Diisopropylethylamine → Tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate

HRID 476381Notes

Reaction equation

HRID 476381 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:43][CH:42]([C:44](O)=[O:45])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:14]1[CH:13]=[C:12]([NH:16][C:17]([C:19]2([C:22](=[O:23])[NH:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[C:11]([F:32])=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:44]([CH:42]2[CH2:43][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41]2)=[O:45])[CH:7]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 27559811-Boc-Azetidine-3-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59596940N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 66604062Tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylateYield 40%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (440 mg, 1 mmol) (as prepared in Example 9) and 1-(tert-butoxycarbonyl) azetidine-3-carboxylic acid (402 mg, 2 mmol) in DMF (5 mL) was added HATU (1.1 g, 3 mmol), followed by DIEA (516 mg, 4 mmol). The mixture was sparged with nitrogen and then stirred 50° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column on a silica gel chromatography to give tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate (250 mg, 40% yield). 1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 10.72 (s, 1H), 9.79 (s, 1H), 8.19 (d, J=5.6 Hz, 1H), 8.10-8.05 (m, 1H), 7.66 (s, 1H), 7.58-7.53 (m, 3H), 7.14 (t, J=8.8 Hz, 2H), 6.77-6.75 (m, 1H), 3.90-3.84 (m, 4H), 3.55-5.53 (m, 1H), 1.63-1.53 (m, 4H), 1.33 (s, 9H).

Workup

  1. customThe mixture was sparged with nitrogen
  2. customThe reaction mixture was partitioned between ethyl acetate and water
  3. washThe organic layer was washed with brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by column on a silica gel chromatography

Sources & evidence

ORD record
ord-02898cd15b414fa6a946871fde656203
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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