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

HRID 2099788Notes

Reaction equation

HRID 2099788 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32](=O)[O:33]C(C)(C)C)[CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17](COCC[Si](C)(C)C)[N:18]=2)[CH:14]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.[NH:62]1[CH2:67][CH2:66][CH:65]([N:68]2[CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[NH:70][C:69]2=[O:78])[CH2:64][CH2:63]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32]([N:62]1[CH2:63][CH2:64][CH:65]([N:68]2[CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[NH:70][C:69]2=[O:78])[CH2:66][CH2:67]1)=[O:33])[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[NH:18][N:17]=[CH:16]2

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 5250894Bis-(1H-imidazol-2-YL)-methanoneHCID 110425973-(Piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-oneHCID 57794677tert-Butyl 1-(1-(3-fluorobenzyl)-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate

Product 1

HCID 11250445N-[1-[1-[(3-fluorophenyl)methyl]imidazol-2-yl]-2-(7-methyl-1H-indazol-5-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 1-(1-(3-fluorobenzyl)-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (14.4 mg, 0.025 mmol) was dissolved in a minimum amount of ethyl acetate, followed by addition of hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen for 3 days. After removing the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was collected by filtration. The resulting solid was dissolved in dimethylformamide (1.0 mL). The mixture was cooled to 0° C. and treated with carbonyl diimidazole (4.7 mg, 1.1 equiv) and triethylamine (7.5 μL, 0.054 mmol). 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 (6.7 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was removed and the residue purified by column chromatography to afford 7.2 mg (47%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.49-1.68 (m, 4H), 2.44 (s, 3H), 2.71-2.84 (m, 2H), 3.20-3.27 (m, 4H), 4.01-4.15 (m, 2H), 4.19 (s, 2H), 4.35 (m, 1H), 5.12 (d, J=16.2, 1H), 5.21-5.30 (m, 2H), 6.57-6.69 (m, 2H), 6.80 (d, J=7.9, 1H), 6.82 (s, 1H), 6.88-7.20 (m, 8H), 7.91 (s, 1H). Mass spec.: 607.71 (MH)+.

Workup

  1. customAfter removing the solvents
  2. additionthe crude mixture was treated with diethyl ether
  3. customto give a precipitate which
  4. filtrationwas collected by filtration
  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 removed
  11. customthe residue purified by column chromatography
  12. customto afford 7.2 mg (47%, 2 steps)

Sources & evidence

ORD record
ord-9ab169709aa9487eb0d9c94694df45ff
Source dataset
uspto-grants-2009_08
Patent number
US07569578B2

Reaction notes

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