Diisopropylethylamine → HCID 178502493, compound

HRID 2172523Notes

Reaction equation

HRID 2172523 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>Cl.CCO>[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([N:45]1[CH2:46][C@@H:47]([CH3:49])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:65])=[O:60]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 10910775(alphaR)-alpha-((Methoxycarbonyl)amino)benzeneacetic acidHCID 75951468(1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphateHCID 178502495HCID 178502495, compound

Product 1

HCID 178502493HCID 178502493, compound

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 702EthanolSolvent

Procedure

A solution of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (80 mg, 0.11 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h. The reaction was concentrated and the crude material dissolved in DMF (1.5 mL). To this solution was added a solution of (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (29 mg, 0.14 mmol) and COMU (52 mg, 0.12 mmol). To the resulting solution was added diisopropylethylamine (0.057 mL, 0.33 mmol). After stirring for 2 h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate: (42 mg, 45%). LCMS-ESI+: calculated for C48H52N8O7: 852.4; observed [M+1]+: 854.2.

Workup

  1. concentrationThe reaction was concentrated
  2. dissolutionthe crude material dissolved in DMF (1.5 mL)
  3. customthe reaction was quenched with 1N HCl (0.200 mL)
  4. custompurified by HPLC
  5. dissolutionAfter lyophilization, the TFA salt was dissolved in EtOAc
  6. washwashed with saturated NaHCO3
  7. dry with materialThe organic phase was dried over Na2SO4
  8. concentrationconcentrated
  9. dissolutionThe free base was then dissolved in MeCN/H2O

Sources & evidence

ORD record
ord-655b59f4aa33401abe0b37a90432bb94
Source dataset
uspto-grants-2015_06
Patent number
US09051340B2

Reaction notes

Loading…