* 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.
Reference:
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 29, p. 7250 - 7253
2
[ 102074-19-1 ]
[ 100910-66-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 20℃;
Step 2. 5-methyl-3-pyridinecarboxaldehyde. A mixture of 5-methyl-3-pyridinemethanol (106 mg, 0.86 mmol) and activated MnO2 (376 mg) in methylenechloride (10 mL) was stirred at room temperature overnight. The black solid of MnO2 was removed by filtration. The filtrate was concentrated in vacuo to yield the title compound as an oil (100 mg, 85percent). 1H NMR (CDCl3): 10.10 (s, 1H), 8.89 (s, 1H), 8.68 (s, 1H), 7.98 (s, 1H), 2.45 (s, 3H)
Reference:
[1] Patent: EP1230232, 2004, B1, . Location in patent: Page 40
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6299 - 6310
[3] Journal of Organic Chemistry, 1988, vol. 53, # 15, p. 3513 - 3521
[4] Patent: WO2016/185423, 2016, A1, . Location in patent: Page/Page column 74
3
[ 342602-12-4 ]
[ 100910-66-5 ]
Yield
Reaction Conditions
Operation in experiment
99%
With lithium aluminium tetrahydride In tetrahydrofuran at -78℃; for 0.5 h;
To a solution of N-methoxy-N,5-dimethylnicotinamide (3.0 g, 16.65 mmol) in THF (50 mL) was added LAH (0.76 g, 19.98 mmol) at -78 °C, and the resulting mixture was stirred at -78 °C for 30 mins. TLC showed the reaction was completed. The reaction was quenched with sat.NH4C1 (100 mL), and the mixture was extracted with EtOAc (100 mL x2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give the desired 5-methylnicotinaldehyde (2.0 g, yield: 99percent) as yellow oil.‘HNMR (400 MHz, CDC13): = 10.10 (s, 1H), 8.89 (s, 1H), 8.68 (s, 1H), 7.97 (s, 1H), 2.57 (s, 3H).
Step 2. 5-methyl-3-pyridinecarboxaldehyde. A mixture of 5-methyl-3-pyridinemethanol (106 mg, 0.86 mmol) and activated MnO2 (376 mg) in methylenechloride (10 mL) was stirred at room temperature overnight. The black solid of MnO2 was removed by filtration. The filtrate was concentrated in vacuo to yield the title compound as an oil (100 mg, 85%). 1H NMR (CDCl3): 10.10 (s, 1H), 8.89 (s, 1H), 8.68 (s, 1H), 7.98 (s, 1H), 2.45 (s, 3H)
With manganese(IV) oxide; In dichloromethane; at 20℃; for 4h;
Step 2: Mn02 (46.2 g, 531 mmol) was added to a stirred solution of (5-methylpyridin- 3-yl)methanol in dry DCM (75 mL). The suspension was stirred at rt for 4 h. The mixturewas filtered and the solvent was removed under reduced pressure to give 1.91 g (60%) of 5- methylpyridine-3-carbaldehyde. Crude product was used without further purification. MS (m/z) 122 (M+H).
ethyl (2Z)-2-benzoyl-3-(5-methyl-3-pyridyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; acetic acid; In ethanol; at 20℃; for 24h;
Preparation 16; A mixture of <strong>[100910-66-5]5-methylnicotinaldehyde</strong> (400 mg), ethyl benzoylacetate (635 mg), AcOH (0.15 ml), piperidine (0.15 ml) in EtOH (5 ml) was stirred at room temperature for 24 hours. After evaporation, the residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give ethyl (2Z)-2-benzoyl-3-(5-methyl-3-pyridyl)acrylate (986 mg) as a yellow oil. 1H-NMR (CDCl3) delta 1.19 (3H, t, J=7 Hz), 2.20 (3H, s), 4.25 (2H, q, J=7 Hz), 7.41-7.48 (3H, m), 7.58 (1H, t, J=7 Hz), 7.90 (2H, s), 7.93 (1H, d, J=7 Hz), 8.32 (1H, s), 8.42 (1H, s) MS (ESI+) 296 (M+1)
EXAMPLE 30 2-Amino-3-cyano-7-methoxy-4-(5-methyl-3-pyridyl)-4H-chromene To a solution of <strong>[100910-66-5]5-methylpyridine-3-carbaldehyde</strong> (120 mg, 0.99 mmol) and 3-methoxyphenol (128 mg, 1.03 mmol) in anhydrous ethanol (10 mL) were added molanonitrile (68 mg, 1.03 mmol) and piperidine (0.1 mL, 1.01 mmol). After stirring at room temperature for 2.5 h, additional 3-methoxyphenol (128 mg, 1.03 mmol) was added. The mixture was stirred for 24 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with EtOAc and hexane (from 1:4 to 1:1) as eluant. One fraction (151 mg) was collected as a mixture of the product and its imine isomer (2-imino-7-methoxy-4-(5-methyl-pyridin-3-yl)-chroman-3-carbonitrile). A portion of this mixture (25 mg, 0.085 mmol) and several drops of piperidine were refluxed in anhydrous ethanol (5 mL) for 18 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with EtOAc and hexane (1:1) as eluant to yield 13 mg (52%) of the product as a yellow solid. 1H NMR (CDCl3): 8.33 (d, J=1.8 Hz, 1H), 8.29 (d, J=1.8 Hz, 1H), 7.28 (t, J=1.8 Hz, 1H), 6.82 (dd, J=8.4, 0.6 Hz, 1H), 6.63 (dd, J=8.4, 2.7 Hz, 1H), 6.56 (d, J=2.7 Hz, 1H), 4.72 (brs, 2H), 4.69 (s, 1H), 3.79 (s, 3H), 2.30 (d, J=0.6 Hz, 3H).
