

Upstream synthesis route of [ 61049-69-2 ]
Downstream synthetic route of [ 61049-69-2 ]

[ 61049-69-2 ] Synthesis Path-Upstream 1~7

1
[ 61049-69-2 ]
[ 30652-11-0 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 18, p. 6114 - 6120
[2] Arzneimittel-Forschung/Drug Research, 1987, vol. 37, # 10, p. 1099 - 1102
[3] Canadian Journal of Chemistry, 1988, vol. 66, p. 123 - 131

2
[ 61049-69-2 ]
[ 74-89-5 ]
[ 30652-11-0 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 4, p. 508 - 512

3
[ 61049-69-2 ]
[ 61160-18-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With ammonia In ethanolHeating / reflux	To a solution of 2 (13.8g, 0.064mol) in ethanol (25mL) was added ammonia solution (5OmL) and refluxed overnight. The solvent was removed under reduced pressure, then taken into water and adjusted to pH 1 with concentrated hydrochloric acid. The aqueous mixture was washed with ethyl acetate (3x) and the pH was adjusted to pH 10 with sodium hydroxide (2M.). The aqueous phase was extracted with chloroform (3?), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from methanol/diethyl ether gave brown cubic crystals, mp 162-164°C. Yield 75percent. 1H NMR (CDCl3) ? 2.15 (3H, s, CH3), 5.03 (2H, s, CH2Ph), 6.35 (1?, d, J=6.9?z, 5-H), 7.25-7.31 (5?, m, CH2PA), 7.39 (IH, d, J=6.9Hz, 6-/2). C13H13NO2.
75%	With ammonia In ethanolReflux	To a solution of 2 (13.8 g, 0.064 mol) in ethanol (25 mL) was added ammonia solution (50 mL) and refluxed overnight. The solvent was removed under reduced pressure, then taken into water and adjusted to pH 1 with concentrated hydrochloric acid. The aqueous mixture was washed with ethyl acetate (3.x.) and the pH was adjusted to pH 10 with sodium hydroxide (2 M.). The aqueous phase was extracted with chloroform (3.x.), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from methanol/diethyl ether gave brown cubic crystals, mp 162-164 °C. Yield 75percent. ¹H NMR (CDCl₃) δ 2.15 (3H, s, CH₃), 5.03 (2H, s, CH₂Ph), 6.35 (1H, d, J = 6.9 Hz, 5-H), 7.25-7.31 (5H, m, CH₂Ph), 7.39 (1H, d, J = 6.9 Hz, 6-H); m/z (ESI): 201.1.
64%	With ammonia In ethanol; water at 20℃; Heating / reflux	A clear solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (150 g, 0.69 mol), ethanol (300 mL) and ammonium hydroxide (28.0-30.0percent solution, 690 mL, 10.5 mol) in a 2 L 3-necked round bottom flask equipped with a mechanical stirrer was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, and a further 230 mL of ammonium hydroxide (3.5 mol) was added. The resulting solution was heated to reflux for another 3.5 h, then allowed to cool to RT and stirred for overnight. A solid product had separated, and was collected by suction filtration. Thus, 95 g of 3-benzyloxy-2-methyl-1H-pyridin-4-one (64percent yield) was obtained as a first crop. HPLC Method 4 (Example 24), RT=10.7 min, HPLC purity (peak percent area): 99percent at λ=280 nm)). ¹H NMR (DMSO-d₆) δ ppm: 11.3 (br s, 1H), 7.46 (s, 1H), 7.35, (m, 5H), 6.13 (s, 1H), 5.04 (s, 2H), 2.05 (s, 3H); ¹H NMR (DMSO-d₆+D₂O) δ ppm: 7.47 (d, J=7.0 Hz, 1H), 7.39, (m, 5H), 6.20 (d, J=7.0 Hz, 1H), 5.01 (s, 2H), 2.03 (s, 3H).

43%	With sodium hydroxide; ammonia In ethanol; water at 90℃; for 1 h;	2) The compound 2 (162, 2g, 750mmol) was dissolved in ethanol (-187ml), and aqueous ammonia (28percent, 974ml) and a 6N aqueous sodium hydroxide solution (150ml, O00mmol) were added. After the reaction solution was stirred at 90 °C for 1 hour, this was cooled to under ice-cooling, and ammonium chloride (58g, 10S0mmol) was added, To the reaction solution was added chloroform, this was extracted, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl alcohol and diethyl ether were added to the residue, and precipitated crystals were filtered to obtain 3-benzyloxy-2-methyl- 1H-pyridine-4-one 3 (69.1g, 43percent) as a pale yellow crystal.NMR (DMSO-dfi)δ: 2.05(3H, s), 5.04(2H, a), 6 14(1H, d, J=7 0Hz), 7,31-7.42(5H, m), 7 46(1H, d, J=7.2Hz), 11.29(1H, brs).
2.3 g	With ammonium hydroxide In water; acetonitrile at 80 - 90℃; for 18 h; Sealed tube	To a solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (2.3 g) in acetonitirle (5 ml) was added aq.N in seal tube. The reaction mixture was heated at 80-90°C for 18 h. After completion of reaction, the reaction mixture was cooled at RT and diluted with ethyl acetate. The organic layer was separated and further aqueous layer was extracted with 10percent MeOH in DCM. The organic layer was concentrated to afford 2.3 g of desired product. 1H NMR (DMSO-d₆): δ2.0 (s, 3H), 5.0 (s, 2H), 6.20 (s, 1H), 7.20- 7.40 (m, 6H), 11.20 (br s, 1H); MS [M+H]⁺ : 216.13.

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 17, p. 2448 - 2458
[2] Journal of Heterocyclic Chemistry, 1992, vol. 29, # 4, p. 1017 - 1019
[3] Tetrahedron, 2001, vol. 57, # 16, p. 3479 - 3486
[4] Patent: WO2006/103463, 2006, A1, . Location in patent: Page/Page column 9; Figure 2
[5] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 3, p. 1285 - 1297
[6] Dalton Transactions, 2012, vol. 41, # 35, p. 10784 - 10791
[7] Dalton Transactions, 2007, # 43, p. 5019 - 5030
[8] Patent: US2008/242706, 2008, A1, . Location in patent: Page/Page column 32
[9] Canadian Journal of Chemistry, 1988, vol. 66, p. 123 - 131
[10] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 24, p. 4371 - 4374
[11] Journal of Medicinal Chemistry, 2006, vol. 49, # 1, p. 43 - 50
[12] Journal of Medicinal Chemistry, 2013, vol. 56, # 3, p. 1124 - 1135
[13] Patent: WO2006/116764, 2006, A1, . Location in patent: Page/Page column 79-80
[14] Journal of Medicinal Chemistry, 1984, vol. 27, # 2, p. 160 - 164
[15] Patent: US5112968, 1992, A,
[16] Patent: EP336369, 1989, A1,
[17] European Journal of Medicinal Chemistry, 2009, vol. 44, # 5, p. 2145 - 2157
[18] Patent: US2006/30619, 2006, A1, . Location in patent: Page/Page column 16; 20-21
[19] Dalton Transactions, 2008, # 45, p. 6364 - 6367
[20] Patent: WO2013/153535, 2013, A1, . Location in patent: Page/Page column 69

4
[ 61049-69-2 ]
[ 61160-18-7 ]

Reference： [1] Patent: US4585780, 1986, A,
[2] Patent: US4650793, 1987, A,

5
[ 61049-69-2 ]
[ 119736-16-2 ]

Reference： [1] Journal of the American Chemical Society, 2006, vol. 128, # 7, p. 2222 - 2223
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 12, p. 3257 - 3261
[3] Medicinal Chemistry Research, 2013, vol. 22, # 5, p. 2351 - 2359
[4] Patent: WO2015/39348, 2015, A1,
[5] Patent: US9133216, 2015, B2,
[6] Patent: JP5848595, 2016, B2,
[7] Patent: JP5848595, 2016, B2,
[8] Journal of Medicinal Chemistry, 2017, vol. 60, # 8, p. 3498 - 3510
[9] Patent: WO2010/11816, 2010, A1,
[10] Patent: WO2006/116764, 2006, A1,

6
[ 61049-69-2 ]
[ 1206102-07-9 ]

Reference： [1] Patent: WO2015/39348, 2015, A1,
[2] Patent: US9133216, 2015, B2,
[3] Patent: JP5848595, 2016, B2,
[4] Patent: JP5848595, 2016, B2,
[5] Patent: JP5848595, 2016, B2,
[6] Patent: JP5848595, 2016, B2,
[7] Patent: WO2010/11816, 2010, A1,

7
[ 61049-69-2 ]
[ 1229006-21-6 ]

Reference： [1] Patent: JP5848595, 2016, B2,
[2] Patent: JP5848595, 2016, B2,

[ 61049-69-2 ] Synthesis Path-Downstream 1~25

1
[ 118-71-8 ]
[ 100-39-0 ]
[ 61049-69-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1.25h; Inert atmosphere;
100%	Stage #1: Maltol; benzyl bromide In N,N-dimethyl-formamide at 80℃; for 0.25h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide for 1h;	A-1.1; B-1.1 1) Mantol 1 (I 89g, 1,5mol) was dissolved in dimethylformamide (1890ml), and benzyl bromide (184ml, l,5mol) was added, Aftor the solution was stirred at 80°C for 15 minutes, potassium carbonate (228g, 1.65mol) was added, and the mixture was stirred for J hour, Aftor the reaction solution was cooled I o room temperature, an inorganic salt was filtered, and the filtrate was distilled off under reduced pressure. To the again precipitated inorganic salt was added tetrahydrofuran (1000ml), this was filtered, and the filtrate was distilled off tinder reduced pressure to obtain the crude product (329g, >100%) of 3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil.NMR (CDClβ)δ: 2.09(3H, s), 5.15(2H, s), 6.36(1PI, d, J=5.6Hz) , 7.29-7.4l(5H, m), 7,60(1H, d, J=5.61Iz) .
100%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	1 Compounds of formula I are protected by benzyl to give compounds of formula II 189 g of a compound of formula I is dissolved in 1890 mL of N,N-dimethylformamide,Add 184 mL of benzyl bromide, 228 g of potassium carbonate, heat to 80 ° C, and keep for 2 hours.Thin layer chromatography was used to detect complete conversion of the starting material and to cool to room temperature.Add 1000 mL of tetrahydrofuran and filter to remove inorganic impurities.The filtrate was spun dry to give 329 gWhite solid, yield 100%.

