Triethylamine → HCID 67298345, compound

HRID 1520371Notes

Reaction equation

HRID 1520371 reaction equation
[F:1][CH:2]([F:28])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1.CCN(CC)CC.[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][N:39]=1>C1COCC1>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:42](=[O:43])[C:41]4[CH:45]=[CH:46][C:38]([O:37][CH3:36])=[N:39][CH:40]=4)[CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 178629506-Methoxypyridine-3-carbonyl chlorideHCID 86677082HCID 86677082, compound

Product 1

HCID 67298345HCID 67298345, compoundYield 18.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 6-methoxynicotinic acid (100 mg, 0.65 mmol) in SOCK, (2 mL) was added DMF (1 drop). The mixture was stirred at 60° C. for 20 min. The volatiles were removed in vacuo to give 6-methoxynicotinoyl chloride, which was used for the next step directly. To a suspension of N4-(3-(difluoromethoxy)phenyl)-2-(pyrazin-2-yl)quinazoline-4,6-diamine (130 mg, 0.34 mmol, 0.5 eq.) in THF (5 mL) and Et3N (101 mg, 1 mmol, 3.0 eq) was added 6-methoxynicotinoyl chloride in anhydrous THF (5 mL) dropwise. The resulting mixture was stirred at room temperature for 18 h. The volatiles were removed in vacuo. The residue was washed with MeOH and re-crystallized from THF/MeOH twice, and purified by reverse phase chromatography PREP-HPLC (A=NH4HCO3—H2O, 10 mmol/L, B=MeOH) to afford 33 mg of N-(4-(3-(difluoromethoxy)phenylamino)-2-(pyrazin-2-yl)quinazolin-6-yl)-6-methoxynicotinamide as a pale yellow solid (18.8%). LCMS m/z=516.1 (M+1), 258.6 (M/2+1) (Method A) (retention time=1.57 min), 1H-NMR (400 MHz, DMSO-(d6): δ 10.71 (s, 1H), 10.18 (s, 1H), 9.57 (d, J=1.6 Hz, 1H), 9.01 (d, J=1.6 Hz, 1H), 8.91 (d, J=2.4 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.34 (dd, J=8.8, 2.8 Hz, 1H), 8.23 (s, 1H), 8.08 (dd, J=8.8, 2.0 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.46-7.50 (m, 1H), 7.32 (t, J=74.4 Hz 1H), 7.02 (d, J=8.8 Hz, 1H), 6.95 (dd, J=8.0, 2.0 Hz, 1H), 3.97 (s, 3H).

Workup

  1. customThe volatiles were removed in vacuo
  2. washThe residue was washed with MeOH
  3. customre-crystallized from THF/MeOH twice
  4. custompurified by reverse phase chromatography PREP-HPLC (A=NH4HCO3—H2O, 10 mmol/L, B=MeOH)

Sources & evidence

ORD record
ord-5c980f04feca43e6a1cd65ce44a443c7
Source dataset
uspto-grants-2015_07
Patent number
US09073890B2

Reaction notes

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