Hydrochloric Acid → N-[2-(7-methyl-1H-indazol-5-yl)-1-[1-(pyridin-2-ylmethyl)imidazol-2-yl]ethyl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide

HRID 2099823Notes

Reaction equation

HRID 2099823 reaction equation
[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([NH:33][C:34](=O)[O:35]C(C)(C)C)[C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:23]=[CH:24][N:25]=2)[CH:3]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH:66]([N:69]2[CH2:78][C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[NH:71][C:70]2=[O:79])[CH2:65][CH2:64]1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:19][CH:20]([NH:33][C:34]([N:63]2[CH2:64][CH2:65][CH:66]([N:69]3[CH2:78][C:77]4[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=4)[NH:71][C:70]3=[O:79])[CH2:67][CH2:68]2)=[O:35])[C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:23]=[CH:24][N:25]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 5250894Bis-(1H-imidazol-2-YL)-methanoneHCID 110425973-(Piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-oneHCID 57794714tert-Butyl 2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(1-(pyridin-2-ylmethyl)-1H-imidazol-2-yl)ethylcarbamate

Product 1

HCID 11456078N-[2-(7-methyl-1H-indazol-5-yl)-1-[1-(pyridin-2-ylmethyl)imidazol-2-yl]ethyl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

tert-Butyl 2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(1-(pyridin-2-ylmethyl)-1H-imidazol-2-yl)ethylcarbamate (35.2 mg, 0.063 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen overnight. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (11.0 mg, 0.066 mmol, 1.05 equiv) and diisopropylethylamine (44.0 μL, 4.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (17.6 mg, 0.066 mmol, 1.05 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 4.6 mg (12%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.48-1.65 (m, 4H), 2.03 (s, 1H), 2.45 (s, 3H), 2.69-2.82 (m, 2H), 3.99-4.16 (m, 2H), 4.19 (s, 2H), 5.24 (d, J=16.5, 1H), 6.67 (d, J=7.6, 1H), 6.80 (d, J=7.9, 1H), 6.89 (s, 1H), 6.97 (dd, J=8.2, 7.6, 1H), 7.10-7.23 (m, 5H), 7.30 (s, 1H), 7.37-7.42 (m, 1H), 7.94 (s, 1H). Mass spec.: 590.3 (MH)+.

Workup

  1. customAfter removal of the solvents
  2. additionthe crude mixture was treated with diethyl ether
  3. customto give a precipitate which
  4. filtrationwas filtered
  5. dissolutionThe resulting solid was dissolved in dimethylformamide (1.0 mL)
  6. stirringThe reaction was stirred for 5 min at 0° C.
  7. temperaturewarmed to room temperature
  8. stirringstirred for 10 min
  9. stirringThe mixture was stirred at room temperature overnight
  10. customThe solvent was evaporated
  11. customthe residue purified by column chromatography
  12. customto afford 4.6 mg (12%, 2 steps)

Sources & evidence

ORD record
ord-e7bca9db7e594b22bb86813808f18786
Source dataset
uspto-grants-2009_08
Patent number
US07569578B2

Reaction notes

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