* 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.
With formaldehyd; sodium thioethylate In N,N-dimethyl-formamide at 145℃; for 1 h;
To a 1.0-L three-neck flask was added sodium ethanethiolate (80percent, 28.5 g, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to 145° C. for 1.5 hours. Then, 3,5-dimethoxy-benzaldehyde (15.0 g, 90.0 mmol) in anhydrous DMF (350 mL) was added over a period of 8 minutes. The reaction was kept at 145° C. for another 1 hour, then cooled to room temperature. Saturated sodium chloride solution (2.5 L) and formaline (37percent, 240 mL) together with acetic acid (500 mL) was added. The resulting solution was thoroughly extracted with ethyl acetate, the organic phase was dried with sodium sulfate, and the solvent was removed under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1) to give 3-hydroxy-5-methoxy-benzaldehyde as a white solid. Yield: 12.0 g (88percent)
70%
With sodium hydride In N,N-dimethyl-formamide; ethanethiol; mineral oil for 1 h; Inert atmosphere; Reflux
NaH (2.72 g, 71.4 mmol, 60percent in mineral oil) was taken in an oven-dried RB flask equipped with magnetic stir bar and anhydrous DMF (60 mL) was added. After cooling the solution at 0° C., ethanethiol (7 mL, 93.4 mmol) was slowly added via a syringe, once the evolution of H2 ceased, it was refluxed under N2 atmosphere for 1 h. Next, aldehyde E (3.84 g, 23.6 mmol) in DMF (90 mL) was added and the resulting solution was refluxed under N2 atmosphere for 1 h. The reaction mixture was then cooled and quenched by the addition of saturated aqueous NaCl (750 mL), 26percent formaline (75 mL), and acetic acid (140 mL). The reaction mixture was then thoroughly extracted with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude dark syrup. The crude syrup was purified by gradient column chromatography using hexanes and ethyl acetate (100:1 to 1:1) to afford the desired aldehyde F as a yellow solid (70percent). [0099] 1H NMR (500 MHz, CDCl3): δ 9.84 (s, 1H, —CHO), 6.96 (d, J=2.5 Hz, 2H), 6.68 (t, J=2.1 Hz, 1H), 3.83 (s, 3H). [0100] 13C NMR (125 MHz, CDCl3): δ 192.8, 161.2, 158.6, 138.1, 109.2, 108.2, 106.0, 55.4
17.6%
With sodium hydride; ethanethiol In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 2.5 h; Heating / reflux
Example 16-1 Preparation for 3-hydroxy-5-methoxybenzaldehyde To a solution of 60percent sodium hydride (2.77g, 69.3mmol) in N,N-dimethylformamide (50ml) was gradually added at 0°C ethanethiol (7ml), and the solution was stirred at 0°C for 30 minutes, followed by refluxing under heating for 1 hour.. The mixture was cooled to room temperature, and thereto was added 3,5-dimethoxybenzaldehyde (3.84g, 23.1mmol) in N,N-dimethylformamide (90ml) and the mixture was refluxed under heating for 1 hour.. The mixture was cooled to room temperature, and thereto were added a saturated aqueous sodium chloride solution (700ml), 26percent aqueous formalin solution (70ml) and acetic acid (130ml) in the order.. The mixture was stirred, extracted with ethyl acetate.. The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, and dried over anhydrous magnesium sulfate.. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=2:1) to give the subject compound (2.68g, 17.6percent).1H NMR (CDCl3, 400 MHz) δ 9.88 (s, 1 H), 7.00 (m, 1 H), 6.96 (m, 1 H), 6.68 (t, 1 H, J = 2.3 Hz), 3.84 (s, 3 H).
