Methyl chloroformate → 3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-2',3',4',5'-tetrahydro-1H-[2,4']biimidazolyl-1'-carboxylic acid methyl ester

HRID 71798Notes

Reaction equation

HRID 71798 reaction equation
CN1CCOCC1.[CH3:8][O:9][C:10](=[O:61])[NH:11][CH: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]([CH:45]5[CH2:49][NH:48][CH2:47][N:46]5[C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=[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:63]([O:65][CH3:66])=[O:64]>ClCCl>[CH3:66][O:65][C:63]([N:48]1[CH2:49][CH:45]([C:42]2[NH:41][C:40]([C:37]3[CH:36]=[CH:35][C:34]([C:31]4[CH:32]=[CH:33][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:61])[CH:13]([CH3:15])[CH3:14])=[N:27][CH:26]=5)=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[CH:44][N:43]=2)[N:46]([C:50](=[O:60])[CH:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])[CH2:47]1)=[O:64]

Participants

5

Reactant 3

HCID 6586Methyl chloroformateHCID 79724-MethylmorpholineHCID 66620775{1-[2-(5-{4'-[3'-(2-Methoxycarbonylamino-3-methyl-butyryl)-2',3',4',5'-tetrahydro-3H,1'H-[2,4']biimidazolyl-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

Product 1

HCID 666201513'-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl]-biphenyl-4-yl)-2',3',4',5'-tetrahydro-1H-[2,4']biimidazolyl-1'-carboxylic acid methyl esterYield 16.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-Methylmorpholine (31 μL, 0.28 mmol) was added to a suspension of {1-[2-(5-{4′-[3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-3H,1′H-[2,4′]biimidazolyl-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (41.1 mg, 0.056 mmol) [prepared via reaction of 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester with HCl-solution] 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 in vacuo. The residue was taken into 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 in vacuo and the aqueous phase was decanted. The residue was dissolved in dimethylformamide (2 mL) and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA). The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3′-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid methyl ester (7.5 mg) C41H51N9O8 calculated 797.4 observed [M+1]+ 798.4; 1H (DMSO-d6): δ=8.08 (s, 1H), 7.83 (m, 8H), 7.58 (d, J=8.0 Hz, 1H), 7.29 (s, J=8.4 Hz, 1H), 5.42 (dd, J=7.6, 3.6 Hz, 1H), 5.26 (d, J=4.8 Hz, 1H), 5.18 (d, J=6.0 Hz, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.88 (m, 1H), 4.08 (t, J=7.6 Hz, 2H), 3.94 (m, 1H), 3.82 (m, 4H), 3.65 (s, 3H), 3.52 (s, 3H), 3.51 (s, 3H), 2.36 (m, 1H), 2.01 (m, 5H), 0.83 (m, 12H).

Workup

  1. customAfter 20 minutes the solvent was removed in vacuo
  2. additionan aqueous solution of sodium hydroxide (2 N, 1 mL) was added
  3. customAfter 2 hours the organic solvents were removed in vacuo
  4. customthe aqueous phase was decanted
  5. dissolutionThe residue was dissolved in dimethylformamide (2 mL)
  6. custompurified via RP-HPLC (eluent: water/MeCN w 0.1% TFA)
  7. customthe solvent was removed by lyophilization

Sources & evidence

ORD record
ord-ed5faa19a3784e04a386c2a4215b3817
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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