2-Chloropyridine → HCID 178457802, compound

HRID 518688Notes

Reaction equation

HRID 518688 reaction equation
[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.Cl[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([O:30][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[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:31][CH:32]=1

Participants

6

Reactant 4

HCID 79772-ChloropyridineHCID 10796Cesium carbonateHCID 13387N-methyl-2-pyrrolidoneHCID 178457790HCID 178457790, compound

Product 1

HCID 178457802HCID 178457802, compound

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A microwave vial was charged with 4-fluoro-N-(6-hydroxy-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide (56 mg, 0.128 mmol), 2-chloropyridine (0.036 mL, 0.383 mmol), cesium carbonate (166 mg, 0.511 mmol), and NMP (0.6 mL) then irradiated in the microwave at 160° C. for 6 hours. The mixture was diluted with EtOAc, washed with water, the water layer back extracted with EtOAc, and the combined organics were washed with brine. The organic layer was dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% MeOH in DCM. The material was further purified by reverse-phase preparative HPLC using a 0.1% TFA in ACN/H2O, gradient 10% to 90%. The material was partitioned between saturated aqueous NaHCO3 and 5% IPA/DCM, the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was isolated as an off-white solid (32 mg, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (d, J=8.00 Hz, 6H) 1.54-1.82 (m, 4H) 2.01-2.14 (m, 2H) 2.42-2.56 (m, 1H) 2.56-2.77 (m, 2H) 3.75-3.93 (m, 1H) 4.80-4.95 (m, 1H) 6.97 (dd, J=8.56, 2.10 Hz, 1H) 6.95-7.10 (m, 1H) 7.00-7.18 (m, 1H) 7.20-7.29 (m, 2H) 7.48 (d, J=2.05 Hz, 1H) 7.51-7.62 (m, 2H) 7.80-7.90 (m, 1H) 8.07-8.19 (m, 1H) 8.27-8.38 (m, 2H) 12.81 (s, 1H). M/Z calc'd for C29H30FN5O3: 515.58. found 516 [M+H].

Workup

  1. customthen irradiated in the microwave at 160° C. for 6 hours
  2. washwashed with water
  3. extractionthe water layer back extracted with EtOAc
  4. washthe combined organics were washed with brine
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. customThe mixture was purified via flash chromatography
  8. customThe material was further purified by reverse-phase preparative HPLC
  9. customThe material was partitioned between saturated aqueous NaHCO3 and 5% IPA/DCM
  10. washthe organic layer washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. customevaporated

Sources & evidence

ORD record
ord-7ff62cb829b44f92ace6b37debf94e46
Source dataset
uspto-grants-2015_08
Patent number
US09115127B2

Reaction notes

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