Toluene → 6-(2-Chlorophenyl)-2-methoxy-3-nitropyridin-4-amine

HRID 570282Notes

Reaction equation

HRID 570282 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.C(OCC)(=O)C.O.C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:13])[CH:3]=1

Participants

9

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 27343222-Chlorophenylboronic acidHCID 866574066-Chloro-2-methoxy-3-nitro-4-pyridinamine

Product 1

HCID 674116886-(2-Chlorophenyl)-2-methoxy-3-nitropyridin-4-amine

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
69 °C

Procedure

A 5 L, four neck round bottom flask equipped with mechanical stirrer, water condenser with nitrogen inlet, thermocouple, and stopper was charged with 6-chloro-2-methoxy-3-nitro-4-pyridinamine (125.30 g, 0.615 mol), 2-chlorophenylboronic acid (116.36 g, 0.744 mol), sodium carbonate (164.97 g, 1.54 mol), toluene (1.80 L), water (0.8 L), and ethanol (0.625 L) and the resulting mixture stirred to achieve a red slurry. The slurry was heated to a mild reflux for 15 min to degas solution and then the temperature was lowered to 60° C. The resulting mixture was treated with (1,1′-bis-(di-tert-butylphosphino)ferrocenepalladium(II) chloride (40.8 g, 61 mmol) and the temperature increased to 69° C., generating a mild reflux. The temperature to 60° C. and stirring was continued for 17 h. The resulting mixture was diluted into water (2 L) and ethyl acetate (1 L), then filtered through CELITE, washing with ethyl acetate (1 L). The layers of filtrate were partitioned and the aqueous further extracted with ethyl acetate (3×500 mL). The combined organics were dried (MgSO4) and concentrated to yield a dark oil. The dark oil was dissolved in dichloromethane and slurried with silica gel (325 g). The slurry was loaded onto a BIOTAGE 150M (2.5 kg silica) and eluted with dichloromethane (3 L) and ethyl acetate-dichloromethane 1:19 (9 L). Fractions of suitable purity were concentrated, lastly from heptane (500 mL) to yield the title compound as a residue. The residue (282 g) was triturated with MTBE (0.50 L), heated in water bath at 40° C. for 30 min, transferred to a mechanically stirred 5 L round bottom flask then diluted with heptane (2 L). The resulting slurry was stirred for 1 h at room temperature and the solids collected by filtration. The filter cake washed with MTBE-heptane (1:9, 500 mL) and heptane (500 mL), then dried in vacuum oven at 50° C. for 45 min to yield 6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-amine as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.62 (s, 1H), 4.07 (s, 3H), 6.14 (br. s., 2H), 6.69 (s, 1H), 7.30-7.40 (m, 2H), 7.42-7.52 (m, 1H), 7.59-7.66 (m, 1H)

Workup

  1. customA 5 L, four neck round bottom flask equipped with mechanical stirrer, water condenser with nitrogen inlet
  2. temperatureThe slurry was heated to
  3. temperaturea mild reflux for 15 min
  4. customto degas solution
  5. customwas lowered to 60° C
  6. stirringThe temperature to 60° C. and stirring
  7. filtrationfiltered through CELITE
  8. washwashing with ethyl acetate (1 L)
  9. customThe layers of filtrate were partitioned
  10. extractionthe aqueous further extracted with ethyl acetate (3×500 mL)
  11. dry with materialThe combined organics were dried (MgSO4)
  12. concentrationconcentrated
  13. customto yield a dark oil
  14. washeluted with dichloromethane (3 L) and ethyl acetate-dichloromethane 1:19 (9 L)
  15. concentrationFractions of suitable purity were concentrated, lastly from heptane (500 mL)

Sources & evidence

ORD record
ord-d18242fe03d2497a83407c66aff998f0
Source dataset
uspto-grants-2015_05
Patent number
US09023846B2

Reaction notes

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