Reference：
[1] Patent: US2013/281399, 2013, A1, . Location in patent: Paragraph 0791; 0797
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 40, p. 5605 - 5614
[3] Journal of Organic Chemistry, 1985, vol. 50, # 13, p. 2236 - 2240
[4] Patent: US2014/309427, 2014, A1, . Location in patent: Paragraph 0097; 0098; 0099; 0100
[5] PLoS ONE, 2015, vol. 10, # 10,
[6] Patent: EP1386913, 2004, A1, . Location in patent: Page 65-66
[7] Patent: WO2016/14529, 2016, A1, . Location in patent: Page/Page column 25
2
[ 26153-38-8 ]
[ 74-88-4 ]
[ 57179-35-8 ]
Yield
Reaction Conditions
Operation in experiment
39%
With potassium carbonate In N,N-dimethyl-formamide at -10℃; Inert atmosphere
To a stirredsuspension of 3,5-dihydroxybenzaldehyde, 12 (2.76 g,20.0 mmol) and K2CO3 (2.76 g, 20.0 mmol) in DMF(50 mL) was added methyl iodide (1.25 mL, 20.0 mmol)dropwise at −10 C under nitrogen atmosphere. The mixturewas stirred for 3 h at this temperature. After completion of thereaction, water (70 mL) was added. The mixture was thenextracted with ether (2 × 80 mL), the combined organic layerwas washed with brine (2 × 80 mL), dried over anhydrousNa2SO4, filtered and the filtrate was concentrated in vacuo.The crude residue was purified by column chromatography(EtOAc/hexane = 1/4) to yield the compound 17 (1.19 g,39percent) as white solid. Rf = 0.23 (EtOAc/hexane = 1/4); mp128–130 C; 1H NMR (300 MHz, CDCl3) δ 9.86 (1H, s),6.98 (1H, dd, J = 2.4, 1.5 Hz), 6.95 (1H, dd, J = 2.4,1.5 Hz), 6.67 (1H, t, J = 2.4 Hz), 5.79 (1H, s), 3.84 (3H, s);13C NMR (75 MHz, CDCl3) δ 191.8, 161.3, 157.2, 138.4,109.0, 108.1, 107.0, 55.7.
39%
With potassium carbonate In N,N-dimethyl-formamide at -10℃; for 3 h; Inert atmosphere
To a suspension of 3,5-dihydroxybenzaldehyde (3,5-dihydroxybenzaldehyde, compound 12) (2.76 g, 20.0 mmol) and K2CO3 (2.76 g, 20.0 mmol) in DMF (50 mL) was added methyl iodide (1.25 mL, 20.0 mmol) in a nitrogen atmosphere, - 10°C. The reaction mixture was stirred at this temperature for three hours. After the reaction was completed, 70 ml of water was added. The reaction mixture was then extracted with ether (2 x 80 mL) and the combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na2SO4,The filtrate was concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc / hexane = 1/4) to obtain a white solid compound 17 (1.19 g, 39percent).
29%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h; Stage #2: at 20℃; for 16 h;
3-Hydroxy-5-methoxybenzaldehyde (240)A stirred solution of 3,5-dihydroxybenzaldehyde (1.0 g, 7.24 mmol) in DMF (20 mL) is treated with sodium hydride (319 mg, 8.0 mmol, 60percent dispersion in mineral EPO <DP n="361"/>oil) at O0C. After warming to RT and stirring 0.5 h, the reaction is treated with iodomethane (0.50 mL, 8.0 mmol) via syringe and stirred 16 h. It is then diluted with 1 M HCl (100 mL) and extracted into EtOAc (50 mL). The EtOAc phase is washed with 1 M HCl (50 mL), water (2 x 50 mL) and brine (50 mL), dried over Na2SO4 then the EtOAc removed in vacuo. The title compound is obtained after chromatography (gradient elution - 0-50percent EtOAc in heptane). Yield: 315 mg (29percent).
29%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h; Stage #2: for 16 h;
3-Hydroxy-5-methoxybenzaldehyde (240)A stirred solution of 3,5-dihydroxybenzaldehyde (1.0 g, 7.24 mmol) in DMF (20 mL) was treated with sodium hydride (319 mg, 8.0 mmol, 60percent dispersion in mineral oil) at 0°C. After warming to RT and stirring 0.5 h, the reaction was treated with iodomethane (0.50 mL, 8.0 mmol) via syringe and stirred 16 h. It was then diluted with 1 M HCl (100 mL) and extracted into EtOAc (50 mL). The EtOAc phase was washed with 1 M HCl (50 mL), water (2 x 50 mL) and brine (50 mL), dried over Na2SO4 then the EtOAc removed in vacuo. The title compound was obtained after chromatography (gradient elution - 0-50percent EtOAc in heptane). Yield: 315 mg (29percent).
