Potassium Carbonate → (S)-7-[(S)-2-(4'-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester

HRID 2369121Notes

Reaction equation

HRID 2369121 reaction equation
[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:42])=[C:13]([NH2:41])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[CH:49]([C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)=[CH:55][CH:54]=1)[C:50](Cl)=[O:51].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[C:12]([O:42][C@@H:49]([C:53]4[CH:58]=[CH:57][C:56]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=5)=[CH:55][CH:54]=4)[C:50](=[O:51])[NH:41]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 593375102-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chlorideHCID 66922945(S)-6-amino-3-[(S)-2-(4'-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

Product 1

HCID 66922703(S)-7-[(S)-2-(4'-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl esterYield 61.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

(S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.75 mmol) was dissolved in 5 mL EtOAc, 10 mL water and 15 g sodium bicarbonate added. 2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride (1.93 mmol) in 5 mL EtOAc was added to the mixture. The resulting mixture stirred at r.t. for 1.5 h. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was dissolved in 5 mL DMF and potassium carbonate (8.75 mmol) added. The reaction stirred at r.t. for 3 h and was poured onto ethyl acetate and water. The organic was dried and concentrated. The residue was purified over silica gel (-hexanes-ethyl acetate) to provide (S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester (931 mg). LC-MS (m/z) 862.

Workup

  1. washThe organic layer was washed with brine
  2. dry with materialdried over sodium sulfate
  3. concentrationconcentrated
  4. dissolutionThe resulting residue was dissolved in 5 mL DMF
  5. stirringThe reaction stirred at r.t. for 3 h
  6. customThe organic was dried
  7. concentrationconcentrated
  8. customThe residue was purified over silica gel (-hexanes-ethyl acetate)

Sources & evidence

ORD record
ord-12bc77e0cd87499e8c0c1494584bfe00
Source dataset
uspto-grants-2014_04
Patent number
US08703766B2

Reaction notes

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