Diisopropylethylamine → 4-[3-[3-(tert-butyldimethylsilanyloxymethyl)-4-tri-fluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide

HRID 1633936Notes

Reaction equation

HRID 1633936 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Si:13]([O:20][CH2:21][C:22]1[CH:23]=[C:24]([NH2:33])[CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:32])([F:31])[F:30])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH:43]1([C:49]2[CH:54]=[CH:53][C:52]([NH:55][CH2:56][C:57]3[CH:70]=[CH:69][C:60]([C:61]([NH:63][C:64]4[N:65]=[N:66][NH:67][N:68]=4)=[O:62])=[CH:59][CH:58]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>ClCCl.CN(C=O)C.C1(C)C=CC=CC=1>[Si:13]([O:20][CH2:21][C:22]1[CH:23]=[C:24]([NH:33][C:5](=[O:11])[N:55]([CH2:56][C:57]2[CH:58]=[CH:59][C:60]([C:61]([NH:63][C:64]3[N:65]=[N:66][NH:67][N:68]=3)=[O:62])=[CH:69][CH:70]=2)[C:52]2[CH:51]=[CH:50][C:49]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:54][CH:53]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]([F:31])([F:32])[F:30])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 94429Triphosgene2×HCID 223111253-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyanilineHCID 225018104-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide

Product 1

HCID 225018154-[3-[3-(tert-butyldimethylsilanyloxymethyl)-4-tri-fluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamideYield 43.2%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
80 °C

Procedure

Triphosgene (0.09 g, 0.31 mmol) was dissolved in dichloromethane (2 mL) under nitrogen and cooled on ice. 3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl amine (0.3 g, 0.93 mmol) was evaporated twice with toluene and dissolved in dichloromethane (2 mL) and diisopropylethylamine (0.32 mL, 1.86 mmol) was added. This solution was then added to the solution of triphosgene, and after 2 hours at room temperature a slurry of 4-[(4-cyclohexylphenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide (0.35 g, 0.93 mmol) in DMF (6 mL) was added. Before adding 4-[(4-cyclohexylhenylamino)methyl]-N-(2H-tetrazol-5-yl)benzamide this was concentrated twice from toluene to remove any content of water. The mixture was stirred under nitrogen at 80° C. for 2 hours and concentrated in vacuo, and the residue was extracted with dichloromethane (80 mL) and citric acid (25 mL, 10%). The aqueous phase was extracted with dichloromethane (30 mL) and the combined organic phases were washed with citrus acid (3×25 mL, 10%), dried and concentrated in vacuo. The residue was purified by column chromatography (35 g silica) using dichloromethane and 10% ammonia in ethanol 85:15 as eluent to give 97 mg of 4-[3-[3-(tert-butyldimethylsilanyloxymethyl)-4-tri-fluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]-N-(2H-tetrazol-5-yl)benzamide.

Workup

  1. temperaturecooled on ice
  2. concentrationthis was concentrated twice from toluene
  3. customto remove any content of water
  4. concentrationconcentrated in vacuo
  5. extractionthe residue was extracted with dichloromethane (80 mL) and citric acid (25 mL, 10%)
  6. extractionThe aqueous phase was extracted with dichloromethane (30 mL)
  7. washthe combined organic phases were washed with citrus acid (3×25 mL, 10%)
  8. customdried
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by column chromatography (35 g silica)

Sources & evidence

ORD record
ord-9fd41ad2c5a0450e89addf5c4328d454
Source dataset
uspto-grants-2003_01
Patent number
US06503949B1

Reaction notes

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