99%	With potassium hydroxide In methanol Ambient temperature;
99%	With potassium carbonate In acetone for 6h; Reflux;	4.1.2 General procedures for the preparation of compounds 2a-c and 7a-b General procedure: A solution of maltol 1 or 6 (60 mmol), iodomethane or benzyl bromide or 4-methoxylbenzyl chloride (90 mmol), anhydrous K2CO3 (12.42 g, 90 mmol) and acetone (150 mL) was refluxed for 6 h. After the reaction was completed, the reaction mixture was evaporated under vacuum, and the residual was resolved in water (100 mL), extracted by DCM (4×100 mL) and washed by saturated brine (2×100 mL). The organic solution was evaporated to dryness to obtain 2a-c as yellow oil, 7a-b as white solid.
99%	With potassium carbonate In acetone for 6h; Reflux;	4; 7-11 preparation method N-(2-(2-Methyl-3-hydroxy-1(4H)-4-oxopyridyl)ethyl)-7-methoxy-2-oxo-2H-benzopyran-3 -Formamide (a2b1) Add maltol (7.56g, 60mmol), benzyl bromide (15.39g, 90mmol), anhydrous potassium carbonate (12.42g, 90mmol), acetone (100mL) into a 250mL single-necked flask, heat and reflux for 6 hours, TLC monitor the reaction, wait After the conversion of the raw materials is complete, stop the reaction, concentrate the reaction solution to obtain a solid, add 100 mL of water to dissolve, extract with 100 mL×4 dichloromethane, combine the organic layers, dry the organic layers with anhydrous sodium sulfate, and concentrate to obtain a yellow oily liquid 2-methyl -3-benzyloxypyran-4-one (12.83g), yield 99%.
98%	In acetone for 6h; Reflux;	3-8 Add maltol (7.56g, 60mmol) and acetone 100mL to a 250mL single-mouth bottle.Benzyl bromide (11.29g, 66mmol), heated under reflux for 6 hours, after the reaction was completed, cooled to room temperature, then the solvent was evaporated, dissolved in 100 mL of water, and extracted with dichloromethane (50 mL) 4 times.The organic layer was dried over anhydrous sodium sulfate.The organic layer was concentrated to give 2-methyl-3-benzyloxypyranone. The yield was 98%.
95%	With potassium carbonate In acetonitrile for 16h; Reflux;	36 4.2.36 3-(Benzyloxy)-2-methyl-4H-pyran-4-one (47) Potassium carbonate (4.8g, 35mmol) and benzyl bromide (1.3mL, 1.9g, 11mmol) were added to a solution of 3-hydroxy-2-methyl-4H-pyran-4-one (1.1g, 8.7mmol) in dry acetonitrile (50mL). After heating the mixture to reflux for 16h, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by flash column chromatography (=4cm, h=15cm, cyclohexane/ethyl acetate=8:2→2:1, V=30mL) to give 47 as yellowish oil (1.8g, 8.3mmol, 95% yield). Rf=0.49 (cyclohexane/ethyl acetate=1:1); 1H NMR (CDCl3): δ [ppm]=2.11 (s, 3H, CH3), 5.16 (s, 2H, OCH2Ph), 6.50 (d, J=5.6Hz, 1H, OCH=CHCO), 7.30-7.36 (m, 3H, 3′-Hphenyl, 4′-Hphenyl, 5′-Hphenyl), 7.37-7.40 (m, 2H, 2′-Hphenyl, 6′-Hphenyl), 7.64 (d, J=5.6Hz, 1H, OCH=CHCO); 13C NMR (CDCl3) δ [ppm]=15.0 (1C, CH3), 73.8 (1C, OCH2Ph), 117.0 (1C, OCH=CHCO), 128.5 (1C, C-4′phenyl), 128.6 (2C, C-3′phenyl, C-5′phenyl), 129.2 (2C, C-2′phenyl, C-6′phenyl), 136.9 (1C, C-1′phenyl), 143.8 (1C, OC=CCH3), 153.8 (1C, OCH=CHCO), 160.6 (1C, OC=CCH3) 175.3 (1C, OCH=CHCO); IR (neat): [cm-1]=3063, 3028, 2959, 2882, 1643, 1574, 1497, 1427, 1389, 1354, 1250, 1173, 1080, 1026, 972, 914, 829, 748, 702; LCMS (m/z): [M+H]+ calcd for C13H13O3: 217.0859, found: 217.0875; HPLC (method 1): tR=17.2min, purity 97.9%.
93%	With sodium hydroxide In methanol for 16h; Heating;
93%	With sodium hydroxide In methanol for 16h; Heating;
93%	With sodium hydroxide In methanol at 75℃; for 6h; Reflux;	Synthesis of 3-benzyloxy-2-methyl-4-pyrone (1). To a solution of 10.00 g 3-hydroxy-2-methyl-4-pyrone(79 mmol) containing the equivalent amount of NaOH (3.16 g, 79 mmol) in 100 mL methanol, 13 mLbenzyl bromide (90 mmol) was dropwise added and then stirred for 6 h under reflux temperature.After cooling, the reaction mixture was evaporated under vacuum, and the residual oil was resolvedin 50 mL dichloromethane and washed with 5% NaOH aqueous solution (5 x 30 mL) and water(3 x 50 mL). The organic solution was evaporated to dryness to obtain the pure product as pale oil(15.7 g, 93%). UV-vis (CH3OH): λmax = 219, 260 nm. FT-IR (KBr): ν = 3065, 3031, 2958, 2877, 1644, 1575,1496, 1455, 1428, 1253, 1186, 1079, 973, 915, 832, 751, 703 cm-1. 1H NMR (300 MHz, CDCl3): δ=7.57 (d,J = 6.0 Hz, 1H), 7.25-7.40 (m, 5H), 6.33 (d, J = 6.0 Hz, 1H), 5.13 (s, 2H, CH2Ph), 2.06 (s, 3H, CH3) ppm.MS (APCI, CH3OH) m/z (%) = 217 (100) [M + H]+. C13H12O3 (216.3): calcd. C 72.22, H 5.56; found: C72.43, H 5.47.
89%	With sodium hydroxide In methanol; water for 20h; Reflux;
87%	With sodium hydroxide In methanol; water for 24h; Reflux;
83%	With sodium hydroxide In methanol at 75℃;
83%	With sodium hydroxide In methanol at 75℃;	a a) BnBr, NaOH(aq), MeOH, 75 C, 83%;
81%	With sodium hydroxide In methanol; water for 6h; Reflux;	2-Methyl-3-benzyloxy-4-(4H)-pyranone (7) To a solution of maltol (50 g, 0.397 mol) in methanol (450 mL) was added aq sodium hydroxide (8.7 M, 50 mL of) and benzylbromide (74.66 g, 0.437 mol). The reaction mixture was heated to reflux for 6 h. After removal of solvent in vacuo, the oily residue was taken up in DCM (190 mL), washed with aq sodium hydroxide (5%, 2 × 190 mL) and water (2 × 190 mL). The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated to yield as an orange oil which solidified upon cooling. Recrystallization from Et2O gave 69.9 g of 7 as colorless needles (81% yield). Mp: 33-34 °C. 1H NMR (90 MHz, DMSO-d6, ppm) δ: 1.99 (s, 3H, CH3), 5.00 (s, 2H, CH2), 6.14-6.24 (m, 1H, ArCH), 7.20 (s, 5H, 5 × ArCH), 7.39-7.49 (m, 1H, ArCH).
80%	With sodium hydroxide In methanol; water Heating;
80%	Stage #1: Maltol With sodium hydroxide In methanol; water Heating / reflux; Stage #2: benzyl bromide In methanol; water for 6h; Heating / reflux;	1.a To a solution of maltol (1) (1Og, 0.079mol) in methanol (2OmL) was added sodium hydroxide (3.49g, 0.087mol, l.lequiv.) in water (1OmL). The reaction mixture was heated to reflux before benzyl bromide (10.4mL, 0.087mol, l.lequiv.) was slowly introduced dropwise and the mixture was left to reflux for 6 hours. After the solvent was removed, the residue was taken into water and dichloromethane. The aqueous fraction was discarded and the organic fraction washed with sodium hydroxide 5% (3?) followed by water (2?). The combined fractions were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from diethyl ether afforded off-white crystals, mp 54-56°C. Yield 80%. 1H NMR (CDCl3) ? 2.07 (3H, s, CH3), 5.15 (2H, s, CH2Ph), 6.36 (IH, d, J=5.7 Hz, 5-H), 7.31- 7.40 (5?, m, CR2Ph), 7.59 (IH5 d, J=5.7 Hz, 6-.H). C13H13O3.
80%	Stage #1: Maltol With sodium hydroxide In methanol; water Reflux; Stage #2: benzyl bromide In methanol; water for 6h; Reflux;	4.1.1. 2-Methyl-3-benzyloxypyran-4(1H)-one (2) To a solution of maltol (1) (10 g, 0.079 mol) in methanol (20 mL) was added sodium hydroxide (3.49 g, 0.087 mol, 1.1 equiv) in water (10 mL). The reaction mixture was heated to reflux before benzyl bromide (10.4 mL, 0.087 mol, 1.1 equiv) was slowly introduced dropwise and the mixture was left to reflux for 6 h. After the solvent was removed, the residue was taken into water and dichloromethane. The aqueous fraction was discarded and the organic fraction washed with sodium hydroxide 5% (3×) followed by water (2×). The combined fractions were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from diethyl ether afforded off-white crystals, mp 54-56 °C. Yield 80%. 1H NMR (CDCl3) δ 2.07 (3H, s, CH3), 5.15 (2H, s, CH2Ph), 6.36 (1H, d, J = 5.7 Hz, 5-H), 7.31-7.40 (5H, m, CH2Ph), 7.59 (1H, d, J = 5.7 Hz, 6-H); m/z (ESI): 202.0.
80%	With potassium carbonate In acetone at 0 - 20℃; for 16h;	8 Synthesis of compound 8b At 0°C, 8.22g of anhydrous K2CO3and 5.7 mL of benzyl bromide were sequentially added to a solution of 5 g of compound 8a in acetone (80 mL), and the reaction was moved to room temperature for 16 hours. After the reaction was completed, it was concentrated, and ethyl acetate and Water, separated the layers, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated, and separated by column chromatography to obtain 6.90 g of compound 8b, yield: 80%.
75%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 16h;
75%	With potassium carbonate In N,N-dimethyl-formamide at 80℃;	3 To a 500 mL flask with 10.0 g (0.08 mol) of maltol (3-hydroxy-2-methyl-4H-pyran-4-one) in 120 mL of anhydrous DMF was added 14.1 mL (0.12 mol) of benzyl bromide and potassium carbonate (16.4 g, 0.12 mol) and heated at 80° C. overnight. After cooling to room temperature, the reaction was filtered and the solvents evaporated. The residual oil was brought up in 100 mL CH2Cl2 and washed twice with a saturated NaHCO3 solution, water, and brine. The organic layer was dried over MgSO4, filtered and concentrated. Product was purified on a silica gel column eluting with 0.5% MeOH in CH2Cl2 to yield a pale yellow solid in 75% yield (12.8 g, 59 mmol). 1H NMR (400 MHz, CDCl3) δ=7.59 (d, J=5.6 Hz, 1H), 7.36 (m, 5H), 6.36 (d, J=5.6 Hz, 1H), 5.15 (s, 2H, OCH2), 2.08 (s, 3H, CH3). ESI-MS(+): m/z 217.03 [M+H]+, 239.07 [M+Na]+.
	With potassium carbonate In acetone for 72h; Ambient temperature;
	With sodium In methanol; water; ethyl acetate	1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one EXAMPLE 1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one 11.5 g of sodium were dissolved in 300 ml CH3 OH and 63g of maltol were added and stirred at room temperature for one hour. 200 ml CH3 OH were added and then 102 g benzylbromide were dropped in (30 minutes). Refluxing for 3 hours and distilling off the CH3 OH then yielded a residue which was dissolved in 300 ml H2 O/300 ml ethyl acetate. The organic phase was washed with water and evaporated. The remaining oil was distilled in vacuo. B.P. (43 mm) =148°-150° C., 81.5 g colorless oil of the title compound was isolated.
	With sodium In methanol; water; ethyl acetate	1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one Example 1 2-Methyl-3-(phenylmethoxy)-4H-pyran-4-one 11.5g of sodium were dissolved in 300ml CH3OH and 63g of maltol were added and stirred at room temperature for one hour. 200ml CH3OH were added and then 102g benzylbromide were dropped in (30 minutes). Refluxing for 3 hours and distilling off the CH3OH then yielded a residue which was dissolved in 300ml H2O/300ml ethyl acetate. The organic phase was washed with water and evaporated. The remaining oil was distilled in vacuo. B.P. (43mm) = 148-150°C, 81.5g colorless oil of the title compound was isolated.
	With potassium carbonate In acetonitrile at 23 - 80℃;	A Example A; Maltol to Benzylmaltol 2a; Maltol: 200OgBnBr: [MW=171.04, d=1.444] 2848.2g (1..05eq) K2CO3 [MW=138.21] 2630.3g (1.2eq) MeCN 14L 7VTo the solution of 200Og of Maltol in MeCN (14L) was added BnBr (2848.2g) and K2CO3 (2630.3g) at room temperature, (around 23°C) After addition of reagent, the temperature of the reaction mixture was getting high.This reaction mixture was kept at 80°C for 5hr and then cooled down to room temperature.The reaction mixture was filtered and washed with MeCN (3L, 1L, 1L). Filtration was concentrated and added THF 2L and concentrated again, (check the KF 1.33%).THF 1.5L was added to the residue and concentrate again. (KF= 0.135%) The residue 2a : 3648g
	With potassium carbonate In acetonitrile at 80℃; for 5h;	1a To a slurry of 200O g of compound 1(1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide(1.05 eq.) and 2630 g of K2CO3(1.2 eq.). The mixture was stirred at 80 0C for 5 h and cooled to 13°C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound 2 as oil. Without further purification, compound 2 was used in the next step.1H NMR(300 MHz, CDCI3) δ 7.60 (d, J = 5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37 (d, J = 5.7 Hz, 1H), 5.17 (S, 2H), 2.09 (s, 3H).
	With potassium carbonate In acetonitrile at 70℃; for 7h; Inert atmosphere;
2.3 g	Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 22 - 26℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 22 - 26℃; for 6h;	1 Intermediate- 11 Methyl 2-((2-chloro-6-fluorophenyl)amino)-l-methyl-7,8-dihydro-lH- [l,4]dioxino[2,3-d]imidazo[ -b]pyridine-5-carboxylate Step-1 : -Preparation of 3-(benzylo -2-methyl-4H-pyran-4-one To a solution of 3-hydroxy-2-methyl-4H-pyran-4-one (2.0g, 0.0158 mol) in DMF (10 mL) was added potassium carbonate (2.6 g, 0.0189 mol). The reaction mass was stirred at RT for 30 minutes. The reaction mixture was added benzyl bromide (2.98 g, 0.017 mol) and continued stirring for 6 h at RT. After completion of reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulphate and concentrated to afford 2.3 g of desired product. 1H NMR (DMSO- 6): δ 2.10 (s, 3Η), 5.0 (s, 2Η), ), 6.37 (d, J = 9.30 Hz, 1H), 7.60-7.30 (m, 5H), 8.07 (d, J= 6.0Hz, 1H), MS [M+H]+ : 258.08.
155 g	With potassium carbonate In acetonitrile at 80℃; for 3h;	1 Example 1: Preparation of 3-(benzyloxy)-2-methyl-4H-pyran-4-one Example 1: Preparation of 3-(benzyloxy)-2-methyl-4H-pyran-4-one Maltol (100 gm) was dissolved in acetonitrile (600 ml) and potassium carbonate (153 gm) and benzyl bromide (116 ml) was added to the solution. The contents were heated to 80°C and stirred for 3 hours. The reaction mass was cooled to room temperature and filtered. The solvent was distilled off from the filtrate thus obtained under reduced pressure to obtain 155 gm of 3-(benzyloxy)-2-methyl-4H-pyran-4-one.
	With potassium carbonate In acetonitrile Inert atmosphere; Reflux; Large scale;	1.A Step A - Synthesis of Intermediate Compound lb Step A - Synthesis of Intermediate Compound lb To a 20L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-hydroxy-2-methyl-4H-pyran-4-one la (2 kg, 15.87 mol, 1.00 equiv), MeCN (10 L), potassium carbonate (2.63 kg, 19.01 mol, 1.20 equiv), BnBr (2.85 kg, 16.67 mol, 1.05 equiv). The resulting solution was heated to reflux overnight. The solid was filtered. The filtrate was concentrated in vacuo. This resulted in 3.5 kg (crude) of 3-(benzyloxy)- 2-methyl-4H-pyran-4-one lb as brown oil which was used directly.
	With potassium carbonate In acetonitrile at 80℃; for 5h;	1.a a) Synthesis of 2-methyl-3-[(phenylmethyl)oxy]-4H-py- ran-4-one (compound P-2). To a slurry of 2000 g ofcompound P-i (1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide (1.05 eq.) and 2630 g ofK2C03 (1.2 eq.). The mixture was stirred at 80° C. for 5h and cooled to 13° C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crudecompound P-2 as oil. Without further purification, com40 pound P-2 was used in the next step. ‘H NMR (300MHz, CDC13) ö 7.60 (d, J5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37 (d, J5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s, 3H).
	In methanol; water at 70℃;
	With potassium carbonate In acetonitrile at 13 - 80℃; for 5h; Large scale;	1a; 3a To a slurry of 2000 g of compound 1(1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide (1.05 eq.) and 2630 g of K2CO3(1.2 eq.). The mixture was stirred at 80° C. for 5 h and cooled to 13° C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound 2 as oil. Without further purification, compound 2 was used in the next step.
	With potassium carbonate In acetonitrile at 80℃; for 5h;	1.a ) Synthesis of 2-methyl-3-[(phenylmethyl)oxy]-4H-pyran-4-one (compound P-2). To a slurry of 200O g of compound P-1(1.0 eq.) in 14.0 L of MeCN were added 2848 g of benzyl bromide(1.05 eq.) and 2630 g of K2CO3(1.2 eq.). The mixture was stirred at 80 °C for 5 h and cooled to 13°C. Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate was concentrated and 3.0 L of THF was added to the residue. The THF solution was concentrated to give 3585 g of crude compound P-2 as oil. Without further purification, compound P-2 was used in the next step. 1H NMR(300 MHz, CDCI3) δ 7.60 (d, J = 5.7 Hz, 1 H), 7.4-7.3 (m, 5H), 6.37 (d, J = 5.7Hz, 1 H), 5.17 (s, 2H), 2.09 (s, 3H).
	With potassium carbonate In acetonitrile at 70℃; for 5h; Large scale;
	With potassium carbonate In acetone for 8h; Reflux;	General procedure for the preparation of compounds 3a-3c General procedure: A mixture of suitable Maltol (7.56g, 60mmol), anhydrous K2CO3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150mL) was refluxed for 8h. Once the reaction was completed, the mixture was cooled to room temperature. After the solvent was removed under reduced pressure, water (100mL) was added and the mixture was extracted four times with dichloromethane (50mL). The combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford intermediate 2a as yellow oil. Intermediates 2b, 2c wasprepared followed the similar procedure of 2a. 2a, 2b or 2c (4.33g, 40mmol) was then dissolved in ethanol 45mL and then 25% ammonia aqueous solution (60mL) was added, and the mixture was refluxed for 12h. Afterward, The solvent was evaporated off to obtain a pale brown solid residue, which was recrystallized from acetone/ethyl acetate, leaving the pure target compound as a pale colored solid.
	With sodium hydroxide In methanol for 24h; Reflux;
	With sodium hydroxide In ethanol for 6h; Reflux;	4.1.2. Synthesis of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (1) Maltol (2-methyl-3-hydroxy-pyran-4-one, 1.261 g, 10 mmol)was dissolved in a solution of 12 mL of EtOH and 1.3 mL of 8.7 NNaOH and benzyl bromide (1.19 mL, d 1.44 g/mL, 10 mmol) wasadded. The solution was kept under stirring at reflux for 6 h. Afterremoval of solvent under reduce pressure, the residue was dissolvedin 20 mL of CH2Cl2 and washed with aqueous NaOH 5%(2 x 5 mL) and H2O (2 x 5 mL). The organic layer was then driedover anhydrous Na2SO4, filtered, and evaporated under vacuum togive the crude product, which was used for subsequent reactionswithout further purification. Yellow oil, 1.76 g, 82% yield. 1H NMR(400 MHz) (MeOD) δ (ppm): 7.94 (d, 1H, J 5.60 Hz, -O-CH]CHeC]O); 7.41e7.33 (m, 5H, aromatic); 6.42 (d, 1H, J 5.60 Hz, -OCH]CHeC]O); 5.08 (s, 2H, Ar-CH2-O-); 2.12 (s, 3H, -CH3).
	With potassium carbonate In N,N-dimethyl-formamide at 80℃;	1 Example 1 : 1-(9a,10-dihydroindeno[1 ,2-a]inden-4b(9H)-yl)-5-hydroxy-3-methyl-2,3- dihydro-1 H-pyrido[2, 1 -f][1 ,2,4]triazine-4,6-dione (A1 ) To a stirred solution of 3-hydroxy-2-methyl-4/-/-pyran-4-one 1 -1 (100 g, 793 mmol) in N,N-dimethylformamide (DMF; 1 L) were added potassium carbonate (219 g, 1.59 mol) and benzyl bromide (188 ml_, 1.59 mol) at room temperature (RT). The reaction mixture was stirred at 80 °C for 12 hours (hr). After consumption of starting material (as determined by TLC), the reaction mixture was quenched with ice-cold water (3 L), extracted with ethyl acetate (EtOAc) (5 x 1 L), dried over sodium sulfate (Na2S04), and concentrated under reduced pressure. The residue was dissolved in diethyl ether (3 L), washed with 1 N HCI (5 x1 L), ice-cold water (1 L), and saturated NaHCCh (2 x 1 L) solution, dried over Na2S04 and concentrated under reduced pressure to afford 3-(benzyloxy)-2-methyl-4/-/-pyran-4-one 1-2. TLC: 40% EtOAc/ petroleum ether; Rf: 0.4. LCMS (ESI): m/z 217.06 (M+H)+.
	With potassium carbonate In acetone for 4h; Reflux;	4.4. General procedure for the preparation of intermediate 8 A mixture of Maltol (1.260 g, 10 mmol), anhydrous K2CO3 (2.740 g,20 mmol), benzyl bromide (2.052 g, 12 mmol) and acetone (60 mL) was refluxed for 4 h. After the reaction was completed, the reaction mixture was evaporated under vacuum, and the residual was resolved in water(50 mL), extracted with DCM (20 mL) three times and washed by saturated brine (20 mL) three times. The organic solution was evaporated to dryness to obtain intermediate 8 as yellow oil.
	With sodium hydroxide In ethanol for 6h; Reflux;
	With potassium hydroxide
	With potassium carbonate In acetone for 4h; Reflux;
	With potassium carbonate In N,N-dimethyl-formamide at 280℃;	43.1 Step 1, the synthesis of compound 43-2 A DMF solution (200 mL) of 43-1 (20 g, 158.6 mmol), BnBr (32.6 g, 190.7 mmol, 22.8 mL) and potassium carbonate (43.8 g, 317.4 mmol) was added to a dry round bottom flask to dissolve,Stir at 80 °C for 2 hours, monitored by LC-MS.After the reaction, extract 3 times with water and ethyl acetate, collect the organic phase, wash twice with saturated brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure without further purification, the crude product can be directly used in the next reaction to obtain the product 43-2 (34g, crude) is a yellow oil.
91.8 %	Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 0℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 80℃;	1 Synthesis of compound 2: At room temperature, compound 1 (100 g, 793 mmol, 1 eq) was dissolved in DMF (1.5 L),Potassium carbonate (219g, 1.59mol, 2eq) was added, cooled to 0°C in an ice-water bath,Benzyl bromide (203g, 1.19mol, 1.5eq) was added dropwise, and after the addition was complete, the reaction was maintained at 0°C for 30 minutes.Then move to an oil bath at 80°C for 5 hours.TLC (EA/PE=1/2, EA is ethyl acetate, and PE is petroleum ether) detects that only a small amount of raw materials remains, and after treatment, the system is lowered to room temperature and poured into water (3L).Ethyl acetate extraction (300mlx3), combined organic phase washing (100mlx3),Wash with saturated brine (200mlx1), dry over anhydrous sodium sulfate for 20 minutes,The organic phase was filtered, concentrated and purified by column chromatography (EA/PE=1/5-1/1) to obtain 157 g of the product.Yellow oil, yield 91.8%.
91.8 %	Stage #1: Maltol With potassium carbonate In N,N-dimethyl-formamide at 0℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 80℃;	1 Synthesis of compound 2: At room temperature, compound 1 (100 g, 793 mmol, 1 eq) was dissolved in DMF (1.5 L),Potassium carbonate (219g, 1.59mol, 2eq) was added, cooled to 0°C in an ice-water bath,Benzyl bromide (203g, 1.19mol, 1.5eq) was added dropwise, and after the addition was complete, the reaction was maintained at 0°C for 30 minutes.Then move to an oil bath at 80°C for 5 hours.TLC (EA/PE=1/2, EA is ethyl acetate, and PE is petroleum ether) detects that only a small amount of raw materials remains, and after treatment, the system is lowered to room temperature and poured into water (3L).Ethyl acetate extraction (300mlx3), combined organic phase washing (100mlx3),Wash with saturated brine (200mlx1), dry over anhydrous sodium sulfate for 20 minutes,The organic phase was filtered, concentrated and purified by column chromatography (EA/PE=1/5-1/1) to obtain 157 g of the product.Yellow oil, yield 91.8%.