29%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h; Stage #2: for 16 h;
3-Hydroxy-5-methoxybenzaldehyde (240); A stirred solution of 3,5-dihydroxybenzaldehyde (1.0 g, 7.24 mmol) in DMF (20 mL) is treated with sodium hydride (319 mg, 8.0 mmol, 60percent dispersion in mineral EPO <DP n="361"/>oil) at 0°C. After warming to RT and stirring 0.5 h, the reaction is treated with iodomethane (0.50 mL, 8.0 mmol) via syringe and stirred 16 h. It is then diluted with 1 M HCl (100 mL) and extracted into EtOAc (50 mL). The EtOAc phase is washed with 1 M HCl (50 mL), water (2 x 50 mL) and brine (50 mL), dried over Na2SO4 then the EtOAc removed in vacuo. The title compound is obtained after chromatography (gradient elution - 0-50percent EtOAc in heptane). Yield: 315 mg (29percent)..
29%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5 h; Stage #2: for 16 h;
Synthesis of Compound 394; 3-Hydroxy-5-methoxybenzaldehyde (240); A stirred solution of 3,5-dihydroxybenzaldehyde (1.0 g, 7.24 mmol) in DMF (20 mL) is treated with sodium hydride (319 mg, 8.0 mmol, 60percent dispersion in mineral EPO <DP n="361"/>oil) at 0°C. After warming to RT and stirring 0.5 h, the reaction is treated with iodomethane (0.50 mL, 8.0 mmol) via syringe and stirred 16 h. It is then diluted with 1 M HCl (100 mL) and extracted into EtOAc (50 mL). The EtOAc phase is washed with 1 M HCl (50 mL), water (2 x 50 mL) and brine (50 mL), dried over Na2SO4 then the EtOAc removed in vacuo. The title compound is obtained after chromatography (gradient elution - 0-50percent EtOAc in heptane). Yield: 315 mg (29percent).
Reference：
[1] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 12, p. 2907 - 2914
[2] Patent: KR2016/115127, 2016, A, . Location in patent: Paragraph 0018; 0019
[3] Patent: WO2008/57497, 2008, A2, . Location in patent: Page/Page column 359-360
[4] Patent: WO2007/89669, 2007, A2, . Location in patent: Page/Page column 256
[5] Patent: WO2008/57469, 2008, A1, . Location in patent: Page/Page column 359-360
[6] Patent: WO2008/57468, 2008, A1, . Location in patent: Page/Page column 359-360
3
[ 67-56-1 ]
[ 26153-38-8 ]
[ 57179-35-8 ]
Yield
Reaction Conditions
Operation in experiment
25%
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 0.5 h;
a) 3 Hydroxy-5-methoxybenzaldehyde Diethyl azodicarboxylate (1.5 mL, 9.53 mmol) was added to a solution of 1.14 g (8.26 mmol) of 3,5-dihydroxybenzaldehyde, 2.39 g (9.12 mmol) of triphenylphosphine, and 380 μL (9.4 mmol) of methanol in anhydrous tetrahydrofuran (20 mL) at 0 °C. The reaction mixture was stirred at ambient temperature for 30 min and quenched with 10percent aqueous citric acid. The reaction mixture was extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (dichloromethane / petroleum ether (2: 1 then 100: 0)) to give the title compound (309 mg, 25percent) as a gum. 1H-NMR (300 MHz, CDCl3) δ 9.82 (s, 1 H), 6.98 - 6.99 (m, 2 H), 6.94 - 6.96 (m, 1 H), 3.80 (s, 3 H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 1, p. 1 - 4
[2] Patent: EP906091, 2006, B1, . Location in patent: Page/Page column 21
4
[ 7311-34-4 ]
[ 811-51-8 ]
[ 57179-35-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: at 145℃; for 1.5 h; Stage #2: at 145℃; for 1.13333 h;
Example 123 Preparation of 5,7-Dimethoxy-2-(3-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one To a 1.0-L three-neck flask was added sodium ethanethiolate (80percent, 28.5 g, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to 145° C. for 1.5 hours. Then, 3,5-dimethoxy-benzaldehyde (15.0 g, 90.0 mmol) in anhydrous DMF (350 mL) was added over a period of 8 minutes. The reaction was kept at 145° C. for another 1 hour, then cooled to room temperature. Saturated sodium chloride solution (2.5 L) and formaline (37percent, 240 mL) together with acetic acid (500 mL) was added. The resulting solution was thoroughly extracted with ethyl acetate, the organic phase was dried with sodium sulfate, and the solvent was removed under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1) to give 3-hydroxy-5-methoxy-benzaldehyde as a white solid. Yield: 12.0 g (88percent).
