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With hydrogenchloride; tin(ll) chloride; In water; at 60℃; for 18h;
Aq. conc. HCl (1 ml, 32.9 mmol) was diluted with water. To the solution was added tin (II) chloride (0.448 g, 2.365 mmol), followed by 2-methoxy-5-nitropyridin-4-amine (0.1 g, 0.591 mmol). The mixture was heated to 60 C. for 18 h. The reaction mixture was cooled to room temperature, then basified using 10% NaOH solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was triturated with 10% ethyl acetate in Pet-ether to afford 6-methoxypyridine-3,4-diamine (0.06 g, 0.366 mmol, 62.0% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): delta ppm 7.21 (s, 1H), 5.83 (s, 1H), 5.39 (b s, 2H), 4.04 (b s, 2H), 3.62 (s, 3H).
With hydrogen;palladium 10% on activated carbon; In ethanol; for 12h;
A solution of 15.51 g of 2-methoxy-5-nitropyridin-4-amine (example E7) in 1.55 l methanol is treated with 4.65 g Pd/C (10% Pd) and hydrogenated for 12 h under atmospheric pressure. The reaction mixture is filtered through a plug of celite and the filtrate is concentrated under vacuum. The resulting residue is treated with 181 ml formic acid and the mixture is refluxed for 50 h. The formic acid is distilled off and the residue is repeatedly purified by flash chromatography (neutral alumina oxide, ethyl acetate / methanol) to yield the title compound. 1H NMR (200 MHz, D6-DMSO): delta = 3.87 (s, 3H), 6.85 (d, J = 0.9 Hz, 1H), 8.24 (s, 1 H), 8.54 (d, J = 0.9Hz, 1 H), 12.5 (bs, 1 H). MS (MH+ found) = 150.1
Representative compounds of the present invention are: ... 5-bromo-4-methyl-2,3-pyridinediamine; 5-(trifluoromethyl-2,3-pyridinediamine; 6-bromo-4-methyl-2,3-pyridinediamine; 5-bromo-6-methyl-2,3-pyridinediamine; 6-methoxy-3,4-pyridinediamine; 2-methoxy-3,4-pyridinediamine; 5-methyl-3,4-pyridinediamine; 5-methoxy-3,4-pyridinediamine; ...
6
[ 924-44-7 ]
[ 127356-26-7 ]
6-methoxypyrido[2,3-b]pyrazin-2(1H)-one[ No CAS ]
[ 917344-37-7 ]
Yield
Reaction Conditions
Operation in experiment
In methanol; at 20℃;
Intermediate 204: 6-Methoxypyridor2,3-&lpyrazin-3(4H)-one To a solution of <strong>[127356-26-7]3,4-diamino-6-methoxypyridine</strong> (1.11 g) in methanol (20 niL) was added ethylglyoxalate (3.5 mL). After stirring overnight at room temperature, it was filtered and washed with methanol (the precipitate contained the undesired regioisomer, 6- methoxypyrido[2,3-delta]pyrazin-2(lH)-one). The filtrate was concentrated and suspended in diethyl ether to give 0.18 g product.MS (ESI) 178 (MH+) for C8H7N3O2 1H NMR (DMSO-DO) delta 6.77 (d, IH); 8.01 (s, IH); 8.07 (d, IH); 12.83 (s, IH).
Step 3: Synthesis of 6-methoxypyridine-3,4-diamine Aq. conc. HCl (1 ml, 32.9 mmol) was diluted with water. To the solution was added tin (II) chloride (0.448 g, 2.365 mmol), followed by 2-methoxy-5-nitropyridin-4-amine (0.1 g, 0.591 mmol). The mixture was heated to 60 C. for 18 h. The reaction mixture was cooled to room temperature, then basified using 10% NaOH solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude compound was triturated with 10% ethyl acetate in Pet-ether to afford 6-methoxypyridine-3,4-diamine (0.06 g, 0.366 mmol, 62.0% yield) as a solid. 1H NMR (400 MHz, DMSO-d6): delta ppm 7.21 (s, 1H), 5.83 (s, 1H), 5.39 (b s, 2H), 4.04 (b s, 2H), 3.62 (s, 3H).