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2
[ 118-71-8 ]
[ 100-44-7 ]
[ 61049-69-2 ]

Yield	Reaction Conditions	Operation in experiment
99.4%	With potassium carbonate In acetonitrile for 5h; Reflux;	4.1 Example 1 Preparation of 3-benzyloxy-2-methyl-4H-pyran-4-one 10.0 g of 3-hydroxy-2-methyl-4H-pyran-4-one and 16.4 g of potassium carbonate were added to 300 ml of acetonitrile.12.0 g of benzyl chloride was added, and the mixture was heated to reflux. After 5 hours, TLC ( petroleum ether: ethyl acetate = 1:1) was obtained.The reaction solution was cooled to room temperature, suction filtered, and the filter cake was washed with 100 ml of ethyl acetate, and the filtrate was directly dried.3-benzyloxy-2-methyl-4H-pyran-4-one 17.0 g was obtained in a yield: 99.4%.
98%	With potassium carbonate In methanol for 1h; Reflux;	1.1 Example 1: (1) 100 g of compound 1, 132 g of potassium carbonate and 105 g of benzyl chloride were added to 300 mL of methanol,The reaction was completed by heating under reflux for 1 hour.The system is cooled to room temperature,Filtration, concentration of the filtrate, and the residue was dissolved in dichloromethane (200 mL).Wash with 5% sodium hydroxide solution (50 mL×2) and saturated sodium chloride solution (50 mL).The organic phase is dry, Concentrated to obtain 168 g of yellow oil, intermediate 2 Yield: 98%.
98.2%	With triethylamine In ethyl acetate Reflux;	1 Example 1: Synthesis of compound 2 At room temperature, 18.00 g of compound 1, 55 ml of ethyl acetate, 8.66 g of triethylamine, and 9.08 g of benzyl chloride were added to the reaction flask at room temperature, heated to reflux, and stirred until the reaction was completed. Add 30ml of water and extract twice and separate the liquids; combine the organic phases and concentrate to dryness to obtain compound 2: 15.12g of brown oil, yield 98.2%;

