Diisopropylethylamine → 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate

HRID 2046416Notes

Reaction equation

HRID 2046416 reaction equation
[F:1][CH:2]([F:20])[C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]2[N:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Cl-].[CH:58]1[C:70]2[CH:69]([CH2:71][O:72][C:73]([NH:75][C@@H:76]3[C@@H:81]([NH3+:82])[C:80]([F:84])([F:83])[CH2:79][CH2:78][CH2:77]3)=[O:74])[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]=2[CH:61]=[CH:60][CH:59]=1>CN(C=O)C.O>[CH:58]1[C:70]2[CH:69]([CH2:71][O:72][C:73](=[O:74])[NH:75][C@H:76]3[CH2:77][CH2:78][CH2:79][C:80]([F:84])([F:83])[C@@H:81]3[NH:82][C:8]([C:6]3[S:7][C:3]([CH:2]([F:1])[F:20])=[C:4]([C:11]4[N:15]5[N:16]=[CH:17][CH:18]=[CH:19][C:14]5=[N:13][CH:12]=4)[CH:5]=3)=[O:10])[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]=2[CH:61]=[CH:60][CH:59]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 580464235-(Difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylic acidHCID 67123027(1R,6S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-difluorocyclohexanaminium chloride

Product 1

HCID 671453369H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To 5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylic acid (26 mg, 0.088 mmol) in DMF (0.4 mL) were added BOP (58 mg, 0.13 mmol) and DIEA (0.062 mL, 0.35 mmol). The mixture was left to stir for 5 min, treated with (1R,6S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-difluorocyclohexanaminium chloride (36 mg, 0.088 mmol), and left to stir for 2 h. The mixture was diluted with water and extracted with EtOAc (×3). The combined organics were dried (sodium sulfate), concentrated, and purified by flash chromatography to afford 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate. LRMS (APCI) calc'd for (C33H28F4N5O3S) [M+H]+, 650.2. found 650.2.

Workup

  1. waitThe mixture was left
  2. waitleft
  3. stirringto stir for 2 h
  4. extractionextracted with EtOAc (×3)
  5. dry with materialThe combined organics were dried (sodium sulfate)
  6. concentrationconcentrated
  7. custompurified by flash chromatography

Sources & evidence

ORD record
ord-9bc9c21daf714ee697e5e9dc7fc970fa
Source dataset
uspto-grants-2013_11
Patent number
US08592425B2

Reaction notes

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