EXAMPLE 31 2-Amino-3-cyano-7-ethylamino-4-(5-methyl-3-pyridyl)-4H-chromene To a solution of <strong>[100910-66-5]5-methyl-pyridine-3-carbaldehyde</strong> (60 mg, 0.5 mmol) and molanonitrile (33 mg, 0.5 mmol) in anhydrous ethanol (5 mL) was added piperidine (0.1 mL, 1.0 mmol). After stirring at room temperature for 2.5 h, 3-ethylamino-phenol (133 mg, 0.97 mmol) was added. The mixture was stirred for 18 h and then refluxed for 0.5 h. The solvent was evaporated. The residue was purified by chromatography on silica gel with EtOAc and hexane (1:1 and 2:1) as eluant to yield 59 mg (39%) of the product as a light yellow solid. 1H NMR (CDCl3 with drops of CD3OD): 8.25 (dd, J=2.1, 0.6 Hz, 1H), 8.23 (d=2.4 Hz, 1H), 7.29 (m, 1H), 6.65 (dd, J=2.7, 0.6 Hz, 1H), 6.29 (dd, J=8.1, 2.4 Hz, 1H), 6.20 (d, J=2.4 Hz, 1H), 4.86 (s, 2H), 4.61 (s, 1H), 3.10 (q, J=7.2 Hz, 2H), 2.28 (d, J=0.6 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H).
EXAMPLE 55 2-Amino-3-cyano-4-(5-methyl-pyridin-3-yl)-4H-indolo[7,6-b]pyran The title compound was prepared from 7-hydroxyindole and <strong>[100910-66-5]5-methylpyridine-3-carbaldehyde</strong> by a procedure similar to that described in Example 46 in 45% yield. 1H NMR (DMSO-d6): 11.24 (brs, 1H), 8.30 (dd, J=2.1, 13.5 Hz, 2H), 7.36-7.35 (m, 2H), 7.23 (d, J=8.1 Hz, 1H), 6.79 (brs, 2H), 6.57 (d, J=8.4 Hz, 1H), 6.45-6.43 (m, 1H), 4.89 (s, 1H), 2.24 (s, 3H).
With lithium aluminium tetrahydride; In tetrahydrofuran; at -78℃; for 0.5h;
To a solution of N-methoxy-N,5-dimethylnicotinamide (3.0 g, 16.65 mmol) in THF (50 mL) was added LAH (0.76 g, 19.98 mmol) at -78 C, and the resulting mixture was stirred at -78 C for 30 mins. TLC showed the reaction was completed. The reaction was quenched with sat.NH4C1 (100 mL), and the mixture was extracted with EtOAc (100 mL x2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give the desired 5-methylnicotinaldehyde (2.0 g, yield: 99%) as yellow oil.?HNMR (400 MHz, CDC13): = 10.10 (s, 1H), 8.89 (s, 1H), 8.68 (s, 1H), 7.97 (s, 1H), 2.57 (s, 3H).
3-methyl-1-((5-methylpyridin-3-yl)methyl)-1H-pyrazol-5-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
To a solution of compound But-3-enenitrile (1.05 g, 15.74 mmol) in THF (30 mL) was added N2H4.H20 (0.826 g, 16.52 mmol) slowly at 0 C, and the resulting mixture was stirred room temperature for 16 hrs. Then to the reaction mixture was added 5 -methylnicotinaldehyde (2.0 g, 16.52 mmol). After stirring for 2.5 hrs, the reaction mixture was concentrated to dryness in vacuum. To the residue in n-Butanol (30 mL) was added MeONa (0.85 g, 15.74 mmol), and the mixture was heated to 120 C for 16 hrs. The reaction mixture was poured into iN HC1 (50 mL), and the mixture was extracted with EtOAc (100 mL x2). The aqueous layer was basified to pH = 14 and extracted with EtOAc (100 mL x2). The extracts were dried over Na2SO4, filtered and concentrated to give 3-methyl-1-((5-methylpyridin-3-yl)methyl)-1H-pyrazol-5-amine (0.75 g, yield: 24%) as brown oil.
6-fluoro-2-[(5-methylpyridin-3-yl)methyl]-1,2,3,4-tetrahydrobenzo[4,5]thieno[2,3-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.8%
General procedure: To a solution of amine (1.0 equiv) in 1,2-dichloroethane (0.1 M) were added aldehyde (1.2 equiv) and acetic acid (0.5 mL), the reaction mixture stirred at rt for 10 min, followed the addition of sodium triacetoxyborohydride (2.0 equiv). The reaction was stirred at rt under nitrogen for 18 h and concentrated. Sat. NaHCO3 (30 mL) was added and extracted with dichloromethane (20 mL x 3) and the combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica gel eluting with 0-10% methanol/dichloromethane to give the desired product.
2-hydroxy-2-(5-methylpyridin-3-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
To a solution of <strong>[100910-66-5]5-methylnicotinaldehyde</strong> (1 dichloromethane (20 mL) was added trimethylsilanecarbonitrile (1.239 mL, 9.91 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated down to afford a light brown oil. The above crude was treated with concentrated H2SO4 (6 mL, 113 mmol) for 4 hours, then poured the reaction mixture into ice, and adjusted the pH to 9 using NH4OH. The reaction mixture was concentrated down with silica, purified by silica column (CombiFlash, 40 g column using 0-10% MeOH/DCM) to afford 2-hydroxy-2-(5- methylpyridin-3-yl)acetamide (636 mg, 3.83 mmol, 46% yield) as a yellow oil. LCMS m/z = 166.9 [M+H]+.