95%	With sodium hydroxide In methanol Heating / reflux;	32.A EXAMPLE 32; Preparation of 3-Hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one; A. Preparation of 3-Benzyloxy-2-methyl-1H-pyridin-4-one; To a suspension of maltol (126 g, 1.0 mol) and methanol (450 mL) in a 2 L 3-necked round bottom flask equipped with a mechanical stirrer was added a 10.0 N sodium hydroxide solution (110 mL, 1.1 mol). A clear solution resulted upon stirring. Benzyl chloride (138 mL, 1.2 mol) was then added, and the resulting solution was heated to reflux for 1.5 h. To the reaction mixture was further added a 10.0 N sodium hydroxide (20 mL, 0.2 mol) and benzyl chloride (27 mL, 0.23 mol), and the reaction mixture was heated to reflux for another 2 h. The progress of the reaction was monitored by HPLC Method 4 (Example 24), and the amount of remaining unreacted maltol was about 2%. The reaction mixture was stirred overnight. The mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo to a volume of about 300 mL, as two phases could be observed. The top layer was collected via separatory funnel, and was concentrated under reduced pressure to give 3-(benzyloxy)-2-methyl-4H-pyran-4-one as an oil (220 g, 95% yield, HPLC Method 4 (Example 24), RT=15.5 min, HPLC purity (peak percent area): 95% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 8.04 (d, J=5.5 Hz, 1H), 7.37, (m, 5H), 6.37 (d, J=5.5 Hz, 1H), 5.02 (s, 2H), 2.12 (s, 3H).
95%	With sodium hydroxide In methanol; water at 74.84℃;	3.2.1 2.3.2.1. 3-(benzyloxy)-2-methyl-4-pyrone. To a solution of 3-hydroxy-2-methyl-4H-pyran-4-one (20.07 g, 159.15 mmol) in 200 mL of MeOH, asolution of sodium hydroxide (6.98 g, 174.50 mmol) in 22 mL of waterwas added to this mixture, followed by dropwise addition of benzylchloride (22.0 mL, 191.00 mmol). The reaction mixture was heated toreflux at T=348 K for 12 h. The solvent was evaporated under reducedpressure and the remaining orange oil was dissolved in DCM (80 mL)and washed with 5% (w/v) of NaOH aqueous solution (3×30 mL) andwith water (2×30 mL). The organic phase was dried over anhydroussodium sulfate and filtered. The solvent was roto-evaporated and driedin vacuum to give a pale yellow oil product (32.93 g, η=95%). TLCswere performed in S1 mixture. 1H NMR (400 MHz, Methanol-d4), δ(ppm): 7.82 (1H, d, 6-HPy), 7.33 (5H, s, Ph), 6.35 (1H, d, 5-HPy), 5.03(2H, s, CH2Ph), 2.05 (3H, s, CH3). 13C NMR (100 MHz, Methanol-d4),δ(ppm): 175.81, 160.98, 155.05, 143.49, 136.81, 128.76, 128.19,128.18, 116.22, 73.37, 13.67; m/z (ESI-MS)=217 (M+1).
94%
94%	With sodium hydroxide In methanol; dichloromethane; water	1 Synthesis of 2-methyl-3-benzyloxy-4-pyranone (1) EXAMPLE 1 Synthesis of 2-methyl-3-benzyloxy-4-pyranone (1) 20.0 g (159 mmol) of 2-methyl-3-hydroxy-4-pyranone and 22.1 g (175 mmol, 1.1 eq.) of benzyl chloride are introduced into 200 mL of methanol; then 6.98 g (175 mmol) of NaOH in 22 mL of water are added. The reaction medium is reflux agitated for 61/2 hours. The solvent is subsequently evaporated and the residue retaken up with 100 mL of dichloromethane. This solution is then washed with a 5% aqueous solution of soda (280 mL) and with water (280 mL). The organic phases are collected, dried on sodium sulphate, filtered and evaporated under reduced pressure; 32.3 g (149 mmol) of 2-methyl-3-benzyloxy-4-pyranone are isolated. Yield: 94%. NMR 1H: δ 8.00 (d, J5,6=5.7 Hz, H-6), 7.42-7.30 (m,5H Ph), 6.37 (d, J5,6=5.7 Hz, H-5), 5.04 (s, CH2-Ph), 2.10 (s, CH3); NMR 1H in CDCl3: δ 7.55 (d, H-6), 7.40 (s, 5H, aromatic H), 6.35 (d, H-5), 5.04 (s, CH2-Ph), 2.10 (s, CH3); NMR 13C: δ 173.9 (C-4), 159.1 (C-3), 154.8 (C-6), 143.1 (C-2), 136.6 (CIpso), 128.5 (2Cortho), 128.2 (2Cmeta), 128.0 (Cpara), 116.4 (C-5), 72.6 (CH2-Ph), 14.3 (CH3).
94%	With sodium hydroxide In methanol; water for 6h; Heating / reflux;	X.a; XIV; XVI.a The iron chelators of the invention include, but are not limited to: 2-Alkyl-N-(2'-hydroxyethoxy)methyl-3-hydroxyl-4-pyridinone chelators, which were synthesized using established methods.82 Briefly, 3-benzyloxyl-2-alkyl-4-pyridinone was synthesized as described by Dobbin et al.83 with a minor modification. First, 2-alkyl-3-hydroxyl-4-pyranone and benzylchloride were refluxed in alkaline condition to protect the 3-hydroxyl group. Then, the substitution reaction of 3-benzyloxyl-2-alkyl-4-pyranone with aqueous ammonia reacted for 48 h. 3-benzyloxyl-2-alkyl-4-pyridinone were silylated in hexamethyldisilazane under refluxing for 2 h and then alkylated using trimethylsilyl trifluoromethanesulfonate as a catalyst with benzyloxyethoxymethylchloride which could be replaced by (2-acetoxyethoxy)methyl bromide. SnCl4 could also be used as catalyst in the alkylation reaction, but resulted in separation difficulties and low yields. Both of the protection groups were removed simultaneously by hydrogenation under H2/catalyst in aqueous ethanol or by BBr3 in CH2Cl2 at 4° C. The new chelators were obtained in pure form after crystallization from a 1:1 solution of CH3Cl/MeOH. Scheme 1. R=Me (1a), Et (1b). a: benzylchloride/NaOH, then NH4OH. b: hexamethyldisilazane, chlorotrimethylsilane. c: benzyloxyethoxymethylchloride, trimethylsilyl trifluoromethanesulfonate in 1,2-dichloroethane. d: H2, Pd/C, in aqueous EtOH (or with BBr3 in CH2Cl2 at 4° C.). Characterizations have been done using proton-NMR, MS, UV-visible spectroscopy and elemental analysis. The molecular structure of chelator 1b was also confirmed by X-ray crystallography and the molecular structure is shown; (2) The chelators of 2-alkyl-N-(2'-aminoethyl or 3'-amniopropyl)-3-hydroxyl-4-pyridinone were synthesized using the procedure as following (Scheme 2). Scheme 2. R=Me, Et. a: benzylchloride/NaOH. b: NH2(CH2)2NH2 and NH2(CH2)3NH2/NaOH. c: H2, Pd/C (or BBr3 in CH2Cl2 at 4° C.). In brief, 3-benzyloxy-2-methyl-4-pyrone was synthesized with benzylchloride in water and methanol (1:8 V/V) in the presence of NaOH and refluxed for 6 h. The product was then extracted 3 times with methylene chloride. It was reacted with 1,2-diaminoethane or 1,3-diamniopropane in 40% EtOH aqueous solution. After one week, the benzyl protective group was removed by BBr3 in CH2Cl2 at 4° C. The final products were purified by crystallization using methanol and ether. The 1H-NMR chemical shift assignments in DMSO-d6 are given as following. For n=2: 8.202 (1H, d, H-6), 7.153 (1H, d, H-5), 4.584 (2H, t, 1'-position ethylenic CH2), 3.295 (2H, m, 2'-position ethylenic CH2), 2.546 (3H, s, 2-position CH3). For n=3: 8.214 (1H, d, H-6), 7.104 (1H, d, H-5), 4.407 (2H, t, 1'-position propylenic CH2), 2.866 (2H, m, 3'-position propylenic CH2), 2.516 (3H, s, 2-position CH3), 2.021 (2H, m, 2'-position propylenic CH3).; The chelator 2-methyl-N-(3'-aminopropyl)-3-hydroxyl-4-pyridinone (MAHP) was synthesized using a modification of a procedure known in the art. In brief, 3-hydroxyl-2-methyl-4-pyranone (44.4 g, 0.352 mol) and benzyl chloride (51 g, 0.403 mol) were mixed in a solution of water (50 ml) and methanol (400 ml) in the presence of NaOH (15 g). The mixture was refluxed for 6 h with magnetic stirring. After removing methanol under vacuum, 70 ml of water were added and 3-benzyloxy-2-methyl-4-pyranone was extracted 3 times with 60 ml portions of methylene chloride. The combined methylene chloride was washed with 5% NaOH aqueous solution (50 ml), followed by water (50 ml) and dried over MgSO4. The product was obtained after evaporation of the solvent under vacuum (94% yield). The product (4.41 g, 0.019 mol) was then reacted with 1,3-diaminopropane (1.15 g, 0.019 mol) in aqueous ethanol solution (30 ml water and 20 ml ethanol) at room temperature. After one week, solvents and residual diamine were evaporated under vacuum and the residue was dissolved in chloroform, washed 3 times with water and dried using Na2SO4. After removing the chloroform, methanol was added and the pH adjusted to 1 with HCl. The 1-(3'-aminopropyl)-3-benzyloxy-2-methyl-4-pyridinone was precipitated as dihydrochloride salt and collected by filtration. The pure product was obtained by crystallization from methanol and ether (yield: 80%) and the product (2 g, 0.0058 mol) further reacted with BBr3 (30 ml, 1.0 M solution of CH2Cl2) in 120 ml of CH2Cl2. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. Then, 160 ml of water was added and stirring was continued for an additional 4 h. The aqueous phase containing the MAHP was separated and evaporated under vacuum. The crude MAHP was purified through crystallization twice using ethanol and ether (96% yield). Pure MAHP was identified by 1H-NMR and elemental analysis. 1H-NMR (DMSO-d6): 8.214 (1H, d, H-6), 7.104 (1H, d, H-5), 4.407 (2H, t, 1'-position propylenic CH2), 2.866 (2H, m, 3'-position propylenic CH2), 2.516 (3H, s, 2-position CH3), 2.021 (2H, m, 2'-position propylenic CH3). Elemental analysis: Calcd. For C9H14N2O2 2HBr C, 31.42; H, 4.69; N, 8.14. Found: 31.52; H, 4.79; N, 7.75, m.p.: 242° C.; Synthesis of iron chelator-nanoparticle systems: The general synthesis of the chelator 1 is described in scheme 3.86 Scheme 3. R=Me, Et. a: benzylchloride/NaOH/. b: NH4OH. C: hexamethyldisilazane/chlorotrimethylsilane/(2-acetoxyethoxy)methyl bromide, trimethylsilyl trifluoromethanesulfonate in 1,2-dichloroethane. c: basic hydrolysis with NH4OH. d: tosyl chloride in pyridine. e: nanoparticles with amino functional groups. f: BBr3/CH2Cl2 at 4° C. for 30 min. Instead of benzyloxyethoxymethylchloride, 2-acetoxyethoxy)methyl bromide is used and the synthetic method is the same as described herein. The acetyl protection group on the side chain is removed by basic hydrolysis in methanolic ammonia solution. The mixture is stirred at room temperature in a sealed flask for 24 h. After purification by silica gel chromatography using CHCl3-MeOH (8:1) as an eluent, the deprotected hydroxyl group is converted into P-toluene-sulphonyl (tosyl) ester by the reaction with tosyl chloride (1.1 moles per mole of chelator) in dry pyridine. After removal of the solvent, the crude ester is often used directly. Before conjugation, 1 mL (100 mg/mL) of amino-modified nanoparticles are washed in 10 mL of 0.1 M sodium phosphate buffer (pH 7.4). After second wash, resuspend pellet in 10 mL of tosyl activeted chelator solution, ensuring that the particles are completely suspended by vortexing. Allow to react at 37° C. for 24 hours with continuous mixing. Separate the particles conjugated with chelators by centrifugation and wash with phosphate buffered saline (pH 7.4) four times. Then, deprotect OH on pyridinone ring by BBr3 in CH2Cl2 at 4° C. with shaking for 30 min. The new chelator-particle system is obtained by centrifugation and wash four times with PBS buffer. Resuspend in 10 mL 25 mM Tris buffer (pH 7.4) and store at 4° C. until used. As mentioned above, if the nanoparticles could be damaged during the deprotective step, we will use an altered method to conjugate the chelator. The toluene sulfonic group (Tosyl-O-group) may be changed into an amino group by nucleophilic displacement reaction. To obtain primary amines in reasonable yield, sufficient excess ammonia is used. After that, first, deprotection of the OH group on the pyridinone ring by using the same deprotective method as above, then conjugate the chelator to Sulfo-NHS(N-hydroxysulfosuccinimide) preactivited carboxylic acid functinal nanoparticles just like chelators 2, 3, and DFO do. The chelator concentrations of the reaction solution before and after conjugation are determined by using UV-visible spectroscopy or HPLC, thereby the amount of the chelator conjugated to nanoparticles can be obtained by simply multiplying the difference of the concentrations with the reaction volume.
92%	With sodium hydroxide In methanol; water for 6h; Heating;
92%	With sodium hydroxide In methanol; water	10 3-Benzyloxy-2-methyl-4-pyrone 3-Benzyloxy-2-methyl-4-pyrone 3-Hydroxy-2-methyl-4-pyrone (22.2 g) in methanol (225 ml) is added to aqueous sodium hydroxide (25 ml H2 O containing 7.5 g NaOH). Benzyl chloride (25.5 g) is added and the mixture is refluxed for 6 hours and is then allowed to cool overnight. The bulk of the methanol is removed under vacuum and the residue is treated with water (50 ml). The mixture is extracted into dichloromethane (325 ml). The extracts are combined, washed with 5% w/v NaOH (225 ml), then water (2*25 ml) and dried over magnesium sulphate. Evaporation of the solvent gives crude 3-benzyloxy-2-methyl-4-pyrone (35 g, 92%) which is purified by distillation in nitrogen under reduced pressure to yield a colourless oil (28 g) of b.p. 148° C./0.2 mm.
91%	With sodium hydroxide In methanol for 8h; Heating;
91%	With sodium hydroxide In methanol; water for 8h; Heating;
88%	With sodium hydroxide In methanol; water for 18h; Reflux;
88%	With sodium hydroxide In ethanol; water at 60℃; for 6h;	1.2 Raw material 2: Preparation of 2-methyl-3-(benzyloxy)-4H-pyran-4-one: Dissolve 2-methyl-3-hydroxy-4H-pyran-4-one (1g, 8.0mmol) in 8ml of 95% ethanol, weigh out sodium hydroxide (352mg, 8.8mmol) and dissolve in 5ml of distilled water After the system was added, benzyl chloride (831ul, 7.2mmol) was added to the mixed system after the system was dissolved, and reacted at 60 degrees for about 6 hours. After the reaction was completed, the ethanol was spun off under reduced pressure, and the aqueous phase was extracted with dichloromethane (3 ×), the organic layers were combined, the organic layer was washed with water (3×), saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 2 (1.52 g, yield 88%).
87%	With sodium hydroxide In methanol; water for 12h; Reflux;
87%	With sodium hydroxide In methanol; water at 85℃; for 2h;
87%	With sodium hydroxide In methanol Reflux;	6.1; 6.2; 6.3 (1) adding methyl maltol to methanol and stirring to dissolve;(2) adding a 7M sodium hydroxide solution to the mixture obtained in the step (1), followed by dropwise addition of a benzyl group, heating, refluxing overnight, molar ratio of methyl maltol to sodium hydroxide solution is 1:0.8, methyl maltol andThe molar mass ratio of the benzyl compound is 1:0.8;(3) The reaction liquid obtained in the step (2) is evaporated to remove the solvent, and the obtained oil is dissolved in dichloromethane.Wash with 5% solution of NaOH and distilled water, then dry the organic phase with anhydrous Na2SO4 overnight.Filtration, rotary evaporation, vacuum drying for 24 h to give compound B; yield 87%;
86%	With sodium hydroxide In methanol Reflux;
85.6%	With sodium hydroxide In methanol; water for 6h; Heating;
85.6%	With sodium hydroxide In methanol; water for 6h; Heating;
85.8%	With sodium hydroxide In methanol for 8h; Reflux;
85%	With sodium hydroxide In ethanol at 60℃; for 6h; Reflux;
84%	With sodium hydroxide In methanol
84%	With sodium hydroxide In ethanol; water at 60℃;	1.1 Step 1: Preparation of 2-methyl-3-benzyloxy-4H-pyran-4-one: Dissolve 100g commercially available benzyl maltol in 80mL 95% ethanol,Then add 83mL benzyl chloride and 115mL 30% sodium hydroxide aqueous solution,Let it react at 60 degrees Celsius for 6-18 hours,After the TLC tracking reaction is completed,45°C under reduced pressure distillation to remove ethanol,Add 300mL dichloromethane to extract,The dichloromethane layer obtained by liquid separation was washed with 30 mL of 4% sodium hydroxide solution,Add 30mL saturated brine to wash,The crude product obtained by evaporation under reduced pressure at 45°C is recrystallized by adding 60 mL ethyl acetate and 120 mL petroleum ether.Thus, 145.3 g of Compound 2 (yield 84%) can be obtained.Light yellow solid,
83%	With sodium hydroxide In methanol; water for 6h; Heating;
83%	With sodium hydroxide In methanol for 12h; Heating;
83%	With sodium hydroxide In ethanol; water at 60℃;	4 3-Hydroxy-2-methyl-4H-pyran-4-one (accession 4-b) 3-Hydroxy-2-methyl-4H-pyrone 100g (800mmol) was added to the reaction flask, 80mL of 95% ethanol was added to form a white cloudy liquid, 35.2g (880mmol) of sodium hydroxide was dissolved in 80mL of water and slowly added dropwise The system was heated to 60 degrees after the addition, and 82.5 mL (720 mmol) of benzyl chloride was added dropwise, the reaction was stirred at 60 degrees, and the reaction was detected by TLC (volume ratio of petroleum ether/ethyl acetate=1:1). After the reaction, the reaction solution was rotated by a rotary evaporator until there was no distillate, dissolved in 120 mL of water, extracted three times with 3×150 mL of dichloromethane, and the organic layers were combined, and the organic layer was washed three times with 3×100 mL of 5% sodium hydroxide solution. Methyl maltol raw material remained, the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation until there was no distillate, cooled and solidified, crushed and air-dried to obtain the product 3-(benzyloxy)-2-methyl 143.3 g of base-4H-pyrone, yield 83%
83%	Stage #1: Maltol With sodium hydroxide In ethanol; water at 60℃; Stage #2: benzyl chloride In ethanol; water at 60℃;	4 3-Hydroxy-2-methyl-4H-pyran-4-one (accession 4-b) 3-Hydroxy-2-methyl-4H-pyrone 100g (800mmol) was added to the reaction flask, 80mL of 95% ethanol was added to form a white cloudy liquid, 35.2g (880mmol) of sodium hydroxide was dissolved in 80mL of water and slowly added dropwise The system was heated to 60 degrees after the addition, and 82.5 mL (720 mmol) of benzyl chloride was added dropwise, the reaction was stirred at 60 degrees, and the reaction was detected by TLC (volume ratio of petroleum ether/ethyl acetate=1:1). After the reaction, the reaction solution was rotated by a rotary evaporator until there was no distillate, dissolved in 120 mL of water, extracted three times with 3×150 mL of dichloromethane, and the organic layers were combined, and the organic layer was washed three times with 3×100 mL of 5% sodium hydroxide solution. Methyl maltol raw material remained, the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporation until there was no distillate, cooled and solidified, crushed and air-dried to obtain the product 3-(benzyloxy)-2-methyl 143.3 g of base-4H-pyrone, yield 83%
82%	Stage #1: Maltol With sodium hydroxide In methanol; water Reflux; Stage #2: benzyl chloride In methanol; water for 18h; Reflux;
82%	With sodium hydroxide In methanol; water for 8.5h; Reflux;
82%	Stage #1: Maltol With sodium hydroxide In methanol; water Stage #2: benzyl chloride In methanol; water for 12.5h; Heating;
81%	With sodium hydroxide In methanol Heating;
81%	Stage #1: Maltol With sodium hydroxide In methanol Reflux; Stage #2: benzyl chloride for 0.5h; Reflux;
81%	With sodium hydroxide In methanol; water Reflux;	1 2-Methyl-3-benzyloxypyran-4(1H)-one (2) 2-Methyl-3-benzyloxypyran-4(1H)-one (2) To a solution of methyl maltol 1 (63 g, 0.5 mol) in methanol (500 mL) was added sodium hydroxide (22 g, 0.55 mol) dissolved in water (50 mL), and the mixture was heated to reflux. Benzyl chloride (70 g, 0.55 mol) was added dropwise over 30 mins, and the resulting mixture was refluxed overnight. After removal of solvent by rotary evaporation, the residue was mixed with water (200 mL) and extracted with dichloromethane (3150 mL). The combined extracts were washed with 5% aqueous sodium hydroxide (2200 mL) followed by water (200 mL). The organic fraction was then dried over anhydrous sodium sulphate, filtered and rotary evaporated to yield an orange oil which solidified on cooling. Recrystallization from diethyl ether gave the pure product 2 as colourless needles (87.5 g, 81%); mp 51-52° C. 1H-NMR (CDCl3) δ: 2.12 (s, 3H), 5.11 (s, 2H), 6.25 (d, J=6 Hz, 1H), 7.28 (s, 5H), 7.47 (d, J=6 Hz, 1H).
79%	With sodium hydroxide In methanol; water Heating;
79%	With sodium hydroxide In water for 40h; Reflux;
78%	With sodium hydroxide In ethanol; water at 60℃; for 3.5h;	1 Example 1. 3-benzyloxy-2-methyl-4H-pyran-4-one Example 1. 3-benzyloxy-2-methyl-4H-pyran-4-one [0037] [0038] 122.3 g NaOH was dissolved into 278 mL water, then mixed into solution of 390 g maltol and 1160 mL ethanol, and 422 g benzyl chloride was then added under stirring. Keep stirring at 60 °C for 3.5 h after fully mixing. After cooling the reaction system, filter it to remove solid impurities, wash the residues with ethanol, which was then mixed with filtrate and spin-dried. The remaining substances were dissolved by methylene chloride (DCM), then washed with 5% NaOH, finally washed with suitable amount of water. The organic layer was dried by anhydrous Na2SO4, then spin-dried the solvent the yellow oily liquid was obtained. After cooling and recrystallization in ether to get crystals, the yield is 78%, melting point is 56∼57°C.
76.8%	With sodium hydroxide In methanol; water	1.1 (1) (1) 3-Benzyloxy-2-methyl-4-pyrone A solution of sodium hydroxide (126 g, 1.1 mol) in 1000 ml of methanol in water (9:1 v/v) was added to 3-hydroxy-2-methyl-4-pyrone (126.12 g, 1 mol). Benzyl chloride (126.59 ml, 1.1 mol) was then added slowly and the mixture was refluxed for 10 hours with rapid stirring. The resultant solution was cooled, the methanol removed by rotary evaporation and the aqueous solution was extracted with dichloromethane (3*250 ml). The combined dichloromethane extracts were washed with 5% sodium hydroxide and then with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The resultant solid was recrystallized from diethylether to yield the title compound in 76.8% yield as colourless needles, m.p. 53°-55° C.
69%	With sodium hydroxide In methanol at 92℃; for 22h;
	With sodium hydroxide In methanol; water	1 Preparation of 1,8-di-(3-hydroxy-2-methyl-4-oxopyrid-1-yl)octane and other related compounds EXAMPLE 1 Preparation of 1,8-di-(3-hydroxy-2-methyl-4-oxopyrid-1-yl)octane and other related compounds 3-Hydroxy-2-methyl-4-pyrone (22.2 g) in methanol (225 ml) is added to aqueous sodium hydroxide (25 ml H2 O containing 7.5 g NaOH). Benzyl chloride (25.5 g) is added and the mixture is refluxed for 6 hours and is then allowed to cool overnight. The bulk of the methanol is removed under vacuum and the residue is treated with water (50 ml). The mixture is extracted into dichloromethane (325 ml). The extracts are combined, washed with 5% w/v NaOH (225 ml), then water (2*25 ml) and dried over magnesium sulphate. Evaporation of the solvent gives crude 3-benzyloxy-2-methyl-4-pyrone or "benzyl maltol" (35 g, 92%) which is purified by distillation in nitrogen under reduced pressure to yield a colourless oil (28 g) of b.p. 148° C./0.2 mm.
	In ethanol; water
	With sodium hydroxide In methanol at 65℃; for 16h;
	With potassium hydroxide
	With sodium hydroxide In methanol Reflux;
	With sodium hydroxide In methanol; water for 6h; Reflux;	1 To a one liter flask were added: 0.35 mole 3-hydroxy-2-methyl-4-pyrone, 450 ml methanol, 0.4 mole benzyl chloride and a solution of 0.37 mole sodium hydroxide in 50 ml water. The mixture was refluxed for six hours and then stirred at room temperature overnight. The methanol was then evaporated using vacuum and the residue was mixed with 200 ml water and then extracted using three separate 100 ml aliquots of methylene chloride. The three methylene chloride extracts were pooled and washed with three changes of 50 ml 5% NaOH and then three changes of 50 ml water. The extract was then dried over solid MgSO4. Following filtration to remove the MgSO4 and evaporation of the solvent, 76.6 gram of crude 3-benzyloxy-2-methyl-4-pyrone was recovered. This material was then mixed in a one-liter flask with 500 ml ethanol, 1.65 mole ethylenediamine and 2 ml water and stirred overnight at room temperature. The solvent and excess ethylenediamine were removed under reduced pressure to yield a yellow-brown oily liquid that was triturated with 400 ml water to yield 65.5 g yellow 1-(2-aminoethyl)-3-benzyloxy-2-methyl-4-(1H)-pyridinone. This product was dissolved in 500 ml 6 M HCl and the solution was stirred at room temperature overnight. A pale yellow product solid was recovered after evaporation to dryness in vacuum. This was re-dissolved in 500 ml 6 M HCl and stirred at room temperature for four days and evaporated to dryness again. The solid residue was washed with approximately 50 ml acetone to obtain the crude product. Because this was difficult to filter, 150 ml 4 M HCl and 70 ml ethanol were added and the mixture was refluxed until the solids had dissolved. The product was then re-crystallized by storage in a refrigerator, washed with acetone dried and weighed. The final AHMP product was yellow.
	In methanol; water Reflux; Alkaline conditions;
	With sodium hydroxide In methanol; water for 20h; Reflux;
	With potassium carbonate In acetonitrile at 70℃; for 15h; Large scale;	1.1; 2.1; 3.1; 4.1; 5.1 (1) Synthesis of 3-o-benzyl maltol: 100kg of maltol and 105.4kg of benzyl chloride were dissolved in 600kg of acetonitrile, To the reaction system, 165kg of solid potassium carbonate was added, and the system was heated to 70°C for 15h. After the reaction of the raw materials is completed, the temperature is lowered and suction filtered, After concentrating to dryness under reduced pressure, 3-o-benzyl maltol was obtained, which was directly used in the next step without purification;
79 %	With sodium hydroxide In ethanol; water at 60℃;	1.1; 2.1; 3.1 Step 1: Preparation of Benzyl Maltol (III) Maltol (II, 50.4g, 0.40mol) was dissolved in a mixed solvent of 80mL ethanol and 80mL water, and sodium hydroxide (17.6g, 0.44mol) and benzyl chloride (46.8g, 0.37mol) were added successively under stirring, React at 60°C overnight (ie, about 12 hours). After TLC detected that the benzyl chloride reaction was complete, the ethanol was removed by rotary evaporation, and the remaining mixed solution was extracted twice with 80 mL of dichloromethane. It was dried over sodium sulfate and concentrated by rotary evaporation to obtain the crude product, which was recrystallized from PE and EA (1:1, v/v) to obtain brown solid III (62 g, 79%).
81 %	Stage #1: Maltol With sodium hydroxide In methanol; water Reflux; Stage #2: benzyl chloride In methanol; water Reflux;	4.1.2. Synthesis of 3-(Benzyloxy)-2-methyl-4H-pyran-4-one (2) Maltol 1 (25.22 g, 0.2 mol) was dissolved in methanol (250 mL) and sodium hydroxide (8.8 g, 0.22 mol) dissolved in water (50 mL) was added to it. The solution was heated to reflux, and benzyl chloride (25.3 g, 0.22 mol) was then added dropwise over 15 min. The reaction mixture was refluxed overnight. The orange oil obtained after the evaporation of the solvent was mixed with 100 mL CH2Cl2 and washed with 5% aqueous sodium hydroxide (3×70 mL) followed by water (3×70 mL). The organic fraction was then dried over magnesium sulfate, filtered, and concentrated. The residue was solidified by diethyl ether and crushing with a glass rod. The obtained precipitate was washed with Et2O to give 2 as pure white solid. Yield: 81%; mp: 50.5-52.0 °C (lit. mp 51.0-52.0 °C); IR (KBr, cm-1): 1643 (C=O)

