1,2-Dichloroethane → HCID 69734328, compound

HRID 1062904Notes

Reaction equation

HRID 1062904 reaction equation
Cl.C(O[C:7]([NH:9][C@@H:10]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH2:11][NH:12][C@H:13]([C:15]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH3:14])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O.[CH2:38]([N:41]([CH2:54][CH2:55][CH3:56])[C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([CH3:53])[CH:52]=1)C(O)=O)=[O:43])[CH2:39][CH3:40].C(Cl)C[Cl:59].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.ClCCl>[ClH:59].[F:29][C:27]1[CH:28]=[C:23]([CH2:22][C@H:10]([NH:9][C:7](=[O:8])[C:46]2[CH:50]=[C:51]([CH3:53])[CH:52]=[C:44]([C:42]([N:41]([CH2:38][CH2:39][CH3:40])[CH2:54][CH2:55][CH3:56])=[O:43])[CH:45]=2)[CH2:11][NH:12][C@H:13]([C:15]([NH:17][CH2:18][CH:19]([CH3:20])[CH3:21])=[O:16])[CH3:14])[CH:24]=[C:25]([F:30])[CH:26]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 6422Trifluoroacetic acidHCID 757711-HydroxybenzotriazoleHCID 113913935-methyl-N,N-dipropylisophthalamic acidHCID 69734489HCID 69734489, compound

Product 1

HCID 69734328HCID 69734328, compoundYield 45%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

N2-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propyl]-N1-isobutyl-L-alaninamide hydrochloride (238 mg, 0.53 mmol) is stirred with 2 mL of TFA and 3 mL of dichloromethane for 1 h. The mixture is concentrated, neutralized with 3 mL of 1 N NaHCO3, and extracted into ethyl acetate containing 2% methanol. The organic phase is washed with brine, dried over Na2SO4, and concentrated to a yellow oil (400 mg) which includes TFA. The residue is dissolved in 2 mL of DMF. To 1 mL of the resulting solution is added a solution of 3-[(dipropylamino)carbonyl]-5-methylbenzoic acid, (80 mg, 0.3 mmol), EDC (58 mg, 0.3 mmol) and HOBT (40 mg, 0.3 mmol) in 3 mL of DMF which has been stirred together under nitrogen for 1 h. The combined mixture is stirred for 5 days, and is then quenched with 20 mL of water and dissolved in 120 mL of ethyl acetate containing 5 mL of methanol. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. It is concentrated and chromatographed over silica gel, eluting with 3% to 5% methanol in chloroform to afford the free base of the title compound as a sticky solid (65 mg, 0.12 mmol, 45%). To a portion of this material is added ether and ethereal HCl, affording the title compound as an off-white solid. MS (CI) m/z 559 (MH+). HRMS (ESI) calcd for C31H44F2N4O3+H1 559.3459, found 559.3455

Workup

  1. concentrationThe mixture is concentrated
  2. extractionextracted into ethyl acetate containing 2% methanol
  3. washThe organic phase is washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated to a yellow oil (400 mg) which
  6. dissolutionThe residue is dissolved in 2 mL of DMF
  7. stirringThe combined mixture is stirred for 5 days
  8. customis then quenched with 20 mL of water
  9. dissolutiondissolved in 120 mL of ethyl acetate containing 5 mL of methanol
  10. washThe organic phase is washed with water, 1 N NaHCO3, and brine
  11. dry with materialdried over Na2SO4
  12. concentrationIt is concentrated
  13. customchromatographed over silica gel
  14. washeluting with 3% to 5% methanol in chloroform

Sources & evidence

ORD record
ord-273bda8f1d1542759c729f79d6b8d417
Source dataset
uspto-grants-2005_11
Patent number
US06962934B2

Reaction notes

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