Sodium hydride → Tert-butyl 3-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methoxy)azetidine-1-carboxylate

HRID 1400931Notes

Reaction equation

HRID 1400931 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CS(O[CH2:20][C:21]1[CH:22]=[N:23][C:24]([C:27]2[S:35][C:34]3[C:29](=[N:30][CH:31]=[CH:32][C:33]=3[O:36][C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][CH:47]4[CH2:49][CH2:48]4)=[O:45])=[CH:39][C:38]=3[F:50])[CH:28]=2)=[CH:25][CH:26]=1)(=O)=O>CN(C=O)C>[CH:47]1([NH:46][C:44](=[O:45])[NH:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][C:33]3[CH:32]=[CH:31][N:30]=[C:29]4[CH:28]=[C:27]([C:24]5[N:23]=[CH:22][C:21]([CH2:20][O:14][CH:12]6[CH2:13][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]6)=[CH:26][CH:25]=5)[S:35][C:34]=34)=[C:38]([F:50])[CH:39]=2)[CH2:49][CH2:48]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 2756801Tert-butyl 3-hydroxyazetidine-1-carboxylateHCID 86658601(6-(7-(4-(3-Cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl methanesulfonate

Product 1

HCID 67443636Tert-butyl 3-((6-(7-(4-(3-cyclopropylureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methoxy)azetidine-1-carboxylateYield 32%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

To a stirred suspension of NaH (271 mg, 60% dispersion in mineral oil, 6.72 mmol) in DMF (2 mL) at 0° C. was added tert-butyl-3-hydroxyazetidine-1-carboxylate (1.0 g, 5.65 mmol). After 30 min, a solution of 403 (1.13 mmol) in DMF (6 mL) and KI (183 mg, 1.13 mmol) were added at 0° C. The reaction mixture was heated to 80° C. for 30 min. The reaction was then quenched by addition of water and the mixture was extracted with AcOEt/MeOH. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified via Biotage [linear gradient 0-10%, (methanol/dichloromethane: SiliaFlash 25 g cartridge]. Title compound 404 was obtained as a beige solid (221 mg, 32% yield for 2 steps). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.57 (brd, 1H), 4.53 (s, 2H), 4.42-4.36 (m, 1H), 4.09-4.00 (m, 2H), 3.77-3.68 (m, 2H), 2.59-2.50 (m, 1H), 1.37 (s, 9H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 606.48 (M+H).

Workup

  1. customThe reaction was then quenched by addition of water
  2. extractionthe mixture was extracted with AcOEt/MeOH
  3. washThe organic phase was washed with brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified via Biotage [linear gradient 0-10%

Sources & evidence

ORD record
ord-b077314055af4ac6a5fbb1627c78b385
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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