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[17]Current Patent Assignee: ATOM HIGH TECH - CN107266359, 2017, A Location in patent: Paragraph 0095; 0112-0114; 0137-0139; 0178; 0198
[18]Zhu, Chun-Feng; Battah, Sinan; Kong, Xiaole; Reeder, Brandon J.; Hider, Robert C.; Zhou, Tao [Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 558 - 561]
[19]Liu, Zu D.; Liu, Ding Y.; Lu, Shu L.; Hider, Robert C. [Arzneimittel-Forschung/Drug Research, 2000, vol. 50, # 5, p. 461 - 470]
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[21]Xie, Yuan-Yuan; Liu, Mu-Song; Hu, Pan-Pan; Kong, Xiao-Le; Qiu, Di-Hong; Xu, Ji-Lin; Hider, Robert C.; Zhou, Tao [Medicinal Chemistry Research, 2013, vol. 22, # 5, p. 2351 - 2359]
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[24]Current Patent Assignee: ZHEJIANG UNIVERSITY; HANGZHOU ZEDE PHARMACY TECH - CN112062763, 2020, A Location in patent: Paragraph 0062-0065
[25]Dobbin; Hider; Hall; Taylor; Sarpong; Porter; Xiao; Van der Helm [Journal of Medicinal Chemistry, 1993, vol. 36, # 17, p. 2448 - 2458]
[26]Rai, Bijaya L.; Dekhordi, Lotfollah S.; Khodr, Hicham; Jin, Yi; Liu, Zudong; Hider, Robert C. [Journal of Medicinal Chemistry, 1998, vol. 41, # 18, p. 3347 - 3359]
[27]Current Patent Assignee: ZHEJIANG UNIVERSITY - CN114716366, 2022, A Location in patent: Paragraph 0021-0023
[28]Current Patent Assignee: ZHEJIANG UNIVERSITY - CN114716366, 2022, A Location in patent: Paragraph 0021-0023
[29]Mukherjee, Riya; Donnay, Edward G.; Radomski, Michal A.; Miller, Catherine; Redfern, Duane A.; Gericke, Arne; Damron, Derek S.; Brasch, Nicola E. [Chemical Communications, 2008, # 32, p. 3783 - 3785]
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[32]Ma, Yongmin; Luo, Wei; Quinn, Peter J.; Liu, Zudong; Hider, Robert C. [Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6349 - 6362]
[33]Chen, Yu-Lin; Barlow, Dave J.; Kong, Xiao-Le; Ma, Yong-Min; Hider, Robert C. [Dalton Transactions, 2012, vol. 41, # 35, p. 10784 - 10791]
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[37]Current Patent Assignee: ZHEJIANG UNIVERSITY - EP2692724, 2014, A1 Location in patent: Paragraph 0037; 0038
[38]Current Patent Assignee: BOSTON SCIENTIFIC CORP - US5480894, 1996, A
[39]Andayi, Warren A.; Egan, Timothy J.; Gut, Jiri; Rosenthal, Philip J.; Chibale, Kelly [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 7, p. 642 - 646]
[40]Current Patent Assignee: BOSTON SCIENTIFIC CORP - US4666927, 1987, A
[41]Location in patent: body text Fassihi, Afshin; Abedi, Daryoush; Saghaie, Lotfollah; Sabet, Razieh; Fazeli, Hossein; Bostaki, Ghasem; Deilami, Omid; Sadinpour, Hekmatollah [European Journal of Medicinal Chemistry, 2009, vol. 44, # 5, p. 2145 - 2157]
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[43]Location in patent: scheme or table Yamaguchi, Tomoko; Watanabe, Shinya; Matsumura, Yuriko; Tokuoka, Yoshikazu; Yokoyama, Akihiro [Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 4, p. 508 - 512]
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3
[ 61049-69-2 ]
[ 61160-18-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With ammonia; In ethanol;Heating / reflux;	To a solution of 2 (13.8g, 0.064mol) in ethanol (25mL) was added ammonia solution (5OmL) and refluxed overnight. The solvent was removed under reduced pressure, then taken into water and adjusted to pH 1 with concentrated hydrochloric acid. The aqueous mixture was washed with ethyl acetate (3x) and the pH was adjusted to pH 10 with sodium hydroxide (2M.). The aqueous phase was extracted with chloroform (3?), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from methanol/diethyl ether gave brown cubic crystals, mp 162-164C. Yield 75%. 1H NMR (CDCl3) ? 2.15 (3H, s, CH3), 5.03 (2H, s, CH2Ph), 6.35 (1?, d, J=6.9?z, 5-H), 7.25-7.31 (5?, m, CH2PA), 7.39 (IH, d, J=6.9Hz, 6-/2). C13H13NO2.
75%	With ammonia; In ethanol;Reflux;	To a solution of 2 (13.8 g, 0.064 mol) in ethanol (25 mL) was added ammonia solution (50 mL) and refluxed overnight. The solvent was removed under reduced pressure, then taken into water and adjusted to pH 1 with concentrated hydrochloric acid. The aqueous mixture was washed with ethyl acetate (3×) and the pH was adjusted to pH 10 with sodium hydroxide (2 M.). The aqueous phase was extracted with chloroform (3×), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. Re-crystallisation from methanol/diethyl ether gave brown cubic crystals, mp 162-164 C. Yield 75%. 1H NMR (CDCl3) delta 2.15 (3H, s, CH3), 5.03 (2H, s, CH2Ph), 6.35 (1H, d, J = 6.9 Hz, 5-H), 7.25-7.31 (5H, m, CH2Ph), 7.39 (1H, d, J = 6.9 Hz, 6-H); m/z (ESI): 201.1.
75%	With ammonium hydroxide; In ethanol; at 75℃; for 12h;	The pyrrolone (8.65 g, 40 mmol) obtained in the above reaction, 60 mL of 25% ammonia water, 50 mL of ethanol was added to a 250 mL single-mouth bottle, and heated under reflux at 75 C for 12 h.After the reaction was completed, it was cooled to room temperature, and the solvent was evaporated to give a brown oily liquid.Recrystallization from acetone/ethyl acetate gave a pale yellow solid of 2-methyl-3-benzyloxypyridone. The yield was 75%.

