1,2-Dichloroethane → HCID 58790126, compound

HRID 418604Notes

Reaction equation

HRID 418604 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:20])[CH2:16][C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[F:31][C:32]1[CH:33]=[C:34]([NH2:54])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12.C(Cl)CCl>>[F:31][C:32]1[CH:33]=[C:34]([NH:54][C:17](=[O:19])[CH2:16][C:15]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:20])[CH:35]=[CH:36][C:37]=1[O:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]2[CH:45]=[C:46]([C:48]3[N:49]([CH3:53])[CH:50]=[CH:51][N:52]=3)[S:47][C:40]=12

Participants

5

Reactant 4

HCID 111,2-Dichloroethane3×HCID 757711-HydroxybenzotriazoleHCID 58790332HCID 58790332, compound3×HCID 594244803-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine

Product 1

HCID 58790126HCID 58790126, compoundYield 13%

Procedure

To a solution of acid 42 (76 mg, 0.266 mmol) and HOBt (40 mg, 0.30 mmol) was added amine 9 (100 mg, 0.29 mmol) and the mixture was stirred at room temperature for 5 min. EDC (62 mg, 0.32 mmol) was added and combined mixture was stirred for additional 48 hours. Additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stirred for a further 24 hours. Again additional 42 (38 mg, 0.133 mmol) and EDC (31 mg, 0.16 mmol) were added and the reaction mixture was stirred for 24 hours more then partitioned between EtOAc and NaHCO3 solution. The organic phase was washed with brine, dried over anhydrous Na2SO4 then filtered and concentrated. The residue was purified by preparative HPLC to afford tert-butyl 4-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-3-oxopropanamido)piperidine-1-carboxylate 42a (20 mg, 13% yield) as a white solid. This material was dissolved in a solution of TFA/DCM (1 mL/2 mL), stirred for 20 min and concentrated. The residue was purified by preparative HPLC (column Aquasil C-18, gradient, MeOH 60% to MeOH 95% in water) to afford the title compound 43 as a tris-trifluoroacetate salt (31 mg, 99%), white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 8.55 (d, 1H), 8.49 (bs, 1H), 8.27 (d, 1H), 8.00 (s, 1H), 7.86 (dd, 1H), 7.55 (s, 1H), 7.49 (t, 1H), 7.39 (dd, 2H), 7.26 (s, 1H), 6.74 (d, 2H), 4.00 (s, 2H), 3.83 (m, 1H), 3.24 (m, 2H), 3.00 (m, 2H), 1.92 (m, 2H), 1.56 (m, 2H). MS (m/z): 509.1 (M+H).

Workup

  1. stirringwas stirred for additional 48 hours
  2. stirringthe reaction mixture was stirred for a further 24 hours
  3. stirringthe reaction mixture was stirred for 24 hours more
  4. custompartitioned between EtOAc and NaHCO3 solution
  5. washThe organic phase was washed with brine
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationthen filtered
  8. concentrationconcentrated
  9. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-95b9420506584454bf7f73afd79cbdf7
Source dataset
uspto-grants-2012_01
Patent number
US08093264B2

Reaction notes

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