Thionyl Chloride → HCID 178457791, compound

HRID 518720Notes

Reaction equation

HRID 518720 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.[NH:39]1[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[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][N:39]4[CH2:43][CH2:42][CH:41]([C:44]([OH:47])([CH3:46])[CH3:45])[CH2:40]4)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 24386Thionyl ChlorideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 66728489a,a-Dimethyl-3-pyrrolidinemethanol HClHCID 178457799HCID 178457799, compound

Product 1

HCID 178457791HCID 178457791, compoundYield 52.2%

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 (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 suspended in ACN (2 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (2 mL), cooled to 0° C., and 2-(pyrrolidin-3-yl)propan-2-ol hydrochloride (110 mg, 0.663 mmol) and TEA (0.154 mL, 1.105 mmol) were added. The reaction was stirred for 16 hours at RT, followed by 4 hours at 50° C. and 6 hours at 80° C. The reaction was cooled to RT, DBU (0.17 mL, 1.105 mmol) was added, and the reaction was stirred overnight at 40° C. The reaction was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM, to provide (E)-4-fluoro-N-(6-((3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a light-yellow powder (65 mg, 52.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.11 (d, J=6.7 Hz, 6H), 1.54-1.79 (m, 7H), 2.09-2.19 (m, 3H), 2.36 (br. s., 2H), 2.52 (br. s., 1H), 2.59 (br. s., 1H), 2.69-2.84 (m, 2H), 3.55 (br. s., 1H), 3.68 (br. s., 1H), 3.99-4.10 (m, 2H), 4.83 (br. s., 1H), 7.14-7.19 (m, 1H), 7.24 (dd, J=8.9 Hz, 8.9 Hz, 2H), 7.48 (d, J=8.0 Hz, 1H), 7.55-7.66 (m, 2H), 8.32 (dd, J=8.7, 6.0 Hz, 2H), 12.74 (br. s., 1H). MS, m/z (C32H42FN5O3): calcd, 563.3. found, 564.0 [M+H].

Workup

  1. customThe solvent was removed at reduced pressure
  2. concentrationre-concentrated
  3. customto remove residual thionyl chloride
  4. temperaturecooled to 0° C.
  5. stirringThe reaction was stirred for 16 hours at RT
  6. waitfollowed by 4 hours at 50° C. and 6 hours at 80° C
  7. temperatureThe reaction was cooled to RT
  8. stirringthe reaction was stirred overnight at 40° C
  9. concentrationThe reaction was concentrated
  10. custompurified by column chromatography
  11. washeluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM

Sources & evidence

ORD record
ord-eafe8e1f50584254b7bd84f2a11a01ab
Source dataset
uspto-grants-2015_08
Patent number
US09115127B2

Reaction notes

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