64%	With ammonia; In ethanol; water; at 20℃;Heating / reflux;	A clear solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (150 g, 0.69 mol), ethanol (300 mL) and ammonium hydroxide (28.0-30.0% solution, 690 mL, 10.5 mol) in a 2 L 3-necked round bottom flask equipped with a mechanical stirrer was heated to reflux for 5 h. The reaction mixture was allowed to cool to room temperature, and a further 230 mL of ammonium hydroxide (3.5 mol) was added. The resulting solution was heated to reflux for another 3.5 h, then allowed to cool to RT and stirred for overnight. A solid product had separated, and was collected by suction filtration. Thus, 95 g of 3-benzyloxy-2-methyl-1H-pyridin-4-one (64% yield) was obtained as a first crop. HPLC Method 4 (Example 24), RT=10.7 min, HPLC purity (peak percent area): 99% at lambda=280 nm)). 1H NMR (DMSO-d6) delta ppm: 11.3 (br s, 1H), 7.46 (s, 1H), 7.35, (m, 5H), 6.13 (s, 1H), 5.04 (s, 2H), 2.05 (s, 3H); 1H NMR (DMSO-d6+D2O) delta ppm: 7.47 (d, J=7.0 Hz, 1H), 7.39, (m, 5H), 6.20 (d, J=7.0 Hz, 1H), 5.01 (s, 2H), 2.03 (s, 3H).
43%	With sodium hydroxide; ammonia; In ethanol; water; at 90℃; for 1h;	2) The compound 2 (162, 2g, 750mmol) was dissolved in ethanol (-187ml), and aqueous ammonia (28%, 974ml) and a 6N aqueous sodium hydroxide solution (150ml, O00mmol) were added. After the reaction solution was stirred at 90 C for 1 hour, this was cooled to under ice-cooling, and ammonium chloride (58g, 10S0mmol) was added, To the reaction solution was added chloroform, this was extracted, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl alcohol and diethyl ether were added to the residue, and precipitated crystals were filtered to obtain 3-benzyloxy-2-methyl- 1H-pyridine-4-one 3 (69.1g, 43%) as a pale yellow crystal.NMR (DMSO-dfi)delta: 2.05(3H, s), 5.04(2H, a), 6 14(1H, d, J=7 0Hz), 7,31-7.42(5H, m), 7 46(1H, d, J=7.2Hz), 11.29(1H, brs).
	With ammonia; In C2 H5 OH;	EXAMPLE 2 2-Methyl-3-(phenylmethoxy)-4(1H)-pyridone 62 g of product of Example 1 were dissolved in 300 ml C2 H5 OH containing 18 g NH3. The solution was kept at 110 C. for 16 hours in a glass autoclave. After cooling, the C2 H5 OH was distilled off and the crystalline residue filtered off and washed with 50 ml C2 H5 OH at 0 C.; 49.7g beige crystals were recovered M.P. =162 C.
	With ammonia; In C2H5OH;	Example 2 2-Methyl-3-(phenylmethoxy)-4(1H)-pyridone 62g of the product of Example 1 were dissolved in 300ml C2H5OH containing 18g NH3. The solution was kept at 110C for 16 hours in a glass autoclave. After cooling, the C2H5OH was distilled off and the crystalline residue filtered off and washed with 50ml C2H5OH at 0C; 49.7g beige crystals were recovered M.P. = 162C.
	With ammonia; In water; for 48h;Product distribution / selectivity;	The iron chelators of the invention include, but are not limited to: 2-Alkyl-N-(2'-hydroxyethoxy)methyl-3-hydroxyl-4-pyridinone chelators, which were synthesized using established methods.82 Briefly, 3-benzyloxyl-2-alkyl-4-pyridinone was synthesized as described by Dobbin et al.83 with a minor modification. First, 2-alkyl-3-hydroxyl-4-pyranone and benzylchloride were refluxed in alkaline condition to protect the 3-hydroxyl group. Then, the substitution reaction of 3-benzyloxyl-2-alkyl-4-pyranone with aqueous ammonia reacted for 48 h. 3-benzyloxyl-2-alkyl-4-pyridinone were silylated in hexamethyldisilazane under refluxing for 2 h and then alkylated using trimethylsilyl trifluoromethanesulfonate as a catalyst with benzyloxyethoxymethylchloride which could be replaced by (2-acetoxyethoxy)methyl bromide. SnCl4 could also be used as catalyst in the alkylation reaction, but resulted in separation difficulties and low yields. Both of the protection groups were removed simultaneously by hydrogenation under H2/catalyst in aqueous ethanol or by BBr3 in CH2Cl2 at 4 C. The new chelators were obtained in pure form after crystallization from a 1:1 solution of CH3Cl/MeOH. Scheme 1. R=Me (1a), Et (1b). a: benzylchloride/NaOH, then NH4OH. b: hexamethyldisilazane, chlorotrimethylsilane. c: benzyloxyethoxymethylchloride, trimethylsilyl trifluoromethanesulfonate in 1,2-dichloroethane. d: H2, Pd/C, in aqueous EtOH (or with BBr3 in CH2Cl2 at 4 C.). Characterizations have been done using proton-NMR, MS, UV-visible spectroscopy and elemental analysis. The molecular structure of chelator 1b was also confirmed by X-ray crystallography and the molecular structure is shown; Synthesis of iron chelator-nanoparticle systems: The general synthesis of the chelator 1 is described in scheme 3.86 Scheme 3. R=Me, Et. a: benzylchloride/NaOH/. b: NH4OH. C: hexamethyldisilazane/chlorotrimethylsilane/(2-acetoxyethoxy)methyl bromide, trimethylsilyl trifluoromethanesulfonate in 1,2-dichloroethane. c: basic hydrolysis with NH4OH. d: tosyl chloride in pyridine. e: nanoparticles with amino functional groups. f: BBr3/CH2Cl2 at 4 C. for 30 min. Instead of benzyloxyethoxymethylchloride, 2-acetoxyethoxy)methyl bromide is used and the synthetic method is the same as described herein. The acetyl protection group on the side chain is removed by basic hydrolysis in methanolic ammonia solution. The mixture is stirred at room temperature in a sealed flask for 24 h. After purification by silica gel chromatography using CHCl3-MeOH (8:1) as an eluent, the deprotected hydroxyl group is converted into P-toluene-sulphonyl (tosyl) ester by the reaction with tosyl chloride (1.1 moles per mole of chelator) in dry pyridine. After removal of the solvent, the crude ester is often used directly. Before conjugation, 1 mL (100 mg/mL) of amino-modified nanoparticles are washed in 10 mL of 0.1 M sodium phosphate buffer (pH 7.4). After second wash, resuspend pellet in 10 mL of tosyl activeted chelator solution, ensuring that the particles are completely suspended by vortexing. Allow to react at 37 C. for 24 hours with continuous mixing. Separate the particles conjugated with chelators by centrifugation and wash with phosphate buffered saline (pH 7.4) four times. Then, deprotect OH on pyridinone ring by BBr3 in CH2Cl2 at 4 C. with shaking for 30 min. The new chelator-particle system is obtained by centrifugation and wash four times with PBS buffer. Resuspend in 10 mL 25 mM Tris buffer (pH 7.4) and store at 4 C. until used. As mentioned above, if the nanoparticles could be damaged during the deprotective step, we will use an altered method to conjugate the chelator. The toluene sulfonic group (Tosyl-O-group) may be changed into an amino group by nucleophilic displacement reaction. To obtain primary amines in reasonable yield, sufficient excess ammonia is used. After that, first, deprotection of the OH group on the pyridinone ring by using the same deprotective method as above, then conjugate the chelator to Sulfo-NHS(N-hydroxysulfosuccinimide) preactivited carboxylic acid functinal nanoparticles just like chelators 2, 3, and DFO do. The chelator concentrations of the reaction solution before and after conjugation are determined by using UV-visible spectroscopy or HPLC, thereby the amount of the chelator conjugated to nanoparticles can be obtained by simply multiplying the difference of the concentrations with the reaction volume.
2.3 g	With ammonium hydroxide; In water; acetonitrile; at 80 - 90℃; for 18h;Sealed tube;	To a solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (2.3 g) in acetonitirle (5 ml) was added aq.N in seal tube. The reaction mixture was heated at 80-90C for 18 h. After completion of reaction, the reaction mixture was cooled at RT and diluted with ethyl acetate. The organic layer was separated and further aqueous layer was extracted with 10% MeOH in DCM. The organic layer was concentrated to afford 2.3 g of desired product. 1H NMR (DMSO-d6): delta2.0 (s, 3H), 5.0 (s, 2H), 6.20 (s, 1H), 7.20- 7.40 (m, 6H), 11.20 (br s, 1H); MS [M+H]+ : 216.13.
	With ammonium hydroxide; In ethanol; water; for 12h;Reflux;	General procedure: A mixture of suitable Maltol (7.56g, 60mmol), anhydrous K2CO3 (9.12g, 66mmol), benzyl bromide (10.78g, 63mmol) and acetone (150mL) was refluxed for 8h. Once the reaction was completed, the mixture was cooled to room temperature. After the solvent was removed under reduced pressure, water (100mL) was added and the mixture was extracted four times with dichloromethane (50mL). The combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford intermediate 2a as yellow oil. Intermediates 2b, 2c wasprepared followed the similar procedure of 2a. 2a, 2b or 2c (4.33g, 40mmol) was then dissolved in ethanol 45mL and then 25% ammonia aqueous solution (60mL) was added, and the mixture was refluxed for 12h. Afterward, The solvent was evaporated off to obtain a pale brown solid residue, which was recrystallized from acetone/ethyl acetate, leaving the pure target compound as a pale colored solid.

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[22]European Journal of Medicinal Chemistry,2019,vol. 180,p. 367 - 382

4
[ 61049-69-2 ]
[ 109-85-3 ]
[ 123742-57-4 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	With sodium hydroxide In methanol; water at 80℃; Reflux;	4.a (a) Synthesis of 3-Benzyloxy-2-methyl-1-(2-methoxyethyl)-pyridin-4(1H)-one; To a solution of 25 g (0.1156 mole) of 3-benzyloxy-2-methyl-pyran-4-one in aqueous methanol (75 ml+75 ml) was added 27.3 g (0.4736 mole) of 2-methylethylamine, 17.4 g (0.2312 mole) followed by 9.5 ml 2N NaOH solution. The reaction mixture was refluxed (set temp 80° C.) for 12-14 h. Progress of the reaction was monitored by TLC (mobile phase: 25% methanol in ethyl acetate). After completion of the reaction, methanol was distilled off completely and the product was extracted to dichloromethane (250 ml) and washed with 50 ml brine solution. After separation, the organic layer was dried over anhydrous sodium sulphate and concentrated to dark yellow oil. This was directly taken for the next stage without any further purification (28.0 g, 93.7%); Purity by HPLC 96.0%.1H-NMR (CDCl3): δ2.1 (s, 3H, CH3), 3.2 (s, 3H, CH3), 3.5 (t, 2H, CH2), 3.8 (t, 2H, CH2), 5.2 (s, 2H, CH2), 6.4 (d, 1H, ArH), 7.3 (d, 1H, ArH), 7.4-7.5 (m, 5H, ArH); 13C-NMR: δ 3.0, 58.0, 60, 72, 74, 118, 128.0, 128.7, 129.4, 138, 139, 142, 146, 178, MS: 274.12 (M+1)
69%	In ethanol at 90℃; for 4h; Inert atmosphere; Microwave irradiation;	2.2.2. Synthesis of 1-(20-methoxyethyl)-2-methyl-3-benzyloxy-4-(1H)-pyridinone (MRB14p) A mixture of amine 2 (2-methoxyethylamine) (0.691 g,0.00928 mol) and protected pyrone (3-benzyloxy-2-methyl-4-pyrone)(0.501 g; 0.00232 mol) dissolved in dried ethanol (2 mL) wasplaced in a 30 mL reaction vial, which was then closed under argonatmosphere and placed in the cavity of a CEM microwave reactor. The reaction vial was irradiated to 90 C during 4 h, using 100W maximum power. The reaction solvent was evaporated and the crude oil resultant was dissolved in 30 mL of H2O and the pH adjusted to 1 with HCl 10%. The starting materials were removed by liquid/liquid extraction with diethyl ether. The organic layer was rejected. The pH of aqueous phase was adjusted to 10 with asolution of NaOH 5% and the product was then extracted to the organic layer with dichloromethane. The organic phase was concentrated to afford compound MRB14p (0.434 g, 69% yield) as darkbrown oil. 400.15 MHz 1H NMR (CDCl3, ppm): d 2.10 (s, 3H, 2-CH3), 3.24 (s,3H, AOCH3), 3.49 (t, J 5.0 Hz, 2H, H20), 3.92 (t, J 5.0 Hz, 2H, H10),5.15 (s, 2H, ACH2C6H5), 6.37 (d, J 7.5 Hz, 1H, H5), 7.28-7.30 (m,1H, H6 and 3H, Hmeta+paraACH2C6H5), 7.38-7.40 (m, 2H, Hortho-CH2-C6H5). 100.62 MHz 13C NMR (CDCl3, ppm): d 12.3 (2-CH3), 52.8(C10), 58.8 (AOCH3), 70.9 (C20), 72.6 (ACH2C6H5), 116.4 (C5),127.6 and 127.9 (Cmeta+paraAC6H5), 128.7 (CorthoAC6H5), 137.2 (Cq,AC6H5), 139.0 (C6), 141.3 (C2), 145.4 (C3), 173.0 (C4).
	With sodium hydroxide In ethanol; water for 18h; Heating;

