Methyl chloroformate → HCID 178502177, compound

HRID 71766Notes

Reaction equation

HRID 71766 reaction equation
Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][C:8]([NH:10][CH:11]([CH:75]([CH3:77])[CH3:76])[C:12]([N:14]1[CH:18]([C:19]2[N:20](COCC[Si](C)(C)C)[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[N:39]=[C:40]([CH:51]6[CH2:55][CH2:54][CH2:53][N:52]6[C:56](=[O:66])[CH:57]([NH:61][C:62]([O:64][CH3:65])=[O:63])[CH:58]([CH3:60])[CH3:59])[N:41](COCC[Si](C)(C)C)[CH:42]=5)=[CH:34][CH:33]=4)=[CH:26][CH:25]=3)[N:23]=2)[CH2:17][NH:16][CH2:15]1)=[O:13])=[O:9].CN1CCOCC1>ClCCl.CN(C)C=O.O.C(O)(C(F)(F)F)=O.C(#N)C>[CH3:5][O:4][C:2]([N:16]1[CH2:17][CH:18]([C:19]2[NH:20][CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:32]4[CH:33]=[CH:34][C:35]([C:38]5[N:39]=[C:40]([CH:51]6[CH2:55][CH2:54][CH2:53][N:52]6[C:56](=[O:66])[CH:57]([NH:61][C:62]([O:64][CH3:65])=[O:63])[CH:58]([CH3:60])[CH3:59])[NH:41][CH:42]=5)=[CH:36][CH:37]=4)=[CH:28][CH:29]=3)[N:23]=2)[N:14]([C:12](=[O:13])[CH:11]([NH:10][C:8]([O:7][CH3:6])=[O:9])[CH:75]([CH3:76])[CH3:77])[CH2:15]1)=[O:3]

Participants

9

Reactant 3

HCID 6586Methyl chloroformateHCID 79724-MethylmorpholineHCID 866488813'-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2',3',4',5'-tetrahydro-1H-[2,4']biimidazole

Product 1

HCID 178502177HCID 178502177, compoundYield 18.9%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent2×

Procedure

Methyl chloroformate (15 μL, 0.19 mmol) was added to a solution of 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazole (97 mg, 0.09 mmol), and 4-methylmorpholine (40 μL, 0.36 mmol) in dichloromethane (3 mL). After 30 minutes the solvent was removed under reduced pressure and azeotroped with toluene. The residue was taken up in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. After 16 hours the volatiles were removed under reduced pressure and the residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL). An aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 30 min the organic solvents were removed under reduced pressure and the resulting precipitate was isolated by filtration. The solid was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid methyl ester (14.1 mg, 0.017 mmol, 10%).

Workup

  1. customAfter 30 minutes the solvent was removed under reduced pressure
  2. customazeotroped with toluene
  3. additiontrifluoroacetic acid (5 mL) was added
  4. customAfter 16 hours the volatiles were removed under reduced pressure
  5. additionAn aqueous solution of sodium hydroxide (2 N, 1 mL) was added
  6. customAfter 30 min the organic solvents were removed under reduced pressure
  7. customthe resulting precipitate was isolated by filtration
  8. customthe solvent was removed by lyophilization

Sources & evidence

ORD record
ord-66c690073e3c40deaa7c2e79ba3634ab
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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