Diisopropylethylamine → N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamide

HRID 1499625Notes

Reaction equation

HRID 1499625 reaction equation
[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:12]=1[F:20].[NH2:21][C:22]1[C:23]([N:31]2[CH2:36][C@H:35]([CH3:37])[CH2:34][C@H:33]([NH:38]C(=O)OC(C)(C)C)[CH2:32]2)=[C:24]2[CH2:30][CH2:29][O:28][C:25]2=[N:26][CH:27]=1.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>[NH2:38][C@H:33]1[CH2:34][C@@H:35]([CH3:37])[CH2:36][N:31]([C:23]2[C:22]([NH:21][C:17]([C:15]3[CH:14]=[CH:13][C:12]([F:20])=[C:11]([C:3]4[C:4]([F:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[F:1])[N:16]=3)=[O:19])=[CH:27][N:26]=[C:25]3[O:28][CH2:29][CH2:30][C:24]=23)[CH2:32]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 592265336-(2,6-Difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acidHCID 86726720tert-Butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate

Product 1

HCID 86726843N-{4-[(3S,5R)-3-Amino-5-methylpiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxamideYield 29.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a mixture of 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (232 mg, 0.492 mmol), tert-butyl [(3S,5R)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (152 mg, 0.436 mmol), and HATU (513 mg, 1.35 mmol) in DMF (3.0 mL), DIPEA (298 mg, 2.30 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. To the resulting residue, DCM (2.0 mL) was added followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (65.9 mg, 29%) LCMS calc. for C26H27F3N5O3 (M+H)+: m/z=514.2. found 514.0. 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.90 (s, 1H), 8.34 (dd, J=8.7, 4.0 Hz, 1H), 8.20 (t, J=8.8 Hz, 1H), 7.50-7.41 (m, 1H), 7.33-7.26 (m, 1H), 4.55-4.43 (m, 2H), 3.93 (s, 3H), 3.35 (t, J=8.5 Hz, 2H), 3.05-2.95 (m, 1H), 2.90-2.82 (m, 1H), 2.64-2.54 (m, 1H), 2.39 (t, J=10.4 Hz, 1H), 2.26 (t, J=11.2 Hz, 1H), 1.64-1.51 (m, 1H), 1.41-1.17 (m, 3H), 0.64-0.55 (m, 4H) ppm.

Workup

  1. additionwas added
  2. concentrationconcentrated under reduced pressure
  3. additionTo the resulting residue, DCM (2.0 mL) was added
  4. stirringThe mixture was stirred at room temperature for 30 min.
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting residue was purified
  7. washeluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.)

Sources & evidence

ORD record
ord-4f21aac5df874874b887686a3954df92
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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