Methyl chloroformate → (R)-{1-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester

HRID 417452Notes

Reaction equation

HRID 417452 reaction equation
CN1CCOCC1.[CH3:8][O:9][C:10](=[O:54])[NH:11][C@@H:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23]1[NH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[NH:41][C:42]([CH2:45][N:46]5[CH2:51][CH2:50][CH2:49][CH:48]([NH2:52])[C:47]5=[O:53])=[N:43][CH:44]=4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)=[CH:26][N:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14].Cl[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH3:59][O:58][C:56](=[O:57])[NH:52][C@@H:48]1[CH2:49][CH2:50][CH2:51][N:46]([CH2:45][C:42]2[NH:41][C:40]([C:37]3[CH:38]=[CH:39][C:34]([C:31]4[CH:30]=[CH:29][C:28]([C:25]5[NH:24][C:23]([CH:19]6[CH2:20][CH2:21][CH2:22][N:18]6[C:16](=[O:17])[CH:12]([NH:11][C:10]([O:9][CH3:8])=[O:54])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:33][CH:32]=4)=[CH:35][CH:36]=3)=[CH:44][N:43]=2)[C:47]1=[O:53]

Participants

5

Reactant 3

HCID 6586Methyl chloroformateHCID 79724-MethylmorpholineHCID 66620099HCID 66620099, compound

Product 1

HCID 66620881(R)-{1-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl esterYield 319%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-Methylmorpholine (71 μL, 0.64 mmol) was added to a suspension of (R)-{1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-yl methyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (137 mg, 0.21 mmol) in dichloromethane (5 mL). Methyl chloroformate (16.5 μL, 0.21 mmol) was added to the resulting solution. After 20 minutes the solvent was removed under reduced pressure. The residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 2 hours the organic solvents were removed under reduced pressure and the aqueous phase was decanted. The residue 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 (R)-{1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid methyl ester (46.7 mg, 0.67 mmol, 32%). C37H44N8O6 calculated 696.3 observed [M+1]+ 697.4; rt=1.58 min. 1H (DMSO-d6,): δ=8.05 (s, 1H), 7.87 (m, 8H) 7.30 (m, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.85 (d, J=15.6 Hz, 1H), 4.53 (d, J=16.0 Hz, 1H), 4.08 (m, 2H), 3.81 (m, 2H), 3.51 (s, 3H), 3.50 (s, 3H), 2.14 (m, 1H), 2.05-1.78 (series m, 8H), 0.78 (m, 6H).

Workup

  1. customAfter 20 minutes the solvent was removed under reduced pressure
  2. additionmethanol (2 mL) and an aqueous solution of sodium hydroxide (2 N, 1 mL) was added
  3. customAfter 2 hours the organic solvents were removed under reduced pressure
  4. customthe aqueous phase was decanted
  5. customthe solvent was removed by lyophilization

Sources & evidence

ORD record
ord-61cf41b1d0674782aa342e045fd260e7
Source dataset
uspto-grants-2012_01
Patent number
US08088368B2

Reaction notes

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