1,2-Dichloroethane → N-[(2S)-3-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)propyl]-L-alanyl-N1-isobutyl-L-valinamide

HRID 1062898Notes

Reaction equation

HRID 1062898 reaction equation
[CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:34][C@@H:35]([CH2:54][C:55]1[CH:60]=[C:59]([F:61])[CH:58]=[C:57]([F:62])[CH:56]=1)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39]>CN(C=O)C>[F:61][C:59]1[CH:60]=[C:55]([CH2:54][C@H:35]([NH:34][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([CH3:16])[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])=[O:6])[CH:8]=2)[CH2:36][NH:37][C@H:38]([C:40]([NH:42][C@H:43]([C:47]([NH:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH3:39])[CH:56]=[C:57]([F:62])[CH:58]=1

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 10126926N-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamideHCID 113913935-methyl-N,N-dipropylisophthalamic acid

Product 1

HCID 10175572N-[(2S)-3-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)propyl]-L-alanyl-N1-isobutyl-L-valinamideYield 69.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

3-[(Dipropylamino)carbonyl]-5-methylbenzoic acid, (90 mg, 0.34 mmol) is combined with EDC(65 mg, 0.34 mmol) and HOBT (46 mg, 0.34 mmol) in 3 mL of DMF and stirred under nitrogen for 1 h. This solution is then added to a solution of N-[(2S)-2-amino-3-(3,5-difluorophenyl)propyl]-L-alanyl-N1-isobutyl-L-valinamide (88 mg, 0.21 mmol) in 1 mL of DMF. The reaction is continued for 3 days at ambient temperature. It is then quenched with 1 N KH2PO4 and diluted with ethyl acetate containing about 1% of methanol. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. Concentration and chromatography over silica gel, eluting with 4% to 6% methanol in dichloromethane, affords 96 mg (0.146 mmol, 69%) of the title compound as a light tan solid. 1H NMR (CDCl3) δ 7.75 (d, J=9 Hz, 1H), 7.54 (s, 1H), 7.37 (s, 1H), 7.21 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.84 (m, 2H), 6.70 (m, 1H), 6.64 (m, 1H), 4.19 (dd, J=7, 9 Hz, 1H), 4.05 (m, 1H), 3.5-3.4 (m, 2H), 3.33 (dd, J=6, 14 Hz, 1H), 3.19-3.02 (m, 5H), 2.88 (dd, J=6, 14 Hz, 1H), 2.68 (dd, J=4, 13.5 Hz, 1H), 2.58 (m, 1H), 2.37 (s, 3H), 1.96 (m, 1H), 1.75-1.64 (m, 4H), 1.50 (m, 2H), 1.35 (d, J=7 Hz, 3H), 0.99 (t, J=7 Hz, 3H), 0.91 (d, J=7 Hz, 3H), 0.86 (m, 9H), 0.71 (t, J=7 Hz, 3H).

Workup

  1. waitThe reaction is continued for 3 days at ambient temperature
  2. customIt is then quenched with 1 N KH2PO4
  3. additiondiluted with ethyl acetate containing about 1% of methanol
  4. washThe organic phase is washed with water, 1 N NaHCO3, and brine
  5. dry with materialdried over Na2SO4
  6. concentrationConcentration and chromatography over silica gel
  7. washeluting with 4% to 6% methanol in dichloromethane

Sources & evidence

ORD record
ord-318e0f9b76dd4cee851b77a2afd94936
Source dataset
uspto-grants-2005_11
Patent number
US06962934B2

Reaction notes

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