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

HRID 1499436Notes

Reaction equation

HRID 1499436 reaction equation
[NH2:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1.[NH2:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31]2)=[C:23]2[CH2:29][CH2:28][O:27][C:24]2=[N:25][CH:26]=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>>[NH2:1][C:2]1[C:3]([C:17]([NH:20][C:21]2[C:22]([N:30]3[CH2:35][CH2:34][CH2:33][C@H:32]([NH2:36])[CH2:31]3)=[C:23]3[CH2:29][CH2:28][O:27][C:24]3=[N:25][CH:26]=2)=[O:19])=[N:4][C:5]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])=[C:6]([F:8])[CH:7]=1

Participants

5

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 592265133-Amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acidHCID 86726677tert-Butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate

Product 1

HCID 867266823-Amino-N-{4-[(3S)-3-aminopiperidin-1-yl]-2,3-dihydrofuro[2,3-b]pyridin-5-yl}-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxamideYield 17.1%

Procedure

To a mixture of 3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (15.9 mg, 0.0592 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.8 mg, 0.0592 mmol) and HATU (72.9 mg, 0.192 mmol) DMF (1.50 mL) was added, followed by DIPEA (84.1 mg, 0.651 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue, 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 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (4.9 mg, 17%). LCMS calc. for C24H24F3N6O2 (M+H)+: m/z=485.2. found 485.2. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (br s, 1H), 8.86 (s, 1H), 7.60 (tt, J=8.3, 6.8 Hz, 1H), 7.40 (br s, 2H), 7.26 (t, J=8.2 Hz, 2H), 7.21 (d, J=11.5 Hz, 1H), 4.47 (t, J=9.0 Hz, 2H), 3.34 (t, J=8.5 Hz, 2H), 3.04-2.93 (m, 1H), 2.88-2.78 (m, 1H), 2.69-2.57 (m, 1H), 2.54-2.46 (m, 1H), 2.46-2.37 (m, 1H), 1.50-1.17 (m, 3H), 0.95-0.78 (m, 1H) ppm.

Workup

  1. additionwas added
  2. concentrationconcentrated under reduced pressure
  3. additionDCM (2.0 mL) was added to the residue
  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 0.15% NH4OH, at flow rate of 30 mL/min.)

Sources & evidence

ORD record
ord-58f9b6827d2349fe910f31a0532c88f1
Source dataset
uspto-grants-2015_12
Patent number
US09200004B2

Reaction notes

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