	With sodium hydroxide In methanol; water for 2.5h; Reflux;
	With sodium hydroxide In methanol; water for 2.5h; Reflux;
	With sodium hydroxide In methanol; water for 2.5h; Reflux;

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[2]Moniz, Tânia; Cunha-Silva, Luís; Mesquita, Raquel B.R.; Miranda, Joana L.A.; Silva, André M.N.; Silva, Ana M.G.; Rangel, António O.S.S.; de Castro, Baltazar; Rangel, Maria [Polyhedron, 2019, vol. 160, p. 145 - 156]
[3]Dobbin; Hider; Hall; Taylor; Sarpong; Porter; Xiao; Van der Helm [Journal of Medicinal Chemistry, 1993, vol. 36, # 17, p. 2448 - 2458]
[4]Zhang, Ming-Xia; Zhu, Chun-Feng; Zhou, Ying-Jun; Kong, Xiao-Le; Hider, Robert C.; Zhou, Tao [Chemical Biology and Drug Design, 2014, vol. 84, # 6, p. 659 - 668]
[5]Zhou, Tao; Shao, Le-Le; Battah, Sinan; Zhu, Chun-Feng; Hider, Robert C.; Reeder, Brandon J.; Jabeen, Asma; MacRobert, Alexander J.; Ren, Gerui; Liang, Xinle [MedChemComm, 2016, vol. 7, # 6, p. 1190 - 1196]
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5
[ 61049-69-2 ]
[ 156-87-6 ]
[ 95215-84-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	In ethanol; water for 10h; Heating;
81.1%	With sodium hydroxide In ethanol; water for 12h; Heating;
	With sodium hydroxide In ethanol; water for 18h; Heating;

	With sodium hydroxide In ethanol; water at 70℃; for 6h;	Synthesis of (31-hydroxypropyl)-3-benzyloxy-2-methyl-4-pyridinone (2d). First 3 g 3-benzyoxy-2-methyl-4-pyrone (13.9 mmol), 3.5 mL 1,3-propanol amine (45.8 mmol) and 0.5 g NaOH were added in aEtOH-water mixture (20/15) mL, and then stirred at 70 °C for 6 h. After cooling, 2 M HCl was addeduntil the pH = 1 and the reaction solution was evaporated under vacuum. The residue was washedwith acetone and dissolved in 20 mL water. The obtained solution was basified with 10 M NaOHuntil pH = 10 and extracted with dichloromethane (5 30 mL). The organic phase was evaporatedand obtained the snow white powder (2.9 g, 75%). UV-vis (CH3OH): λmax = 216, 274 nm. FT-IR (KBr): ν = 3336, 1632, 1522, 1494, 1419, 1352, 1263, 1159, 1157, 1084, 1035, 960, 842, 754, 706 cm-1. 1H-NMR(300 MHz, CD3OD): δ = 7.62 (d, J = 7.4 Hz, 1H), 7.32-7.46 (5H, m), 6.46 (d, J = 7.4 Hz, 1H), 5.06 (s,2H, CH2Ph), 4.13 (t, J = 7.1 Hz, 2H, HOCH2CH2), 4.03 (t, J = 7.1 Hz, 2H, HOCH2CH2CH2), 2.13 (s,3H, CH3), 2.00 (t, J = 6.2 Hz, 2H, HOCH2CH2CH2) ppm. MS (APCI) m/z (%) = 274 (100) [M + H]+.C16H19O3N (273): calcd. C 70.33,H 6.96, N 5.13; found: C 70.08, H 6.78, N 5.26.
	With sodium hydroxide

Reference： [1]Faerber, M.; Osiander, H.; Severin, T. [Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 947 - 956]
[2]Liu, Zu D.; Liu, Ding Y.; Lu, Shu L.; Hider, Robert C. [Arzneimittel-Forschung/Drug Research, 2000, vol. 50, # 5, p. 461 - 470]
[3]Dobbin; Hider; Hall; Taylor; Sarpong; Porter; Xiao; Van der Helm [Journal of Medicinal Chemistry, 1993, vol. 36, # 17, p. 2448 - 2458]
[4]Jin, Bo; Zheng, Rongzong; Peng, Rufang; Chu, Shijin; Dehaen, Wim [Molecules, 2016, vol. 21, # 3]
[5]Zhang, Qingchun; Feng, Shufan; Zhao, Yulian; Jin, Bo; Peng, Rufang [Journal of Biological Inorganic Chemistry, 2021, vol. 26, # 4, p. 467 - 478]

6
[ 5036-48-6 ]
[ 61049-69-2 ]
1-(3-(1H-imidazol-1-yl)propyl)-3-(benzyloxy)-2-methylpyridin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With sodium hydroxide In ethanol; water monomer for 18h; Reflux;	1.2.2 General procedure for the synthesis of deferiprone derivatives (2a - 5a) General procedure: The opportune amine was added to a solution of 1 in 10 mL of 50% aq EtOH, in a molar ratio of 1:1. The pH of the reaction mixture was adjusted to pH 13 with aq NaOH (10 N). The reaction was heated to reflux for 18 h. The solvents were removed under reduced pressure and the residue was taken up in CHCl3 (3 x 20 mL); the organic phase was washed with water (3 x 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by flash chromatography using AcOEt/MeOH as eluent to afford compounds 2a - 5a.
	With sodium hydroxide In ethanol; water monomer for 12h; Heating;
	With sodium hydroxide In ethanol; water monomer for 12h; Heating;

With sodium hydroxide In ethanol; water monomer at 100℃; for 12h;

Reference： [1]Bortolami, Martina; Pandolfi, Fabiana; Messore, Antonella; Rocco, Daniele; Feroci, Marta; Di Santo, Roberto; De Vita, Daniela; Costi, Roberta; Cascarino, Paola; Simonetti, Giovanna; Scipione, Luigi [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 42]
[2]Liu, Zu D.; Khodr, Hicham H.; Lu, Shu L.; Hider, Robert C. [Journal of Pharmacy and Pharmacology, 2000, vol. 52, # 3, p. 263 - 272]
[3]Dehkordi, Lotfollah S.; Liu, Zu D.; Hider, Robert C. [European Journal of Medicinal Chemistry, 2008, vol. 43, # 5, p. 1035 - 1047]
[4]Fateeva, Anna A.; Kovaleva, Olga N.; Mazur, Dmitrii M.; Milaeva, Elena R.; Nazarov, Alexey A.; Shutkov, Ilya A. [Mendeleev Communications, 2022, vol. 32, # 2, p. 186 - 188]

7
[ 61049-69-2 ]
[ 306-67-2 ]
1-(12-amino-4,9-diazadodecyl)-2-methyl-3-(phenylmethoxy)-4(1H)-pyridinone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 5478 - 5483

8
[ 61049-69-2 ]
[ 500371-01-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With pyridine N-oxide; at 160℃; for 20h;	(1) Add 21.6 g (100 mmol) of compound 2 to a 500 ml reaction flask with a magnetic stir bar(It can be prepared in one step from the cheap and readily available commercial reagent, dentin, see Organic Process Research&Development, 2012, 16(11), 1783-1786)And 250 ml of bromobenzene solvent,Then 0.95 g (10 mmol) of pyridine-N-oxide was added and a vial was connected to the reflux condenser.Another bottle of mouth is filled with oxygen,Then, the mixture was heated to 160 C under stirring to reflux the solvent, and the reaction system was kept under reflux for 20 hours.After the compound 2 was completely reacted, it was cooled to room temperature.Then, the bromobenzene solvent is separated by distillation under reduced pressure to obtain a residual crude product which is dried and re-steamed and then reused.The residual crude product was transferred to a sand core filter funnel (pre-laid 5 cm thick fine silica gel) for suction filtration.Wash with 1000 mL of petroleum ether, collect the filtrate, and concentrate under reduced pressure to remove petroleum ether.Made a brownish yellow liquid 20.9 grams,This is compound 3 (3-benzyloxy-4-oxo-4-hydropyran-2-carbaldehyde),Product yield is 91%,The product can be used as a starting material for further reaction without further purification.
78%	With selenium(IV) oxide; In bromobenzene; at 155℃;	b) SeO2, bromobenzene, 155 C, 78%;
71%	With selenium(IV) oxide; In bromobenzene; at 160℃; for 16h;	1) Selenium dioxide (666mg, B.0mmol) was added to the solution of compound 2 (216mg, l.0mmol) in bromobenzene (2ml). Then the mixture was heated up to 360C, and stirred for 16h. After celite filtration the solvent was evaporate, The precipitate was purified by silicagel column chromatography, and fractions oluting with n-hexan/EtOAc were concentrated under reduced pressure to obtain compound 100 (I64mg, 71%) as a yellow oil . l l?-NMR (CDCl3)S1 5.52(1H, s), 6.50(1H, d, J=6.0Hz), 7.36(5H, m), 7.74(1H, d, J =6 3Hz), 9.88 (1H, s).

65%	With selenium(IV) oxide; In bromobenzene; at 140℃; for 13h;	To a bromobenzene (238 ml) solution of compound A (23.8 g, 110 mmol), selene dioxide (24.4 g, 220 mmol) was added. The reaction mixture was stirred for 13 hours at 140 0C with removing water by Dean-Stark trap. Insoluble particles were removed by filtration after cooling, and solvent was evaporated. Toluene was added to the residue and precipitates were filtered off. After concentration in vaccuo, the residue was purified by silica gel column chromatography (hexane / ethyl acetate). Compound B (16.5 g, 65%) was obtained as yellow oil. 1H-NMR (CDCI3) delta: 5.51 (2H, s), 6.50(1 H, d, J=5.4Hz), 7.36(5H, s), 7.75(1 H, d, J=5.4Hz), 9.88(1 H, s).
65%	With selenium(IV) oxide; bromobenzene; at 140℃; for 13h;Dean-Stark;	Toabromobenzene (238 ml) solution of compoundA(23.8 g, 110 mmol), selene dioxide (24.4 g, 220 mmol) was added. The reaction mixture was stirred for 13 hours at 140 C. with removing water by Dean-Stark trap. Insoluble particles were removed by filtration after cooling, and solvent was evaporated. Toluene was added to the residue and precipitates were filtered off. After concentration in vaccuo, the residue was purified by silica gel column chromatography (hexane/ethyl acetate). Compound B (16.5 g, 65%) was obtained as yellow oil.
54 g	With selenium(IV) oxide; bromobenzene; at 160℃; for 24h;	Example 2: Preparation of 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehvde To a 3-(benzyloxy)-2-methyl-4H-pyran-4-one (80 gm) was added bromo benzene (800 ml) and selenium oxide (82 gm) at room temperature. The reaction mixture was heated to 160C and stirred for 24 hours. The reaction mass was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to obtain 54 gm of 3- (benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde.
	With selenium(IV) oxide; at 160℃; for 24h;	To a stirred solution of 3-(benzyloxy)-2-methyl-4/-/-pyran-4-one 1-2 (100 g, 463 mmol) in bromobenzene (1500 mL), was added selenium dioxide (154 g, 1.39 mol) at RT. The reaction mixture was stirred at 160 C for 24 hr, progress of the reaction was monitored by TLC (-50% conversion), the reaction mixture was cooled to RT, excess of SeC>2 solid was filtered, and the solid quenched with ice-cold water and saturated NaOH solution. The filtrate was concentrated under reduced pressure and the crude compound was purified by silica gel (100-200 mesh) column chromatography and compound eluted with 40% of EtOAc/ pet ether to afford 3-(benzyloxy)-4-oxo-4/-/-pyran-2-carbaldehyde 1-3 . TLC: 40% EtOAc/ pet ether; Rf = 0.5.

Reference： [1]Patent: CN110305091,2019,A .Location in patent: Paragraph 0033-0038; 0045-0048; 0050-0053
[2]Patent: WO2007/2109,2007,A2 .Location in patent: Page/Page column 21
[3]Medicinal Chemistry Research,2013,vol. 22,p. 2351 - 2359
[4]Patent: WO2006/116764,2006,A1 .Location in patent: Page/Page column 113
[5]Organic Process Research and Development,2019,vol. 23,p. 558 - 564
[6]Patent: WO2010/68262,2010,A1 .Location in patent: Page/Page column 28-29
[7]Patent: JP5848595,2016,B2 .Location in patent: Paragraph 0046
[8]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3257 - 3261
[9]Journal of the American Chemical Society,2006,vol. 128,p. 2222 - 2223
[10]Patent: WO2015/1572,2015,A2 .Location in patent: Page/Page column 20
[11]Journal of Medicinal Chemistry,2017,vol. 60,p. 3498 - 3510
[12]Organic Process Research and Development,2019,vol. 23,p. 558 - 564
[13]Patent: CN109912553,2019,A
[14]Patent: WO2020/55858,2020,A1 .Location in patent: Paragraph 00267; 00268

9
[ 61049-69-2 ]
[ 30652-11-0 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 6114 - 6120
[2]Arzneimittel-Forschung/Drug Research,1987,vol. 37,p. 1099 - 1102
[3]Canadian Journal of Chemistry,1988,vol. 66,p. 123 - 131

10
[ 61049-69-2 ]
[ 306-67-2 ]
1-(12-amino-4,9-diazadodecyl)-2-methyl-3-(phenylmethoxy)-4(1H)-pyridinone tetrahydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With sodium hydroxide; In ethanol; water; at 0 - 20℃; for 24h;	1- (12-Amino-4 9-DIAZADODECYI)-2-METHYL-3-(PHENVLMETHOXY .-4 (I H)-PYRIDINONE TETRAHVDROCHLORIDE (Compound 2) Sodium hydroxide (2 N, 190 mL, 0.38 mol) was added in portions to a solution of 3-benzyloxy-2-methyl-4-pyrone (Compound 1) (11.49 g, 53.15 MMOL) and SPERMINE4HCT (20.20 g, 58.01 MMOL) in 39% aqueous ETOH (570 mL) with ice bath cooling. The reaction mixture was stirred at room temperature for 1 day, and its volume was reduced by rotary evaporation. Water (200 mL) was added, followed by several CHC13 extractions. The organic portion was washed with saturated NACI, dried with sodium sulfate, and concentrated under reduced pressure. Flash chromatography (30% concentrated NH40H/CH30H) and acidification with concentrated HCI in ETOH gave Compound 2 (3.35 g, 12%) as a white solid: mp 188-190 C ;H NMR 8 1.7-1. 8 (m, 4 H), 2.0-2. 2 (m, 4 H), 2.28 (s, 3 H), 3.0-3. 2 (m, 10 H), 4.23 (t, 2 H, J= 7.7), 5.12 (s, 2 H), 6.91 (d, 1 H, J= 7.2), 7.4-7. 5 (m, 5 H), 7.98 (d, 1 H, J= 7.5) ; 13C NMR 8 13.5, 23.4, 24.4, 26.8, 37.2, 44.8, 45.2, 47.6, 47.7, 53.7, 76.0, 114.3, 129.5, 129.9, 130.3, 135.8, 142.5, 143.7, 150.6, 165.9. Anal. (C23H4OC14N402-2H20) C, H, N.