With triphenylphosphine In tetrahydrofuran; methanol; Petroleum ether
a 3-Hydroxy-5-methoxybenzaldehyde Diethyl azodicarboxylate (1.5 mL, 9.53 mmol) was added to a solution of 1.14 g (8.26 mmol) of 3,5-dihydroxybenzaldehyde, 2.39 g (9.12 mmol) of triphenylphosphine, and 380 μL (9.4 mmol) of methanol in anhydrous tetrahydrofuran (20 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 30 min and quenched with 10percent aqueous citric acid. The reaction mixture was extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (dichloromethane/petroleum ether (2:1 then 100:0)) to give the title compound (309 mg, 25percent) as a gum. 1 H-NMR (300 MHz, CDCl3) δ 9.82 (s, 1 H), 6.98-6.99 (m, 2 H), 6.94-6.96 (m, 1 H), 3.80 (s, 3 H).
With formaldehyd; sodium thioethylate In N,N-dimethyl-formamide at 145℃; for 1h;
114; 115
To a 1.0-L three-neck flask was added sodium ethanethiolate (80%, 28.5 g, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to 145° C. for 1.5 hours. Then, 3,5-dimethoxy-benzaldehyde (15.0 g, 90.0 mmol) in anhydrous DMF (350 mL) was added over a period of 8 minutes. The reaction was kept at 145° C. for another 1 hour, then cooled to room temperature. Saturated sodium chloride solution (2.5 L) and formaline (37%, 240 mL) together with acetic acid (500 mL) was added. The resulting solution was thoroughly extracted with ethyl acetate, the organic phase was dried with sodium sulfate, and the solvent was removed under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1) to give 3-hydroxy-5-methoxy-benzaldehyde as a white solid. Yield: 12.0 g (88%)
84%
Stage #1: 3,5-dimethoxybenzaldehdye With sodium hydride; 2-methylpropan-2-thiol In N,N-dimethyl-formamide; mineral oil at 120℃; for 3h; Inert atmosphere;
Stage #2: Inert atmosphere;
73%
With sodium hydride; ethanethiol In N,N-dimethyl-formamide for 1h; Heating;
70%
With sodium hydride In N,N-dimethyl-formamide; ethanethiol; mineral oil for 1h; Inert atmosphere; Reflux;
Synthesis of 3-hydroxy-5-methoxybenzaldehyde
NaH (2.72 g, 71.4 mmol, 60% in mineral oil) was taken in an oven-dried RB flask equipped with magnetic stir bar and anhydrous DMF (60 mL) was added. After cooling the solution at 0° C., ethanethiol (7 mL, 93.4 mmol) was slowly added via a syringe, once the evolution of H2 ceased, it was refluxed under N2 atmosphere for 1 h. Next, aldehyde E (3.84 g, 23.6 mmol) in DMF (90 mL) was added and the resulting solution was refluxed under N2 atmosphere for 1 h. The reaction mixture was then cooled and quenched by the addition of saturated aqueous NaCl (750 mL), 26% formaline (75 mL), and acetic acid (140 mL). The reaction mixture was then thoroughly extracted with ethyl acetate, the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain a crude dark syrup. The crude syrup was purified by gradient column chromatography using hexanes and ethyl acetate (100:1 to 1:1) to afford the desired aldehyde F as a yellow solid (70%). [0099] 1H NMR (500 MHz, CDCl3): δ 9.84 (s, 1H, -CHO), 6.96 (d, J=2.5 Hz, 2H), 6.68 (t, J=2.1 Hz, 1H), 3.83 (s, 3H). [0100] 13C NMR (125 MHz, CDCl3): δ 192.8, 161.2, 158.6, 138.1, 109.2, 108.2, 106.0, 55.4
53%
With sodium hydride In N,N-dimethyl-formamide; ethanethiol Inert atmosphere; Reflux;
17.6%
With sodium hydride; ethanethiol In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 2.5h; Heating / reflux;
16-1
Example 16-1 Preparation for 3-hydroxy-5-methoxybenzaldehyde To a solution of 60% sodium hydride (2.77g, 69.3mmol) in N,N-dimethylformamide (50ml) was gradually added at 0°C ethanethiol (7ml), and the solution was stirred at 0°C for 30 minutes, followed by refluxing under heating for 1 hour.. The mixture was cooled to room temperature, and thereto was added 3,5-dimethoxybenzaldehyde (3.84g, 23.1mmol) in N,N-dimethylformamide (90ml) and the mixture was refluxed under heating for 1 hour.. The mixture was cooled to room temperature, and thereto were added a saturated aqueous sodium chloride solution (700ml), 26% aqueous formalin solution (70ml) and acetic acid (130ml) in the order.. The mixture was stirred, extracted with ethyl acetate.. The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, and dried over anhydrous magnesium sulfate.. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=2:1) to give the subject compound (2.68g, 17.6%).1H NMR (CDCl3, 400 MHz) δ 9.88 (s, 1 H), 7.00 (m, 1 H), 6.96 (m, 1 H), 6.68 (t, 1 H, J = 2.3 Hz), 3.84 (s, 3 H).
