Diisopropylethylamine → HCID 178433216, compound

HRID 241459Notes

Reaction equation

HRID 241459 reaction equation
C([O-])=O.[CH3:4][C:5]1[N:6]=[C:7]([NH3+:20])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:31]=[C:32]([C:39](O)=[O:40])[C:33]([CH:36]([F:38])[F:37])=[N:34][CH:35]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[F:38][CH:36]([F:37])[C:33]1[N:34]=[CH:35][C:30]([CH2:29][NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:31][C:32]=1[C:39](=[O:40])[NH:20][C:7]1[NH:8][C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)=[C:5]([CH3:4])[N:6]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate2×HCID 710606065-[(Tert-butoxycarbonylamino)methyl]-2-(difluoromethyl)pyridine-3-carboxylic acidHCID 178433220HCID 178433220, compound

Product 1

HCID 178433216HCID 178433216, compoundYield 56.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

Dissolve [4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]ammonium formate (0.205 g, 0.714 mmol) and 5-[(tert-butoxycarbonylamino)methyl]-2-(difluoromethyl)pyridine-3-carboxylic acid (0.283 g, 0.749 mmol) in DCM (5 mL). Add DIPEA (0.50 mL, 2.855 mmol) followed by BOP (0.350 g, 0.792 mmol). Heat the mixture to 60° C., and stir 16 hours. Add benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.150 g, 0.339 mmol). Stir the mixture for 2 hours. Pour the reaction mixture into water (15 mL). Extract with EtOAc (3×15 mL, and sequentially wash the combined organics with a saturated sodium chloride aqueous solution (4×15 mL) and a saturated sodium bicarbonate aqueous solution (15 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by reverse phase flash chromatography (Analogix® 55 g @ 40 mL/min) eluting with a gradient of 5-75% ACN/water over 30 minutes. Concentrate the appropriate fractions under reduced pressure until only water remains and the product is a suspended solid. Add a saturated NaHCO3 aqueous solution (50 mL), and extract with EtOAc (2×30 mL) to give the title compound (0.212 g, 56%) as a white solid. LCMS (m/z) 526 (M+1) 524 (M−1).

Workup

  1. stirringStir the mixture for 2 hours
  2. extractionExtract with EtOAc (3×15 mL
  3. washsequentially wash the combined organics with a saturated sodium chloride aqueous solution (4×15 mL)
  4. dry with materialDry the organic extracts over sodium sulfate
  5. filtrationfilter
  6. customcollect the filtrate
  7. concentrationand concentrate the filtrate under reduced pressure
  8. customPurify the residue by reverse phase flash chromatography (Analogix® 55 g @ 40 mL/min)
  9. washeluting with a gradient of 5-75% ACN/water over 30 minutes
  10. concentrationConcentrate the appropriate fractions under reduced pressure until only water
  11. additionAdd a saturated NaHCO3 aqueous solution (50 mL)
  12. extractionextract with EtOAc (2×30 mL)

Sources & evidence

ORD record
ord-44e1defacc1442f7adeb2432ad9e4f8d
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

Loading…