Step 4: Synthesis of 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol To a solution of <strong>[127356-26-7]6-methoxypyridine-3,4-diamine</strong> (0.45 g, 3.23 mmol) in ethanol was added ethyl trifluoropyruvate (0.393 mL, 3.23 mmol). The reaction mixture was heated to reflux at 90 C. for 16 h. The volatiles were removed under reduced pressure. To the residue was added Pet-ether. The resultant solid was isolated via filtration and dried to afford 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol as mixture of regioisomer (0.37 g 46% yield). MS: MS m/z 246.2 (M++1).
In ethanol; at 90℃; for 16h;
To a solution of <strong>[127356-26-7]6-methoxypyridine-3,4-diamine</strong> (0.45 g, 3.23 mmol) in ethanol was added ethyl trifluoropyruvate (0.393 mL, 3.23 mmol). The reaction mixture was heated to reflux at 90 C. for 16 h. The volatiles were removed under reduced pressure. To the residue was added Pet-ether. The resultant solid was isolated via filtration and dried to afford 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol as mixture of regioisomer (0.37 g 46% yield). MS: MS m/z 246.2 (M++1).
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-yl)oxy)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a, 14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate[ No CAS ]
tert-butyl ((2R,6S,7R,9R,13aS,14aR,16aS,Z)-7-ethyl-2-((2-hydroxy-7-methoxypyrido[3,4-b]pyrazin-3-yl)oxy)-9-methyl-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate[ No CAS ]
To a solution of <strong>[127356-26-7]6-methoxypyridine-3,4-diamine</strong> (0.45 g, 3.23 mmol) in ethanol was added ethyl trifluoropyruvate (0.393 mL, 3.23 mmol). The reaction mixture was heated to reflux at 90 C. for 16 h. The volatiles were removed under reduced pressure. To the residue was added Pet-ether. The resultant solid was isolated via filtration and dried to afford 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol as mixture of regioisomer (0.37 g 46% yield). MS: MS m/z 246.2 (M++1).; A solution of 7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazin-2-ol and 7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-3-ol (0.37 g, 1.509 mmol) in POCl3 (5 mL) was heated to 100 C. for 2 h. The solvent was removed under reduced pressure and the residue was diluted with ice cold water. The aqueous solution was basified to pH ?9.0 by using sodium bicarbonate, then was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography using 10% ethyl acetate in Pet-ether to get 2-chloro-7-methoxy-3-(trifluoromethyl)pyrido[3,4-b]pyrazine (0.135 g, 0.435 mmol, 28.8% yield) and 3-chloro-7-methoxy-2-(trifluoromethyl)pyrido[3,4-b]pyrazine (0.035 g, 0.435 mmol, 4.8% yield) as yellow solids.
(R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid[ No CAS ]
[ 127356-26-7 ]
(R)-N-(4-amino-6-methoxypyridin-3-yl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
The compound (R)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propionic acid 28c (301 mg, 1 mmol) was dissolved in dichloromethane (10 ml), cooled to 0 C, Then oxalyl chloride (254 mg, 2 mmol) and N,N'-dimethylformamide (0.025 ml) were added in that order. After stirring at room temperature for 1 hour, The solvent was removed under reduced pressure. The residue was added to a mixture of 2-amino-4-chloroaniline (208 mg, 1.5 mmol), diisopropylethylamine (258 mg, 2 mmol) and THF. After stirring for 1 hour, The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1), To give the object product (R)-N-(4-amino-6-methoxypyridin-3-yl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide 32a (150mg , white solid), yield: 35%.
2-(4-(6-fluoroquinolin-4-yl)-cyclohexyl)acetic acid[ No CAS ]
[ 127356-26-7 ]
N-(4-amino-6-methoxypyridin-3-yl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 5h;
The compound <strong>[127356-26-7]6-methoxypyridine-3,4-diamine</strong> 10a (58.4 mg, 0.42 mmol), 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetic acid 3 g (100 mg, 0.35 mmol), Diisopropylethylamine (90.3 mg, 0.7 mmol) and N,N-dimethylformamide (5 ml) were mixed, followed by 2-(7-azabenzotriazole)-N,N,N ', N'-tetramethyluronium hexafluorophosphate (198 mg, 0.52 mmol) and stirred at room temperature for 5 hours. The reaction mixture was quenched with water, extracted with ethyl acetate (100ml × 2).After the organic phases are combined, the solvent is removed under reduced pressure.The residue was purified by silica gel column chromatography(dichloromethane/methanol = 100/1 to 10/1), To give the desired product N-(4-amino-6-methoxypyridin-3-yl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide 10b (102 mg, brown solid), yield: 72%.
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