Diisopropylethylamine → HCID 56945614, compound

HRID 1262123Notes

Reaction equation

HRID 1262123 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:44][CH2:43]2)=[CH:38][C:37]=1[O:53][CH3:54]>COCC(O)C>[CH3:54][O:53][C:37]1[CH:38]=[C:39]([CH:42]2[CH2:43][CH2:44][N:45]([CH2:48][C@H:49]([OH:52])[CH2:50][OH:51])[CH2:46][CH2:47]2)[CH:40]=[CH:41][C:36]=1[NH:35][C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 66711316HCID 66711316, compoundHCID 86661678Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester

Product 1

HCID 56945614HCID 56945614, compoundYield 27%

Reagents, catalysts & solvents 1

HCID 79001-Methoxy-2-propanolSolvent

Conditions

Temperature
100 °C

Procedure

Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (320.00 mg, 0.857 mmol), N,N-Diisopropylethylamine (0.779 mL, 4.47 mmol), and (S)-3-[4-(4-Amino-3-methoxy-phenyl)-piperidin-1-yl]-propane-1,2-diol (600.65 mg, 2.142 mmol) were dissolved in 1-methoxy-2-propanol (2.3 mL) and the reaction mixture was heated at 100° C. for 8 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered. The solvent was evaporated under reduced pressure and the product was isolated by column chromatography (ISCO, Silicagel, methanol/dichloromethane 0-10%). The product needed to be further purified by preparative reverse phase HPLC (Gilson, 0.1% TFA water/acetonitrile gradient) followed by neutralization of the resulting TFA salt to afford (S)-3-(4-{3-methoxy-4-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-propane-1,2-diol as a light orange solid (115 mg, 27%). MP: 66-80° C.; 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.99 (dd, J=8.0, 1.6 Hz, 1H), 7.44 (m, 2H), 7.13 (m, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.02 (d, J=4.7 Hz, 1H), 6.83 (d, J=4.7 Hz, 1H), 6.72 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.86 (m, 1H), 3.85 (s, 3H), 3.77 (m, 1H), 3.55 (m, 1H), 3.22 (d, J=10.6 Hz, 1H), 3.08 (d, J=10.6 Hz, 1H), 2.77 (br s, 2H), 2.69 (m, 1H), 2.48 (m, 3H), 2.20 (m, 1H), 1.85 (m, 4H); LC/MS (ESI+): 504.19 (M+H).

Workup

  1. customThe reaction mixture was partitioned between dichloromethane and saturated aqueous NaHCO3
  2. customthe organic layer was separated
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. customThe solvent was evaporated under reduced pressure
  6. customthe product was isolated by column chromatography (ISCO, Silicagel, methanol/dichloromethane 0-10%)
  7. customto be further purified by preparative reverse phase HPLC (Gilson, 0.1% TFA water/acetonitrile gradient)

Sources & evidence

ORD record
ord-b94476c4db764e778949b2db4a985b6c
Source dataset
uspto-grants-2013_06
Patent number
US08471005B2

Reaction notes

Loading…