Pyridine → 1-Cyclopropyl-3-(3-fluoro-4-(2-(5-(2-(2-oxopyrrolidin-1-yl)ethyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)urea

HRID 1400909Notes

Reaction equation

HRID 1400909 reaction equation
[NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=C[CH:34]=1.ClC(OC1C=CC=CC=1)=[O:41].C1(N)CC1>CN(C=O)C>[CH:38]1([NH:33][C:34]([NH:1][C:2]2[CH:31]=[CH:30][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]6[CH2:28][CH2:27][CH2:26][C:25]6=[O:29])=[CH:20][N:21]=5)[S:15][C:8]=34)=[C:4]([F:32])[CH:3]=2)=[O:41])[CH2:36][CH2:37]1

Participants

6

Reactant 4

HCID 1049PyridineHCID 15891Phenyl chloroformateHCID 69828CyclopropylamineHCID 584747051-(2-(6-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)ethyl)pyrrolidin-2-one

Product 1

HCID 674418341-Cyclopropyl-3-(3-fluoro-4-(2-(5-(2-(2-oxopyrrolidin-1-yl)ethyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)ureaYield 54%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 294 (0.33 g, 0.74 mmol) and pyridine (0.13 mL, 1.6 mmol) in DMF (15 mL) at 0° C. was added phenyl chloroformate (0.12 mL, 0.96 mmol). The reaction mixture was stirred for 15 min then cyclopropylamine (2.0 mL, 28 mmol) was added. The mixture was warmed to RT, stirred for an additional 18 h and partitioned between water and ethyl acetate. The organic phase was collected, washed with water, 1M NaOH, and brine, dried (anhydrous MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (20% methanol/ethyl acetate) to afford title compound 295 (0.21 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H); 8.52-8.50 (m, 2H); 8.31 (s, 1H); 8.20 (d, J=8.2, 1H): 7.82 (dd, J=8.2, 2.2, 1H); 7.73 (dd, J=13.5, 2.5, 1H); 7.38 (t, J=9.0, 1H); 7.22-7.18 (m, 1H); 6.64 (d, J=5.5, 1H); 6.59 (d, J=2.5, 1H); 3.48 (t, J=7.0, 2H); 3.35 (t?, obscured by water peak), 2.85 (t, J=6.8, 2H); 2.58-2.52 (m, 1H); 2.16 (t. J=7.8, 2H); 1.89 (quintet, J=7.4, 2H); 0.68-0.63 (m, 2H); 0.45-0.41 (m, 2H). MS: (calc.) 531.17 (found) 532.4 (MH)+

Workup

  1. stirringstirred for an additional 18 h
  2. custompartitioned between water and ethyl acetate
  3. customThe organic phase was collected
  4. washwashed with water, 1M NaOH, and brine
  5. dry with materialdried (anhydrous MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by silica gel chromatography (20% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-84fb75bfb4bf4ca4a5d8c99f5b37cd45
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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