Reference： [1]Patent: WO2005/23310,2005,A2 .Location in patent: Page/Page column 30-31; 1/16

11
concentrated (s.g. 0.880) ammonia [ No CAS ]
[ 61049-69-2 ]
[ 61160-18-7 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	3-Benzyloxy-2-methylpyrid-4-one 3-Benzyloxy-2-methyl-4-pyrone (20 g), concentrated (s.g. 0.880) ammonia (200 ml) and ethanol (100 ml) are mixed and kept at room temperature for 3 days. The solvent and excess ammonia are then removed by rotary evaporation to yield an oil which on trituration with acetone gives 3-benzyloxy-2-methylpyrid-4-one as white crystals m.p. 162°-163° C.
	In ethanol;	3-Benzyloxy-2-methylpyrid-4-one 3-Benzyloxy-2-methyl-4-pyrone (20 g), concentrated (s.g. 0.880) ammonia (200 ml) and ethanol (100 ml) are mixed and kept at room temperature for 3 days. The solvent and excess ammonia are then removed by rotary evaporation to yield an oil which on trituration with acetone gives 3-benzyloxy-2-methylpyrid-4-one as white crystals m.p. 162°-163° C.

Reference： [1]Patent: US4585780,1986,A
[2]Patent: US4650793,1987,A

12
[ 61049-69-2 ]
[ 373-88-6 ]
[ 1259498-81-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With pyridine; at 75℃; for 5h;Sealed flask;	Example 1; Preparation of 3-hydroxy-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1 H)-one; (a) Preparation of 3-(benzyloxy)-2-methyl-1 -(2,2,2-trifluoroethyl)pyridin-4(1 H)-onbeta.; 3-(Benzyloxy)-2-methyl-4H-pyran-4-one (1.00 g, 4.6 mmol) was mixed withtrifluoroethyiamine hydrochloride (1.35 g, 10.0 mmol) in pyridine (10 mL). The reaction mixture was heated in a sealed flask at 75 C for 5 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel with 5% methanol in ethyl acetate as eluant to give 3-(benzyloxy)-2-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1 H)-one (0.82 mg) as beige solid. Yield = 60%; 1H NMR (CDCI3, 90 MHz) delta (ppm): 7.02 - 7.58 (m, 6H), 6.42 (d, J = 7.5 Hz, 1 H), 5.20 (s, 2H), 4.30 (q, J = 8.3 Hz, 2H) and 2.10 (s, 3H).

Reference： [1]Patent: WO2011/104,2011,A1 .Location in patent: Page/Page column 48

13
[ 61049-69-2 ]
[ 74-89-5 ]
[ 30652-11-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2012,vol. 60,p. 508 - 512

14
[ 61049-69-2 ]
[ 29390-67-8 ]
C₅₅H₈₁NO₃₆ [ No CAS ]

Reference： [1]Dalton Transactions,2012,vol. 41,p. 2877 - 2883

15
[ 61049-69-2 ]
[ 77-78-1 ]
[ 4780-14-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium hydroxide In acetone at 20℃; for 12h;

Reference： [1]Andayi, Warren A.; Egan, Timothy J.; Gut, Jiri; Rosenthal, Philip J.; Chibale, Kelly [ACS Medicinal Chemistry Letters, 2013, vol. 4, # 7, p. 642 - 646]

16
[ 61049-69-2 ]
[ 7533-40-6 ]
3-hydroxy-1-(1,3-dihydroxy propyl-2-)-2-methyl pyridine-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.8%		Example 26. 3-Hydroxy-1-(1,3-dihydroxy propyl-2-)-2-methyl pyridine-4(1H)-one hydrochloride, Number: CN350. 12.65 g 3-phenyloxy-2-methyl-4H-pyran-4-one (Example 1) was dissolved in 8.5 mL n-butanol, then 8.0 g <strong>[7533-40-6]D-leucinol</strong> was added in, after thoroughly mixing, the solution was refluxed at 118C for 36 h, after cooling and filtration, products were separated by silica gel column chromatography with eluent ethanol: ethyl acetate= 1:20. After elution, light brown oily liquid was obtained after rotary evaporation, the solid was then dissolved into 50 mL ethanol and 5 mL water, then it was hydrogenated and debenzylated with 5% Pd/C as catalyst, the solvent was removed under rotary evaporation, the resulting residue was recrystallized with methanol and ether, leading to 7.43 g white solid, the yield was 58.8%.

Reference： [1]Patent: EP2692724,2014,A1 .Location in patent: Paragraph 0087; 0088

17
[ 61049-69-2 ]
[ 1206102-11-5 ]

Reference： [1]Patent: WO2015/1572,2015,A2
[2]Patent: WO2015/1572,2015,A2
[3]Patent: JP5848595,2016,B2
[4]Patent: JP5848595,2016,B2
[5]Patent: JP5848595,2016,B2
[6]Patent: JP5848595,2016,B2
[7]Organic Process Research and Development,2019,vol. 23,p. 565 - 570
[8]Organic Process Research and Development,2019,vol. 23,p. 558 - 564
[9]Organic Process Research and Development,2019,vol. 23,p. 558 - 564

18
[ 61049-69-2 ]
[ 1206102-07-9 ]

Reference： [1]Patent: WO2015/39348,2015,A1
[2]Patent: US9133216,2015,B2
[3]Patent: JP5848595,2016,B2
[4]Patent: JP5848595,2016,B2
[5]Patent: JP5848595,2016,B2
[6]Patent: JP5848595,2016,B2
[7]Patent: WO2010/11816,2010,A1
[8]Patent: CN108299466,2018,A
[9]Organic Process Research and Development,2019,vol. 23,p. 565 - 570
[10]Organic Process Research and Development,2019,vol. 23,p. 558 - 564
[11]Organic Process Research and Development,2019,vol. 23,p. 558 - 564

19
[ 61049-69-2 ]
[ 1206102-05-7 ]

Reference： [1]Patent: WO2015/39348,2015,A1
[2]Patent: US9133216,2015,B2
[3]Patent: WO2010/11816,2010,A1
[4]Organic Process Research and Development,2019,vol. 23,p. 558 - 564

20
[ 61049-69-2 ]
[ 1051375-10-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -60 °C 1.2: 1 h / -60 °C 2.1: triethylamine; methanesulfonyl chloride / tetrahydrofuran / 30 °C 2.2: 0.5 h / 30 °C 3.1: sodium periodate; rhodium(III) chloride hydrate; water / acetonitrile; ethyl acetate / 1 h / 25 °C 3.2: 1 h / 25 °C 4.1: pyridine / ethanol / 8.5 h / 65 - 80 °C 5.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 6.1: sodium periodate; acetic acid; water / acetonitrile / 2 h / 20 °C 7.1: acetic acid / acetonitrile; methanol / 4 h / 70 °C 8.1: N-Bromosuccinimide / 1-methyl-pyrrolidin-2-one / 2.5 h / 20 °C 9.1: N-ethyl-N,N-diisopropylamine; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / dimethyl sulfoxide / 9 h / 90 °C 10.1: hydrogen; 10% Pd/C / tetrahydrofuran; methanol / 3.33 h
	Multi-step reaction with 10 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -60 °C 1.2: 1 h / -60 °C 2.1: triethylamine; methanesulfonyl chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.5 h / 30 °C 3.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 3.2: 1.5 h / 25 °C 4.1: ethanol / 8.5 h / 65 - 80 °C 5.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 6.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 7.1: acetic acid / methanol; acetonitrile / 4 h / 70 °C 8.1: N-Bromosuccinimide / 1-methyl-pyrrolidin-2-one / 2.5 h / 20 °C 9.1: N-ethyl-N,N-diisopropylamine; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / dimethyl sulfoxide / 7 h / 90 °C 10.1: 10% Pd/C; hydrogen / tetrahydrofuran; methanol / 3 h
	Multi-step reaction with 10 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2 h / -60 °C 1.2: 1 h / -60 °C 2.1: triethylamine; methanesulfonyl chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran; 1-methyl-pyrrolidin-2-one / 0.5 h / 30 °C 3.1: rhodium(III) chloride hydrate; sodium periodate; sulfuric acid / water; acetonitrile / 3.5 h / 20 °C 3.2: 1.5 h / 25 °C 4.1: ethanol / 8.5 h / 65 - 80 °C 5.1: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 6.1: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 7.1: acetic acid / methanol; acetonitrile / 4 h / 70 °C 8.1: N-Bromosuccinimide / 1-methyl-pyrrolidin-2-one / 2.5 h / 20 °C 9.1: N-ethyl-N,N-diisopropylamine; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / dimethyl sulfoxide / 7 h / 90 °C 10.1: 10% Pd/C; hydrogen / tetrahydrofuran; methanol / 3 h

	Multi-step reaction with 9 steps 1: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 2: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 3: ethanol / 8.5 h / 65 - 80 °C 4: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 28 - 35 °C / Large scale 5: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 6: acetic acid / methanol; acetonitrile / 4 h / 70 °C 7: N-Bromosuccinimide / 1-methyl-pyrrolidin-2-one / 2.5 h / 20 °C 8: N-ethyl-N,N-diisopropylamine; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / dimethyl sulfoxide / 7 h / 90 °C 9: 10% Pd/C; hydrogen / tetrahydrofuran; methanol / 3 h
	Multi-step reaction with 9 steps 1: bromobenzene; selenium(IV) oxide / 13 h / 140 °C / Dean-Stark 2: sodium chlorite; aminosulfonic acid / water; acetone / 0.67 h / 20 °C / Cooling with ice 3: ethanol / 8.5 h / 65 - 80 °C 4: sodium hydrogencarbonate / 1-methyl-pyrrolidin-2-one; water / 4 h / 20 °C 5: sodium periodate; sulfuric acid / water; acetonitrile / 1 h / 14 - 17 °C 6: acetic acid / methanol; acetonitrile / 4 h / 70 °C 7: N-Bromosuccinimide / 1-methyl-pyrrolidin-2-one / 2.5 h / 20 °C 8: N-ethyl-N,N-diisopropylamine; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / dimethyl sulfoxide / 7 h / 90 °C 9: 10% Pd/C; hydrogen / tetrahydrofuran; methanol / 3 h

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD.; GLAXOSMITHKLINE PLC - US9133216, 2015, B2
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC; SHIONOGI & CO., LTD. - JP5848595, 2016, B2
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC; SHIONOGI & CO., LTD. - JP5848595, 2016, B2
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC; SHIONOGI & CO., LTD. - JP5848595, 2016, B2
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC; SHIONOGI & CO., LTD. - JP5848595, 2016, B2

21
[ 61049-69-2 ]
[ 6291-84-5 ]
3-(benzyloxy)-2-methyl-1-(3-(methylamino)propyl)pyridin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydroxide; In ethanol; water; for 12h;pH 13.0;Reflux;	Analogous reactions of 1a with ethylenediamine, N-methyl-1,3-propanediaminegave compound 3a and 4a.

Reference： [1]Polymer,2016,vol. 87,p. 64 - 72

22
[ 61049-69-2 ]
[ 1051375-19-9 ]

Reference： [1]Patent: JP5848595,2016,B2
[2]Patent: JP5848595,2016,B2
[3]Patent: JP5848595,2016,B2
[4]Patent: JP5848595,2016,B2
[5]Organic Process Research and Development,2019,vol. 23,p. 565 - 570
[6]Organic Process Research and Development,2019,vol. 23,p. 558 - 564
[7]Organic Process Research and Development,2019,vol. 23,p. 558 - 564

23
[ 61049-69-2 ]
[ 1229006-21-6 ]

Reference： [1]Patent: JP5848595,2016,B2
[2]Patent: JP5848595,2016,B2

24
[ 61049-69-2 ]
[ 906657-86-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydroxide; ammonia / ethanol; water / 1 h / 90 °C 2: N-Bromosuccinimide / acetonitrile / 1.5 h / 20 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC; SHIONOGI & CO., LTD. - WO2006/116764, 2006, A1

25
[ 61049-69-2 ]
[ 30652-21-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / ethanol; water / 18 h / Reflux 2: 5%-palladium/activated carbon; hydrogen / ethanol; water / 4 h / 20 °C / 760.05 Torr
	Multi-step reaction with 2 steps 1: sodium hydroxide 2: palladium on activated charcoal; hydrogen

Reference： [1]Chen, Wenteng; Yuan, Xin; Li, Zhi; Lu, Zidong; Kong, Sisi; Jiang, Huidi; Du, Houbing; Pan, Xiuhong; Nandi, Manasi; Kong, Xiaole; Brown, Kathryn; Liu, Zudong; Zhang, Guolin; Hider, Robert C.; Yu, Yongping [Journal of Medicinal Chemistry, 2020, vol. 63, # 8, p. 4215 - 4226]
[2]Zhang, Qingchun; Feng, Shufan; Zhao, Yulian; Jin, Bo; Peng, Rufang [Journal of Biological Inorganic Chemistry, 2021, vol. 26, # 4, p. 467 - 478]

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 61049-69-2 ] {[proInfo.proName]}

Quality Control of [ 61049-69-2 ]

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Product Details of [ 61049-69-2 ]

Safety of [ 61049-69-2 ]

Application In Synthesis of [ 61049-69-2 ]

[ 61049-69-2 ] Synthesis Path-Upstream 1~7

[ 61049-69-2 ] Synthesis Path-Downstream 1~25

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry