Thionyl Chloride → HCID 178457795, compound

HRID 518726Notes

Reaction equation

HRID 518726 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:45])[CH2:44][CH2:43][NH:42][CH2:41]1.[H-].[Na+]>C(Cl)Cl.C(#N)C>[F:39][C:40]1([F:45])[CH2:44][CH2:43][N:42]([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:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=4)/[N:13]([C@H:14]4[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]4)[C:12]=3[CH:26]=2)[CH2:41]1

Participants

7

Reactant 4

HCID 24386Thionyl ChlorideHCID 24758Sodium hydrideHCID 249034823,3-Difluoropyrrolidine hydrochlorideHCID 178457799HCID 178457799, compound

Product 1

HCID 178457795HCID 178457795, compoundYield 49.3%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 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 at reduced pressure, and the residue was dried in vacuo for 5 minutes. The residue was resuspended in ACN (1 mL) and cooled to 0° C. A suspension of 3,3-difluoropyrrolidine hydrochloride (317 mg, 2.210 mmol) and sodium hydride (88 mg, 2.210 mmol) in ACN (1 mL) was added, and the reaction was stirred overnight at RT. The solvent was removed at reduced pressure, and the residue was redissolved in 2 mL of MeOH. The residual material was purified by reverse-phase preparative HPLC, using 0.1% TFA in ACN/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-((3,3-difluoropyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (59 mg, 49.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.77 (s, 1H), 8.32 (s, 2H), 7.63 (brs, 2H), 7.50 (d, J=7.3 Hz, 1H), 7.24 (brs, 2H), 7.15, (d, J=8.0 Hz, 1H), 4.87 (brs, 1H), 4.02-4.05 (m, 1H), 3.69 (s, 2H), 2.89 (t, J=13.1 Hz, 2H), 2.71-2.77 (m, 4H), 2.53 (brs, 1H), 2.27 (m, 2H), 2.12-2.15 (m, 2H), 1.62-1.73 (m, 4H), 1.10 (d, J=5.6 Hz, 6H). MS, m/z (C29H34F3N5O2): calcd, 541.3. found, 541.8 [M+H].

Workup

  1. customThe solvent was removed at reduced pressure
  2. customthe residue was dried in vacuo for 5 minutes
  3. temperaturecooled to 0° C
  4. additionwas added
  5. stirringthe reaction was stirred overnight at RT
  6. customThe solvent was removed at reduced pressure
  7. dissolutionthe residue was redissolved in 2 mL of MeOH
  8. customThe residual material was purified by reverse-phase preparative HPLC
  9. extractionextracted with EtOAc (×2)
  10. washThe combined organic layers were washed with brine
  11. dry with materialdried over anhydrous magnesium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-5610a15930464414ab4a249d48c28218
Source dataset
uspto-grants-2015_08
Patent number
US09115127B2

Reaction notes

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