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

HRID 879765Notes

Reaction equation

HRID 879765 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](O)=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76](=[O:94])[C@@H:77]([NH2:93])[CH2:78][C:79]1[CH:84]=[CH:83][C:82]([C:85]2[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=2)=[CH:81][CH:80]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:23])[NH:93][C@H:77]([C:76]([O:75][CH3:74])=[O:94])[CH2:78][C:79]2[CH:80]=[CH:81][C:82]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=3)=[CH:83][CH:84]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59337513Methyl (s)-2-amino-3-(4'-cyano-[1,1'-biphenyl]-4-yl)propanoateHCID 66719246(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester

Product 1

HCID 67250762(S)-7-[(S)-2-(4'-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl esterYield 79.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirring solution of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (146 mg), HBTU (95 mg) and DIEA in DMF (5 mL) was added (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (79 mg). After 4 hours, a sufficient amount of water was added and the mixture extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3 and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the crude amide. The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate from 80:20 to 60:40) to give the product (169 mg).

Workup

  1. extractionthe mixture extracted with ethyl acetate
  2. washThe organic layer was washed with 1 N HCl, saturated NaHCO3 and brine
  3. dry with materialdried over sodium sulfate
  4. customThe solvent was removed under reduced pressure
  5. customto provide the crude amide
  6. customThe residue was purified by column chromatography on silica gel (hexanes/ethyl acetate from 80:20 to 60:40)

Sources & evidence

ORD record
ord-95f1c6466d274089a693dc2b2607911b
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Reaction notes

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