Thionyl Chloride → HCID 178457796, compound

HRID 518723Notes

Reaction equation

HRID 518723 reaction equation
[F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[F:39][C:40]1([F:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[F:39][C:40]1([F:46])[CH2:45][CH2:44][N:43]([CH2:30][C:27]2[CH:28]=[CH:29][C:11]3[NH:10]/[C:9](=[N:8]\[C:6](=[O:7])[C:5]4[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=4)/[N:13]([C@H:14]4[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]4)[C:12]=3[CH:26]=2)[CH2:42][CH2:41]1

Participants

5

Reactant 3

HCID 24386Thionyl ChlorideHCID 27583514,4-Difluoropiperidine hydrochlorideHCID 178457799HCID 178457799, compound

Product 1

HCID 178457796HCID 178457796, compoundYield 57.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed, and the residue was resuspended in 2 mL DMSO, cooled to 0° C., and 4,4-difluoropiperidine hydrochloride (348 mg, 2.210 mmol) and TEA (0.308 mL, 2.210 mmol) were added. The reaction was stirred for 30 minutes at 0° C. and then at RT for 16 hours. The reaction was concentrated, and the residue was purified by reverse-phase preparative HPLC, using 0.1% TFA in AC/water (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-N-(6-((4,4-difluoropiperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (71 mg, 57.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 6H), 1.54-1.83 (m, 5H), 1.94-2.18 (m, 7H), 2.53 (br. s., 3H), 2.67-2.86 (m, 2H), 3.64 (s, 2H), 3.94-4.09 (m, 1H), 4.91 (br. s., 1H), 7.13 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.60-7.82 (m, 2H), 8.20-8.43 (m, 2H), 12.75 (br. s., 1H). MS, m/z (C30H36F3N5O2): calcd, 555.3. found, 555.9 [M+H].

Workup

  1. customThe solvent was removed
  2. temperaturecooled to 0° C.
  3. stirringThe reaction was stirred for 30 minutes at 0° C.
  4. waitat RT for 16 hours
  5. concentrationThe reaction was concentrated
  6. customthe residue was purified by reverse-phase preparative HPLC
  7. extractionextracted with EtOAc (×2)
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over anhydrous magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-727516f7defb49cebeab428a4b863811
Source dataset
uspto-grants-2015_08
Patent number
US09115127B2

Reaction notes

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