With sodium hydride; thiophenol In N,N-dimethyl-formamide at 0℃;
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 16h;
114; 115
3-Hydroxy-5-methoxy-benzaldehyde (12.0 g, 78.9 mmol) and [1,3]dioxolan-2-one (13.9 g, 157.0 mmol) in anhydrous DMF (50 mL) was added potassium carbonate (21.6 g, 157.0 mmol). The mixture was then heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature. Solid potassium carbonate was filtered and washed with ethyl acetate. The organic phase was collected and solvent was removed. The residue was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1), to give 3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde as a brown liquid. Yield: 10.0 g (65%)
65%
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 16h;
123
3-Hydroxy-5-methoxy-benzaldehyde (12.0 g, 78.9 mmol) and [1,3]dioxolan-2-one (13.9 g, 157.0 mmol) in anhydrous DMF (50 mL) was added potassium carbonate (21.6 g, 157.0 mmol). The mixture was then heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature. Solid potassium carbonate was filtered and washed with ethyl acetate. The organic phase was collected and solvent was removed. The residue was purified by column chromatography (silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate 7:1), to give 3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde as a brown liquid. Yield: 10.0 g (65%).
With potassium carbonate; In acetonitrile; for 15.0h;Reflux;
General procedure: Vanilline (3a, 6.85 g, 45 mmol) and 1-(2-bromoethyl)pyrrolidine-2,5-dione1(4a, 10.2 g, 49.5 mmol) were heated with K2CO3 (8.28 g, 60 mmol) in 200 ml of acetonitrileunder reflux for 15 h. The precipitated KBr was filtered off, the filtrate was evaporated, theresidue was dissolved in 200 ml of dichloromethane, washed with water and 2N NaOHsolution, dried with Na2SO4 and evaporated. The remaining oil was triturated with n-hexaneto result in the desired 4-[2-(2,5-dioxopyrrolidin-1-yl)ethoxy]-3-methoxybenzaldehyde (5a)as white crystals.
With potassium carbonate; In acetonitrile; for 15.0h;Reflux;
General procedure: Vanilline (3a, 6.85 g, 45 mmol) and <strong>[55943-72-1]1-(2-bromoethyl)pyrrolidine-2,5-dione</strong>1(4a, 10.2 g, 49.5 mmol) were heated with K2CO3 (8.28 g, 60 mmol) in 200 ml of acetonitrileunder reflux for 15 h. The precipitated KBr was filtered off, the filtrate was evaporated, theresidue was dissolved in 200 ml of dichloromethane, washed with water and 2N NaOHsolution, dried with Na2SO4 and evaporated. The remaining oil was triturated with n-hexaneto result in the desired 4-[2-(2,5-dioxopyrrolidin-1-yl)ethoxy]-3-methoxybenzaldehyde (5a)as white crystals.
3‐methoxy‐5‐((4‐(trifluoromethyl)benzyl)oxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium carbonate In acetonitrile at 80℃; for 5h;
3.1.1. General Procedure for Synthesis of Intermediate Compounds 3a-c
General procedure: Potassium carbonate (1.5 mmol) was added to a solution of aldehyde (1.0 mmol) withdifferent substituents and benzyl chloride (1.0 mmol) with different substituents or 1-(2-chloroethyl)-4-trifluoromethylbenzene (1.0 mmol) in acetonitrile (15 mL). The mixturewas heated to 80 °C for 5 h. After the reaction was complete and the solvent was spindriedunder reduced pressure, the mixture was diluted with water (20 mL) and extractedwith ethyl acetate (60 mL), and the organic layer was separated and dried over anhydroussodium sulfate. After the evaporation of solvent under reduced pressure, the crude productwas purified on a silica gel column to produce compounds 3a-c as a white solid.
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