Diisopropylethylamine → HCID 178462172, compound

HRID 1943406Notes

Reaction equation

HRID 1943406 reaction equation
[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.C(OC([NH:51][C@H:52]([CH3:56])[C:53](O)=[O:54])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:51][C@@H:52]([C:53]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1)=[O:54])[CH3:56]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 637606BOC-D-alanineHCID 178511624HCID 178511624, compound

Product 1

HCID 178462172HCID 178462172, compoundYield 26.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-(pyridin-2-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (0.020 g, 0.043 mmol) in DMF (1 mL) at room temperature was added DIEA (0.038 mL, 0.217 mmol), (R)-2-(tert-butoxycarbonylamino)propanoic acid (0.016 g, 0.087 mmol), and BOP (0.058 g, 0.130 mmol). The resulting clear, colorless solution was stirred at room temperature for 30 minutes. Volatiles were removed in vacuo and the crude material was suspended in dichloromethane (0.5 mL) and TFA (0.5 mL). The resulting suspension was stirred vigorously at room temperature for 1.5 h. Volatiles were removed via a stream of nitrogen, and the crude material was diluted with 1 mL MeOH and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=49.547 min. 6-((trans-4-(D-alanylamino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (0.006 g, 18.20% yield) was obtained as a white solid. LC/MS, m/z 533.2 (M+1). HPLC Rt=3.616 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.27 (1H, d, J=1.76 Hz), 9.85 (1H, s), 8.67 (1H, d, J=2.77 Hz), 8.48-8.55 (1H, m), 8.44 (1H, d, J=5.54 Hz), 8.34 (1H, dd, J=4.91, 1.38 Hz), 8.28 (1H, d, J=7.55 Hz), 8.13 (1H, s), 8.04 (2H, d, J=4.53 Hz), 7.98 (1H, s), 7.71-7.78 (1H, m), 7.51 (1H, d, J=8.31 Hz), 7.28 (1H, d, J=8.31 Hz), 7.02 (1H, dd, J=7.05, 5.79 Hz), 3.87 (1H, s), 3.73-3.81 (1H, m), 3.58 (1H, s), 2.07 (2H, d, J=3.78 Hz), 1.86 (2H, s), 1.34 (3H, d, J=6.80 Hz), 1.28-1.44 (4H, m).

Workup

  1. customVolatiles were removed in vacuo
  2. stirringThe resulting suspension was stirred vigorously at room temperature for 1.5 h
  3. customVolatiles were removed via a stream of nitrogen
  4. additionthe crude material was diluted with 1 mL MeOH
  5. custompurified via preparatory HPLC
  6. customB=100, gradient time 60 min, flow rate 25 mL/min

Sources & evidence

ORD record
ord-8035ed02f64440a7bc0c4a33b7a07fcf
Source dataset
uspto-grants-2013_03
Patent number
US08389527B2

Reaction notes

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