Trifluoroacetic acid → HCID 89995469, compound

HRID 1487324Notes

Reaction equation

HRID 1487324 reaction equation
[C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)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.[CH3:45][N:46]1[CH:50]=[C:49]([C:51]2[N:52]=[C:53]3[C:58]([NH:59][C@H:60]4[C@@H:64]([CH3:65])[CH2:63][NH:62][CH2:61]4)=[C:57]([C:66]([NH2:68])=[O:67])[CH:56]=[N:55][N:54]3[CH:69]=2)[CH:48]=[N:47]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1([C:6]([N:62]2[CH2:63][C@H:64]([CH3:65])[C@H:60]([NH:59][C:58]3[C:53]4[N:54]([CH:69]=[C:51]([C:49]5[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=5)[N:52]=4)[N:55]=[CH:56][C:57]=3[C:66]([NH2:68])=[O:67])[CH2:61]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]

Participants

7

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 27332591-Cyanocyclopropanecarboxylic acidHCID 89995478HCID 89995478, compound

Product 1

HCID 89995469HCID 89995469, compoundYield 59.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of cyanocyclopropanecarboxylic acid (3.67 mg, 0.033 mmol) in DCM (330 μl) were added DIEA (14.41 μl, 0.083 mmol) and BOP (17.52 mg, 0.040 mmol). The solution was stirred at room temperature for 10 minutes. 2-(1-Methyl-1H-pyrazol-4-yl)-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, TFA (15 mg, 0.033 mmol) was added. The reaction mixture was stirred at room temperature for another 30 min and concentrated to give an orange oil. The oil was partitioned between ethyl acetate and water. The organic layer was washed with (sat.) sodium chloride, dried with sodium sulfate, filtered and concentrated. The crude product was purified via preparative LCMS (prep. LCMS Method A) to afford 8-(((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide (8.5 mg, 0.020 mmol, 59.4% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-d6, 2 rotamers) δ 10.74 (d, J=8.4 Hz, 1H), 10.69 (d, J=8.9 Hz, 1H), 8.48 (br. s., 1H), 8.47 (br. s., 1H), 8.28 (s, 1H), 8.27 (s, 1H), 8.12 (s, 2H), 8.01 (br. s., 2H), 7.88 (s, 1H), 7.87 (s, 1H), 7.41 (br. s., 2H), 6.00-5.88 (m, 1H), 5.82 (d, J=5.9 Hz, 1H), 4.25 (dd, J=10.9, 5.0 Hz, 1H), 4.13 (dd, J=10.2, 7.7 Hz, 2H), 3.92 (d, J=3.5 Hz, 1H), 3.88 (s, 6H), 3.79 (dd, J=12.6, 5.2 Hz, 1H), 3.69 (dd, J=12.1, 7.7 Hz, 1H), 3.58 (s, 1H), 3.54-3.50 (m, 1H), 2.80-2.74 (m, 1H), 2.72-2.65 (m, 1H), 1.64-1.52 (m, 6H), 1.50-1.45 (m, 1H), 1.39-1.34 (m, 1H), 1.08 (d, J=6.9 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H). HPLC/LCMS (Method F): m/z 434.10 ([M+H]+), Rt. 1.066 min.

Workup

  1. stirringThe reaction mixture was stirred at room temperature for another 30 min
  2. concentrationconcentrated
  3. customto give an orange oil
  4. customThe oil was partitioned between ethyl acetate and water
  5. washThe organic layer was washed with (sat.) sodium chloride
  6. dry with materialdried with sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified via preparative LCMS (prep. LCMS Method A)

Sources & evidence

ORD record
ord-be4289f81f2949e7b3ba69808dda4fc4
Source dataset
uspto-grants-2016_08
Patent number
US09428511B2

Reaction notes

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