Hydrochloric Acid → HCID 67540239, compound

HRID 1192385Notes

Reaction equation

HRID 1192385 reaction equation
[ClH:1].Cl.[N:3]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(OC([NH:26][C@@H:27]([C:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([CH3:33])[CH3:32])[C:28](O)=[O:29])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.O1CCOCC1>CN(C=O)C>[ClH:40].[ClH:1].[NH2:26][C@H:27]([C:31]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)([CH3:33])[CH3:32])[C:28]([N:6]1[CH2:7][CH2:8][N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:5]1)=[O:29]

Participants

9

Reactant 7

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 312751,4-DioxaneHCID 757711-HydroxybenzotriazoleHCID 66570482HCID 66570482, compoundHCID 67539146HCID 67539146, compound

Product 1

HCID 67540239HCID 67540239, compoundYield 145.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

The 4-piperazin-1-yl-quinazoline bis-hydrochloride (220 mg, 0.766 mmol), (S)-2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-3-methyl-butyric acid (251 mg, 0.766 mmol, 1.0 equiv), 1-hydroxybenzotriazole (109 mg, 0.804 mmol, 1.05 equiv), and EDCI (154 mg, 0.804 mmol, 1.05 equiv) were dissolved/suspended in 6.0 mL of DMF. The mixture was treated with triethylamine (427 μL, 3.06 mmol) and allowed to stir overnight to completion. The reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was eluted through a small plug of silica gel with ethyl acetate and concentrated in vacuo. The protected intermediate was immediately dissolved in 1 mL of dioxane and treated with 4M HCl in dioxane (1.92 mL, 7.66 mmol) at room temperature for four hours. The resulting precipitate was triturated with ether, then filtered to afford the (R)-2-amino-3-(4-chlorophenyl)-3-methyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-butan-1-one bis-hydrochloride as a light-yellow solid (277 mg, 73%) upon drying under vacuum. 1H NMR (DMSO-d6, 400 MHz) δ 8.89 (s, 1H), 8.46 (brs, 3H), 8.17 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.53 (brs, 1H), 4.09 (m, 3H), 3.90 (m, 3H), 3.32 (m, 1H), 3.04 (t, J=9.2 Hz, 1H), 1.51 (s, 3H), 1.43 (s, 3H). LCMS (APCI+) m/z 424 [M+H]+; Rt=1.90 min.

Workup

  1. customThe reaction was partitioned between ethyl acetate and diluted NaHCO3 solution
  2. extractionThe aqueous was extracted with ethyl acetate
  3. washThe organic was washed with water
  4. custombrine, separated
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. washThe residue was eluted through a small plug of silica gel with ethyl acetate
  9. concentrationconcentrated in vacuo
  10. dissolutionThe protected intermediate was immediately dissolved in 1 mL of dioxane
  11. customThe resulting precipitate was triturated with ether
  12. filtrationfiltered

Sources & evidence

ORD record
ord-b7ac97ec052146a79fbfc973bdd17b8b
Source dataset
uspto-grants-2014_03
Patent number
US08680114B2

Reaction notes

Loading…