1,2-Dichloroethane → N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-1-(2-hydroxy-2-pyridin-2-ylpropanoyl)-L-prolinamide

HRID 857757Notes

Reaction equation

HRID 857757 reaction equation
[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:3]([OH:5])=O.[Na+].[Cl-].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[C:19]([CH:29]=1)[CH2:20][NH:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.[CH:35]1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:30]2[CH:34]=[N:33][N:32]=[N:31]2)=[C:19]([CH:29]=1)[CH2:20][NH:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:3](=[O:5])[C:2]([OH:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:35]

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 5234Sodium ChlorideHCID 81531DiisopropylethylamineHCID 4150612-Hydroxy-2-(2-pyridyl)acetic acidHCID 27960291-Hydroxybenzotriazole hydrateHCID 69655818N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide

Product 1

HCID 58760167N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-1-(2-hydroxy-2-pyridin-2-ylpropanoyl)-L-prolinamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-hydroxy-2-(2-pyridyl)acetic acid from the previous step (160 mg as a 1:1 mixture with NaCl, 0.71 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (215 mg, 0.71 mmol, HPLC RT=2.25 min, method A), and HOBt hydrate (110 mg, 0.71 mmol) in DMF (5 mL) was added EDC (175 mg, 0.92 mmol). Diisopropylethylamine was then added slowly in portions (˜0.1 mL total) to bring the pH of the solution to 6–7 as measured on wetted E. Merck pH indicator strips. The mixture was stirred at ambient temperature for 18 h, and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (75 mL) and saturated aqueous NaHCO3 (20 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using a gradient elution of 2%, 3%, 4%, 5%, 6% MeOH in dichloromethane. Product-containing fractions were combined and the solvent was removed under reduced pressure to give two diastereomers of the title compound, both as amorphous solids (first eluting diastereomer: 96 mg; TLC Rf=0.3 (96:4 CH2Cl2:MeOH); HPLC RT=2.32 min, method A; LC-MS m/z=456; second eluting diastereomer: TLC Rf=0.2 (96:4 CH2Cl2:MeOH); HPLC RT=2.33 min, method A; LCMS m/z=456).

Workup

  1. customthe solvent was removed under reduced pressure
  2. customThe residue was partitioned between EtOAc (75 mL) and saturated aqueous NaHCO3 (20 mL)
  3. customThe EtOAc layer was separated
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationfiltered
  6. customThe filtrate solvent was removed under reduced pressure
  7. customthe residue was purified by pressurized silica gel column chromatography
  8. washa gradient elution of 2%, 3%, 4%, 5%, 6% MeOH in dichloromethane
  9. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-d8d43be467254a788cb81fac8b2ca48f
Source dataset
uspto-grants-2006_12
Patent number
US07144899B2

Reaction notes

Loading…