Diisopropylethylamine → HCID 58790289, compound

HRID 418598Notes

Reaction equation

HRID 418598 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.Cl[C:26](=[O:43])[CH2:27][C:28]([NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)=[O:29].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>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:26](=[O:43])[CH2:27][C:28]([NH:30][CH:31]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32]2)=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 594244803-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamineHCID 86609851HCID 86609851, compound

Product 1

HCID 58790289HCID 58790289, compoundYield 21.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of the amine 9 (80 mg, 0.235 mmol), acid 35 (64 mg, 0.235 mmol) and BOP (114.6 mg, 0.254 mmol) in DMF (2.4 mL) was added DIPEA (0.164 mL, 0.941 mmol) and the mixture stirred 2 h at room temperature. EtOAc (100 mL) and water (50 mL) were added and the mixture was filtered through a paper filter. The organic phase was collected, washed with water (50 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent EtOAc/MeOH 7:1) giving tert-butyl 3-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-3-oxopropanamido)pyrrolidine-1-carboxylate (35a, 29.7 mg, 21% yield) as a glassy solid. MS (m/z): 595.1 (M+H). This material was dissolved in a solution of TFA (0.5 mL) and DCM (0.5 mL) and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was lyophilized. The resultant solid was purified by preparative HPLC (Aquasil C-18 column, gradient: MeOH 60% to MeOH 95% in water) to afford the title compound 36 as tris-trifluoroacetate salt (13.9 mg, 35%), creamy fluffy solid. 1H NMR (DMSO-d6) δ (ppm): 10.51 (s, 1H), 8.81 (bs, 1H), 8.72 (bs, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.47 (d, J=6.3 Hz, 1H), 7.86 (m, 1H), 7.58 (s, 1H), 7.50 (t, J=9.0 Hz, 1H), 7.40 (m, 1H), 7.31 (s, 1H), 6.76 (d, J=5.4 Hz, 1H), 4.29 (m, 1H), 3.82 (s, 3H), 3.40 (m, 1H), 3.36-3.20 (m, 4H), 2.99 (m, 1H), 2.16 (m, 1H), 1.85 (m, 1H). MS (m/z): 495.2 (M+H).

Workup

  1. filtrationthe mixture was filtered through a paper
  2. filtrationfilter
  3. customThe organic phase was collected
  4. washwashed with water (50 mL), brine (20 mL)
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by flash chromatography (eluent EtOAc/MeOH 7:1)

Sources & evidence

ORD record
ord-09c9e61d8feb4d21ab209478aebc8c2a
Source dataset
uspto-grants-2012_01
Patent number
US08093264B2

Reaction notes

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