Diisopropylethylamine → {2-[4-(2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-6-(6-fluoro-1H-indol-3-yl)-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester

HRID 1949660Notes

Reaction equation

HRID 1949660 reaction equation
[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:9](O)=[O:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:52]([O:56][C:57](=[O:86])[NH:58][CH:59]([CH:80]1[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1)[C:60]([N:62]1[CH2:66][CH2:65][CH:64]2[NH:67][CH2:68][CH:69]([C:70]3[C:78]4[C:73](=[CH:74][C:75]([F:79])=[CH:76][CH:77]=4)[NH:72][CH:71]=3)[CH:63]12)=[O:61])([CH3:55])([CH3:54])[CH3:53]>CN1C(=O)CCC1.C(OCC)C>[C:52]([O:56][C:57](=[O:86])[NH:58][CH:59]([CH:80]1[CH2:81][CH2:82][CH2:83][CH2:84][CH2:85]1)[C:60]([N:62]1[CH2:66][CH2:65][CH:64]2[N:67]([C:9](=[O:10])[CH:2]([NH:1][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH2:68][CH:69]([C:70]3[C:78]4[C:73](=[CH:74][C:75]([F:79])=[CH:76][CH:77]=4)[NH:72][CH:71]=3)[CH:63]12)=[O:61])([CH3:55])([CH3:53])[CH3:54]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 7004938N-(tert-Butoxycarbonyl)-L-cyclohexylglycineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67410158HCID 67410158, compound

Product 1

HCID 67407842{2-[4-(2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-6-(6-fluoro-1H-indol-3-yl)-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl esterYield 82.4%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution containing Boc-Chg-OH (167 mg, 0.64 mmol) in anhydrous NMP (6 mL) was cooled to 0° C. HATU (247 mg, 0.64 mmol) and DIPEA (94 mg, 0.73 mmol) were added followed by the addition of crude 49 (300 mg, 0.62 mmol). The reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and washed successively with water, 1M HCl, water, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (2:1-1:1 hexanes/EtOAc) to afford 370 mg (82%) of 121 as a white solid. 1H NMR (300 MHz, CDCl3), mixture of rotomers: δ8.32 (dd, J=5.4, 8.7 Hz, 0.4H, minor rotomer), 8.21 (dd, J=5.7, 9.0 Hz, 1.6H, major rotomer), 8.12 (br s, 0.4H), 8.06 (br s, 1.6H), 7.06 (m, 2H), 7.01 (m, 2H), 6.98 (m, 2H), 6.94 (m, 2H), 5.31 (app d, J=9.3 Hz, 2H), 5.22 (app d, J=9.6 Hz, 2H), 4.60 (d, J=5.1 Hz, 2H), 4.46-4.32 (m, 10H), 4.04 (d, J=5.7 Hz, 2H), 3.64 (dd, J=6.0, 10.8 Hz, 2H), 3.33 (m, 2H), 2.43 (dd, J=5.4, 13.4 Hz, 2H), 1.89-1.55 (m, 10H), 1.47 (s, 3.6H, minor rotomer), 1.44 (s, 14.4H, major rotomer), 1.28-1.02 (m, 10H) ppm. Mass spectrum, m/z [724.5] (M+H)+.

Workup

  1. temperatureThe reaction mixture was slowly warmed to ambient temperature
  2. washwashed successively with water, 1M HCl, water, aqueous NaHCO3, and brine
  3. dry with materialdried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified by flash silica gel chromatography (2:1-1:1 hexanes/EtOAc)

Sources & evidence

ORD record
ord-67f0b78b93494876b797fe82051bb04d
Source dataset
uspto-grants-2013_03
Patent number
US08399683B2

Reaction notes

Loading…