Pyridine → 1-(4-Chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea hydrochloride

HRID 1430511Notes

Reaction equation

HRID 1430511 reaction equation
[NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[C:36]([N:38]=[C:39]=[O:40])[CH:35]=[C:34]([F:41])[CH:33]=1>C(Cl)Cl>[ClH:23].[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:39]([NH:38][C:36]2[CH:35]=[C:34]([F:41])[CH:33]=[C:32]([F:31])[CH:37]=2)=[O:40])=[C:3]([F:24])[CH:4]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 27792821,3-Difluoro-5-isocyanatobenzeneHCID 690386333-(5-Amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1h)-one

Product 1

HCID 896061211-(4-Chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea hydrochlorideYield 47.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A 0° C. solution of Example A5 (200 mg, 0.58 mmol) and pyridine (91 mg, 1.16 mmol) in DCM (4 mL) was treated drop-wise with 1,3-difluoro-5-isocyanato-benzene (98 mg, 0.64 mmol) and stirred at RT overnight as the cooling bath expired. The mixture was concentrated to dryness and purified by prep-HPLC. The resulting solution was treated with HCl (1 mL) and lyophilized to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea hydrochloride (74 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 8.14 (b s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.57 (d, J=11.2 Hz, 1H), 7.16-7.12 (m, 2H), 6.78 (t, J=8.8 Hz, 1H), 6.57 (s, 1H), 4.16-4.13 (m, 2H), 2.96 (s, 3H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 502.3 [M+H]+.

Workup

  1. concentrationThe mixture was concentrated to dryness
  2. custompurified by prep-HPLC
  3. additionThe resulting solution was treated with HCl (1 mL)

Sources & evidence

ORD record
ord-a497ce4a5ff748ffb989bd886d3e2d15
Source dataset
uspto-grants-2015_01
Patent number
US08940756B2

Reaction notes

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