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11.2 Reference Example 11; 4,7-Dichloropyrido [4,3-d]pyrimidine (Compound R11)
Step 2: 4-Amino-6-chloronicotinic acid (7.0 g, 41 mmol) obtained in Step 1 was stirred in thionyl chloride (100 mL) at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, whereby crude 4-amino-6-chloronicotinoyl chloride was obtained. This compound was used in the subsequent reaction without particularly performing further purification.
With thionyl chloride at 80℃; for 12h;
40.B [0753] Step B:
A mixture of 4-amino-6-chloro-pyridine-3-carboxylic acid (630 mg, 3.65 mmol, 1.00 eq) and thionyl chloride (16.4 g, 138 mmol, 10.0 mL, 37.8 eq) was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 4- amino-6-chloro-pyridine-3 -carbonyl chloride (697 mg, crude) was obtained as a yellow solid, which was used into next step directly without further purification.
With sodium hydroxide; In methanol; water; at 20.0℃; for 12.0h;
Step 1: Methyl 4-amino-6-chloronicotinate (15 g, 80 mmol) obtained by the method described in US2012/184562 and sodium hydroxide (13 g, 322 mmol) were stirred in a mixed solution of methanol (100 mL) and water (50 mL) at room temperature for 12 hours. The reaction mixture was adjusted to pH 6 with a 6.0 mol/L aqueous hydrochloric acid solution, and the resulting solid was collected by filtration, whereby 4-amino-6-chloronicotinic acid (8.0 g, yield: 58%) was obtained. 1H-NMR (300 MHz, DMSO-d6, delta): 8.47 (s, 1H), 7.52 (br s, 2H), 6.75 (s, 1H)
Multi-step reaction with 4 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: trimethyl orthoformate / 5 h / 150 °C
4: trichlorophosphate / <i>N</i>,<i>N</i>-dimethyl-aniline / 15 h / Reflux
Multi-step reaction with 4 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
With diazomethyl-trimethyl-silane In hexane; dichloromethane at 20℃; for 2h;
2 2A. Methyl 4-amino-6-chloronicotinate
To a suspension of 4-amino-6-chloronicotinic acid (500 mg, 2.90 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added TMS-diazomethane (2.90 mL, 5.79 mmol, 2.0 M in hexanes). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the resulting grey solid was used in the next step without purification. LC/MS [M+H]+ = 187.0. 1H-NMR (400 MHz, CHLOROFORM-d) d 8.89 (s, 1H), 6.78 (s, 1H), and 3.97 (s, 3H).
Multi-step reaction with 5 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
5: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C
Multi-step reaction with 7 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
5: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C
6: potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 1,4-dioxane / 80 °C / Inert atmosphere
7: dichloromethane / 1 h / 20 °C
Multi-step reaction with 8 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
5: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C
6: potassium carbonate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / 1,4-dioxane / 80 °C / Inert atmosphere
7: dichloromethane / 1 h / 20 °C
8: N-ethyl-N,N-diisopropylamine / dichloromethane; acetonitrile / 0.33 h / 20 °C
Multi-step reaction with 5 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
5: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -40 °C / Molecular sieve
Multi-step reaction with 6 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
5: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -40 °C / Molecular sieve
6: caesium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 5 h / 100 °C / Inert atmosphere
Multi-step reaction with 7 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
5: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -40 °C / Molecular sieve
6: caesium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 5 h / 100 °C / Inert atmosphere
7: hydrogenchloride / acetonitrile; 1,4-dioxane / 0.5 h / 20 °C
Multi-step reaction with 8 steps
1: thionyl chloride / 12 h / 80 °C
2: ammonium hydroxide / 4 h / 20 °C
3: 5 h / 150 °C
4: N-ethyl-N,N-diisopropylamine; trichlorophosphate / 12 h / 120 °C
5: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -40 °C / Molecular sieve
6: caesium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 5 h / 100 °C / Inert atmosphere
7: hydrogenchloride / acetonitrile; 1,4-dioxane / 0.5 h / 20 °C
8: triethylamine / dichloromethane / 1 h / -40 °C
Multi-step reaction with 3 steps
1.1: 2-methoxy-ethanol / 3 h / 150 °C / Microwave irradiation
2.1: 4 h / 70 °C
3.1: trichlorophosphate / chloroform / 1 h / 70 °C / Inert atmosphere
3.2: 4 h / 70 °C / Inert atmosphere
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