1,2-Dichloroethane → HCID 69940075, compound

HRID 1058298Notes

Reaction equation

HRID 1058298 reaction equation
C([C:3]([CH3:13])([CH3:12])[C:4]#[C:5][C:6]([OH:11])([CH3:10])[C:7]([OH:9])=O)C.[C:14]([O:18][C:19]([NH:21][CH2:22][C:23]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:24]=1[CH2:25][NH:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:10][C:6]([OH:11])([C:5]#[C:4][CH:3]([CH3:12])[CH3:13])[C:7]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27]([NH:26][CH2:25][C:24]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:23]=1[CH2:22][NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])=[O:33])=[O:9]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 11428605L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amideHCID 18672385HCID 18672385, compound

Product 1

HCID 69940075HCID 69940075, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of ethyl 2-hydroxy-2,5-dimethyl-3-hexynoic acid from the previous step (0.033 g, 0.21 mmol), L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.080 g, 0.22 mmol) and HOBT hydrate (0.088 g, 0.24 mmol) in DMF (3 mL) was added EDC (0.032 g, 0.24 mmol). Diisopropylethylamine was then added in portions (˜0.15 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 2 days, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO3 (10 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oil residue was purified by preparative reverse-phase HPLC using a Waters PrepPak column and a gradient of 5-95% CH3CN:H2O with 0.1% TFA as eluant over 60 min. The product-containing fractions were combined and lyophilized to give 1-(2,5-dimethyl-2-hydroxy-3-hexynoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide as a white solid. (72 mg, 68%; HPLC RT=2.61 min, method B; LC-MS M+H=506). 1H NMR, 400 MHz, DMSO-d6, 8.22 ppm (d, J=15.9 Hz, 2H); 7.17-7.32 ppm (m, 2H); 4.25-4.30 ppm (m, 2H), 4.06 ppm (s, 2H); 3.69-3.73 ppm (m, 1H); 2.51-2.56 ppm (m, 1H); 2.07-2.09 ppm (m, 2H); 1.91-1.94 ppm (m, 2H); 1.68-1.78 ppm (m, 2H); 1.45 ppm, (d, J=7.69 Hz, 3H); 1.35 ppm (s, 9H); 1.04-1.08 ppm, (m, 6H).

Workup

  1. customconsumption of the proline starting material
  2. customThe DMF was removed under reduced pressure
  3. customthe residue was partitioned between EtOAc (40 mL) and saturated aqueous NaHCO3 (10 mL)
  4. customThe EtOAc layer was separated
  5. dry with materialdried over anhydrous MgSO4
  6. filtrationfiltered
  7. customThe filtrate solvent was removed under reduced pressure
  8. customthe oil residue was purified by preparative reverse-phase
  9. waita gradient of 5-95% CH3CN:H2O with 0.1% TFA as eluant over 60 min

Sources & evidence

ORD record
ord-6d93915ed82f45c5aac85509d4097294
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

Loading…