Ammonium Chloride → HCID 74221010, compound

HRID 928846Notes

Reaction equation

HRID 928846 reaction equation
[Cl-].[Li+].C([Mg]Cl)(C)C.Br[C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1.[N:15]1([C:20]2[CH:48]=[CH:47][C:23]([CH2:24][C:25]3[C:26]([O:45][CH3:46])=[N:27][C:28]4[C:33]([C:34]=3[Cl:35])=[CH:32][C:31]([C:36]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)=[O:37])=[CH:30][CH:29]=4)=[CH:22][CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1.[Cl-].[NH4+]>O1CCCC1>[N:15]1([C:20]2[CH:48]=[CH:47][C:23]([CH2:24][C:25]3[C:26]([O:45][CH3:46])=[N:27][C:28]4[C:33]([C:34]=3[Cl:35])=[CH:32][C:31]([C:36]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)([C:9]3[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=3)[OH:37])=[CH:30][CH:29]=4)=[CH:22][CH:21]=2)[CH:19]=[N:18][CH:17]=[N:16]1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 15152585-Bromo-1-methyl-1H-imidazoleHCID 86715670HCID 86715670, compound2×HCID 178461733HCID 178461733, compound

Product 1

HCID 74221010HCID 74221010, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

Isopropylmagnesium chloride lithium chloride complex (1.3 M in tetrahydrofuran, 2.0 mL, 2.60 mmol) was added to an ice-water cooled solution of 5-bromo-1-methyl-1H-imidazole (444 mg, 2.76 mmol) in tetrahydrofuran (12 mL). The resulting white suspension was stirred for 5 minutes then the cooling bath was removed. After 10 minutes, the suspension was added dropwise by syringe to an ice-water cooled mixture of (3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-chlorophenyl)methanone (772 mg, 1.59 mmol, Intermediate 45, step e) and lanthanum(III) chloride bis(lithium chloride) complex solution (0.6 M in tetrahydrofuran, 5.25 mL, 3.16 mmol) in tetrahydrofuran (15 mL). After 20 minutes, saturated aqueous ammonium chloride solution was added (2 mL) then the cooling bath was removed. The mixture was diluted with water (25 mL) and ethyl acetate (50 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (25 mL). The organic layers were combined and the combined solution was dried with sodium sulfate. The dried solution was filtered and the filtrate was absorbed onto 6 g of silica gel for dry-load flash-column chromatography on silica gel eluting with 100% dichloromethane initially for 5 minutes, grading to 7% methanol-dichloromethane over 30 minutes to afford the titled compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (s, 1H), 8.12 (d, J=2.1 Hz, 1H), 8.06 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.58-7.50 (m, 3H), 7.41 (d, J=8.5 Hz, 2H), 7.36 (d, J=1.1 Hz, 1H), 7.31 (s, 4H), 6.38 (d, J=1.1 Hz, 1H), 4.33 (s, 2H), 4.12 (s, 1H), 4.08 (s, 3H), 3.38 (s, 3H); MS m/e 571.1 [M+H]+. (3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol was purified by HPLC (Chiralpak IA column, 50 mm×250 mm, ethanol with 0.2% triethylamine as eluent, 30 mL/minute, 254 nm wavelength) to give two enantiomers. The first eluting enantiomer was Example 64B: 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (s, 1H), 8.12 (d, J=2.1 Hz, 1H), 8.06 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.56-7.50 (m, 3H), 7.41 (d, J=8.5 Hz, 2H), 7.36 (d, J=1.1 Hz, 1H), 7.31 (s, 4H), 6.38 (d, J=1.1 Hz, 1H), 4.33 (s, 2H), 4.08 (s, 3H), 3.38 (s, 3H); MS m/e 571.1 [M+H]+ and the second eluting enantiomer was Example 64C: 1H NMR (400 MHz, CDCl3) δ ppm 8.43 (s, 1H), 8.12 (d, J=2.1 Hz, 1H), 8.06 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.58-7.49 (m, 3H), 7.41 (d, J=8.6 Hz, 2H), 7.35 (s, 1H), 7.31 (s, 4H), 6.38 (s, 1H), 4.33 (s, 2H), 4.21 (s, 1H), 4.08 (s, 3H), 3.38 (s, 3H); MS m/e 571.1 [M+H]+.

Workup

  1. customthe cooling bath was removed
  2. waitAfter 10 minutes
  3. additionthe suspension was added dropwise by syringe to an ice-water
  4. temperaturecooled
  5. waitAfter 20 minutes
  6. customthe cooling bath was removed
  7. additionThe mixture was diluted with water (25 mL) and ethyl acetate (50 mL)
  8. customThe layers were separated
  9. extractionThe aqueous layer was extracted with ethyl acetate (25 mL)
  10. dry with materialthe combined solution was dried with sodium sulfate
  11. filtrationThe dried solution was filtered
  12. customthe filtrate was absorbed onto 6 g of silica gel
  13. dry with materialfor dry-load flash-column chromatography on silica gel eluting with 100% dichloromethane initially for 5 minutes
  14. waitgrading to 7% methanol-dichloromethane over 30 minutes

Sources & evidence

ORD record
ord-7d4244035f73485d881ced26c4230134
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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