Diisopropylethylamine → {1-[4-Cyclopentyl-6-(6-fluoro-1H-indol-3-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carbonyl]-2,2-dimethyl-propyl}-carbamic acid tert-butyl ester

HRID 1949625Notes

Reaction equation

HRID 1949625 reaction equation
[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].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.[CH:50]1([N:55]2[CH2:59][CH:58]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:57]3[NH:70][CH2:71][CH2:72][CH:56]23)[CH2:54][CH2:53][CH2:52][CH2:51]1>CN1C(=O)CCC1.CCOC(C)=O>[C:13]([O:12][C:10](=[O:11])[NH:1][CH:2]([C:7]([N:70]1[CH2:71][CH2:72][CH:56]2[N:55]([CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)[CH2:59][CH:58]([C:60]3[C:68]4[C:63](=[CH:64][C:65]([F:69])=[CH:66][CH:67]=4)[NH:62][CH:61]=3)[CH:57]12)=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6])([CH3:16])([CH3:15])[CH3:14]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2734668(S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 674097773-(1-Cyclopentyl-octahydro-pyrrolo[3,2-b]pyrrol-3-yl)-6-fluoro-1H-indole

Product 1

HCID 67408721{1-[4-Cyclopentyl-6-(6-fluoro-1H-indol-3-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carbonyl]-2,2-dimethyl-propyl}-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution containing Boc-L-Tle-OH (160 mg, 0.7 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (264 mg, 0.7 mmol) and DIPEA (148 mg, 0.7 mmol) were added followed by the addition of crude 37 (220 mg, 0.7 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc and washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel HPLC (2″ Dynamax SiO2, 20-100% EtOAc/hexanes over 30 min; Flow: 40 mL/min) to afford 280 mg (66%, 2 steps) of 38. 1H NMR (CDCl3, 300 MHz): δ8.37 (s, 1H), 7.58 (dd, J=5.7, 8.4 Hz, 1H), 7.12 (s, 1H), 6.73 (dd, J=1.8, 9.6 Hz, 1H), 6.65-6.58 (m, 1H), 5.07 (d, J=9.3 Hz, 1H), 4.76 (app t, J=8.4 Hz, 1H), 3.76 (d, J=9.3 Hz, 1H), 3.69 (app t, J=7.2 Hz, 1H), 3.41 (app t, J=8.7 Hz, 1H), 3.09 (app t, J=6.9 Hz, 1H), 3.00-2.94 (m, 2H), 2.66-2.50 (m, 2H), 1.69-1.51 (m, 5H), 1.39 (m, 3H), 1.18 (s, 9H), 0.01 (s, 9H) ppm. Mass spectrum, m/z [527.4] (M+H)+.

Workup

  1. temperatureThe reaction mixture was slowly warmed to ambient temperature
  2. washwashed successively with aqueous NaHCO3 and brine
  3. dry with materialdried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified by silica gel HPLC (2″ Dynamax SiO2, 20-100% EtOAc/hexanes over 30 min

Sources & evidence

ORD record
ord-b185a60074af454f8d96069d1f383b35
Source dataset
uspto-grants-2013_03
Patent number
US08399683B2

Reaction notes

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