1,2-Dichloroethane → HCID 178502342, compound

HRID 1429260Notes

Reaction equation

HRID 1429260 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([N:15]2[C@@H:19]([C:20]3[C:21]([F:34])=[CH:22][C:23]4[N:27]=[C:26]([C@@H:28]5[CH2:32][CH2:31][CH2:30][NH:29]5)[NH:25][C:24]=4[CH:33]=3)[CH2:18][CH2:17][C@@H:16]2[C:35]2[C:36]([F:49])=[CH:37][C:38]3[N:42]=[C:41]([C@@H:43]4[CH2:47][CH2:46][CH2:45][NH:44]4)[NH:40][C:39]=3[CH:48]=2)[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:50][O:51][C:52]([NH:54][C@@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])=[O:53].C(Cl)CCl.[CH:66]1[CH:67]=CC2N(O)N=NC=2[CH:71]=1.C[N:77]1[CH2:82][CH2:81][O:80]CC1.C[CH2:84][O:85][C:86](C)=[O:87]>CN(C=O)C>[CH3:84][O:85][C:86](=[O:87])[NH:77][C@@H:82]([CH:66]([CH3:67])[CH3:71])[C:81]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:26]1[NH:27][C:23]2[CH:22]=[C:21]([F:34])[C:20]([C@H:19]3[CH2:18][CH2:17][C@H:16]([C:35]4[C:36]([F:49])=[CH:37][C:38]5[NH:42][C:41]([C@@H:43]6[CH2:47][CH2:46][CH2:45][N:44]6[C:56](=[O:57])[C@@H:55]([NH:54][C:52]([O:51][CH3:50])=[O:53])[CH:59]([CH3:61])[CH3:60])=[N:40][C:39]=5[CH:48]=4)[N:15]3[C:4]3[CH:3]=[C:2]([F:1])[C:7]([N:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)=[C:6]([F:14])[CH:5]=3)=[CH:33][C:24]=2[N:25]=1)=[O:80]

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 8857Ethyl AcetateHCID 757711-HydroxybenzotriazoleHCID 10942966(2S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acidHCID 58226834HCID 58226834, compound

Product 1

HCID 178502342HCID 178502342, compoundYield 46.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 6,6′-{(2R,5R)-1-[3,5-difluoro-4-(piperidin-1-yl)phenyl]pyrrolidine-2,5-diyl}bis{5-fluoro-2-[(2S)-pyrrolidin-2-yl]-1H-benzimidazole} (64 mg, 0.095 mmol) in DMF (2378 μL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (35.0 mg, 0.200 mmol), EDC (45.6 mg, 0.238 mmol), HOBT (36.4 mg, 0.238 mmol) and N-methylmorpholine (105 μL, 0.951 mmol), and the resultant solution was stirred at ambient temperature overnight. The reaction solution was diluted with EtOAc, washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude material was dissolved in 1:1 CH3CN:0.1% TFA/H2O and purified by HPLC (C18, 0-100% CH3CN/0.1% TFA/H2O). The product containing fractions were combined, made basic with saturated sodium bicarbonate solution, and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated to give the title compound (43.3 mg, 0.044 mmol, 46.1% yield). The title compound can also be prepared according to General Procedure 12C described above. 1H NMR (400 MHz, CDCl3) δ ppm 10.25-10.70 (m, 2H) 6.83-7.53 (m, 4H) 5.70-5.91 (m, 2H) 5.20-5.52 (m, 4H) 4.21-4.42 (m, 2H) 3.70 (s, 6H) 3.53-3.94 (m, 6H) 1.75-3.17 (m, 16H) 0.63-1.74 (m, 18H); MS (ESI) m/z 987 (M+H)+.

Workup

  1. washwashed with H2O and brine
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. dissolutionThe crude material was dissolved in 1:1 CH3CN
  6. custom0.1% TFA/H2O and purified by HPLC (C18, 0-100% CH3CN/0.1% TFA/H2O)
  7. additionThe product containing fractions
  8. extractionextracted with EtOAc
  9. dry with materialThe organic layer was dried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-aa89169ff8e1430d9d0933f8337272ce
Source dataset
uspto-grants-2015_01
Patent number
US08937150B2

Reaction notes

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