Diisopropylethylamine → HCID 86680151, compound

HRID 1915831Notes

Reaction equation

HRID 1915831 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH:11]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]([CH3:26])[N:20]=[CH:21][C:22]=3[N+:23]([O-])=O)[CH2:14][CH2:13][CH:12]2[OH:27])=[CH:5][CH:4]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[S:40][C:39]([C:41]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=2[F:48])=[N:38][C:37]=1[C:49](O)=[O:50])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCO.O.CN(C=O)C.[Fe]>[F:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=1[C:39]1[S:40][C:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[C:37]([C:49](=[O:50])[NH:23][C:22]2[CH:21]=[N:20][N:19]([CH3:26])[C:18]=2[N:15]2[CH2:16][CH2:17][CH:11]([O:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]([OH:27])[CH2:13][CH2:14]2)[N:38]=1

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 89456514HCID 89456514, compound

Product 1

HCID 86680151HCID 86680151, compound

Reagents, catalysts & solvents 4

HCID 23925IronCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 5-((4-methoxyphenyl)methoxy)-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-ol (0.80 g, 2.18 mmol) in EtOH (30 mL) and water (3 mL) was added iron powder (0.90 g, 16.11 mmol) The reaction mixture was heated at 100° C. for 2 hr, cooled to room temperature, filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with water (50 mL). The aqueous layer was re-extracted with DCM (50 mL) and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure to give a pale orange gum. To a solution of this gum (0.55 g, 1.60 mmol) in DMF (5 mL) was added 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (0.62 g, 1.76 mmol), HATU (0.85 g, 2.40 mmol) and DIPEA (0.56 mL, 3.20 mmol). The reaction mixture was stirred at room temperature for 66 hr, quenched with a saturated aqueous NaHCO3 (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (100 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-10% MeOH/EtOAc) gave tert-butyl N-(2-(2,6-difluorophenyl)-4-((5-(4-hydroxy-5-((4-methoxyphenyl)methoxy)azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)thiazol-5-yl]carbamate as a pale pink solid (530 mg, 35% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 9.02 (s, 1H), 7.91 (s, 1H), 7.38-7.28 (m, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 6.92-6.84 (m, 2H), 4.61 (d, J=11.1 Hz, 1H), 4.40 (d, J=11.1 Hz, 1H), 3.91 (t, J=8.6 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.55 (td, J=8.4, 3.4 Hz, 1H), 3.34-3.13 (m, 4H), 3.10 (s, 1H), 2.22-2.14 (m, 2H), 1.93-1.77 (m, 2H), 1.62-1.50 (m, 9H).

Workup

  1. temperaturecooled to room temperature
  2. filtrationfiltered through Celite®
  3. concentrationthe filtrate concentrated under reduced pressure
  4. dissolutionThe residue was dissolved in DCM (50 mL)
  5. washwashed with water (50 mL)
  6. extractionThe aqueous layer was re-extracted with DCM (50 mL)
  7. customthe combined organic layers passed through a phase separation cartridge
  8. concentrationconcentrated under reduced pressure
  9. customto give a pale orange gum
  10. customquenched with a saturated aqueous NaHCO3 (200 mL)
  11. extractionextracted with EtOAc (3×150 mL)
  12. washThe combined organic layers were washed with brine (100 mL)
  13. customseparated
  14. dry with materialdried over MgSO4
  15. concentrationconcentrated under reduced pressure
  16. customPurification via silica gel column chromatography (0-10% MeOH/EtOAc)

Sources & evidence

ORD record
ord-b8af2bafba8e4d55b2b59b220c8d6e76
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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