1,2-Dichloroethane → HCID 69656183, compound

HRID 857774Notes

Reaction equation

HRID 857774 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:35](O)=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:35]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][CH2:7][C:6]1[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)=[O:15])=[O:36])[CH2:31][CH:32]1[CH2:34][CH2:33]1)=[O:28])([CH3:24])([CH3:25])[CH3:23]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 81531DiisopropylethylamineHCID 2756015(R)-2-((tert-Butoxycarbonyl)amino)-3-cyclopropylpropanoic acidHCID 27960291-Hydroxybenzotriazole hydrateHCID 69655833HCID 69655833, compound

Product 1

HCID 69656183HCID 69656183, compoundYield 28%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of N-[5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (86 mg, 0.25 mmol), N-(tert-butoxycarbonyl)-3-cyclopropyl-D-alanine (Example 31, Step C, 57 mg, 0.25 mmol) and HOBt hydrate (33 mg, 0.25 mmol) in DMF (2 mL) was added EDC (48 mg, 0.25 mmol). Diisopropylethylamine was then added 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 4 hours. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the oily residue was purified by preparative reverse phase HPLC eluting with 95/5 to 5/95 1%TFA H2O/CH3CN in 30 min at a flow rate of 15 mL/min. The product fractions were combined and lyophilized to give 35 mg of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.12 (s, 1H), 7.63 (m, 1H), 7.23–7.29 (m, 1H), 7.02–7.06 (m, 1H), 5.17 (d, J=5.5 Hz, 1H 4.62 (d, J=5.6 Hz, 1H), 4.22–4.41 (m, 4H), 3.94 (br, s, 1H), 3.60 (m, 1H), 2.34 (s, 1H), 1.98 (s, 2H), 1.44 (m, 1H), 1.30 (s, 9H), 0.71–0.73 (m, 1H), 0.47–0.51 (m, 2H), 0.12 (br s, 2H).

Workup

  1. customThe DMF was removed under reduced pressure
  2. customthe residue was partitioned between EtOAc and saturated aqueous NaHCO3
  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 oily residue was purified by preparative reverse phase HPLC
  8. washeluting with 95/5 to 5/95 1%TFA H2O/CH3CN in 30 min at a flow rate of 15 mL/min

Sources & evidence

ORD record
ord-8b41783a1dbd42d1b1545389103091b4
Source dataset
uspto-grants-2006_12
Patent number
US07144899B2

Reaction notes

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