N-methyl-2-pyrrolidone → (1-{1-[6-(3,4-Difluoro-phenoxy)-4-(tetrahydro-pyran-4-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester

HRID 1965176Notes

Reaction equation

HRID 1965176 reaction equation
CN(C(ON1N=NC2C=[CH:13][CH:14]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:35]([CH3:41])[C@H:36]([C:38]([OH:40])=O)[CH3:37])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(C(C)C)C(C)C.[NH2:51][CH:52]([C:78]([CH3:81])([CH3:80])[CH3:79])[C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([C:72]3N=CC=CN=3)[CH2:61][CH:62]([O:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[C:66]([F:71])[CH:65]=3)[CH:56]12)=[O:54].CN1[C:87](=[O:88])[CH2:86]CC1>>[CH2:28]([O:27][C:25](=[O:26])[N:35]([CH:36]([C:38](=[O:40])[NH:51][CH:52]([C:53]([N:55]1[CH2:59][CH2:58][CH:57]2[N:60]([CH:72]3[CH2:14][CH2:13][O:88][CH2:87][CH2:86]3)[CH2:61][CH:62]([O:63][C:64]3[CH:69]=[CH:68][C:67]([F:70])=[C:66]([F:71])[CH:65]=3)[CH:56]12)=[O:54])[C:78]([CH3:79])([CH3:81])[CH3:80])[CH3:37])[CH3:41])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1

Participants

6

Reactant 5

HCID 13387N-methyl-2-pyrrolidone2×HCID 81531DiisopropylethylamineHCID 7016365Z-N-Me-Ala-OHHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 675059372-Amino-1-[6-(3,4-difluoro-phenoxy)-4-pyrimidin-2-yl-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl]-3,3-dimethyl-butan-1-one

Product 1

HCID 67608273(1-{1-[6-(3,4-Difluoro-phenoxy)-4-(tetrahydro-pyran-4-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl esterYield 100%

Conditions

Temperature
0 °C

Procedure

HATU (105 mg, 0.28 mmol) and Cbz-N(Me)Ala-OH (65 mg, 0.28 mmol) were dissolved in NMP (0.5 mL) and DIPEA (65 μL, 0.36 mmol) was added. The reaction mixture was cooled to 0° C. and a solution of 30 (106 mg, 0.25 mmol) in NMP (2 mL) was added. The reaction mixture was warmed to ambient temperature. After 12 h, the reaction mixture was quenched with 1N NaOH (0.5 mL) and diluted with water, extracted with 10:1 Et2O/EtOAc. The combined organic extracts were washed successively with water, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 180 mg (100%) of 31 as a beige-colored foam which was used without further purification. Mass spectrum, m/z [651.2] (M+H)+.

Workup

  1. temperatureThe reaction mixture was warmed to ambient temperature
  2. customthe reaction mixture was quenched with 1N NaOH (0.5 mL)
  3. additiondiluted with water
  4. extractionextracted with 10:1 Et2O/EtOAc
  5. washThe combined organic extracts were washed successively with water, saturated aqueous NaHCO3, and brine
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-714609eaa61e48d396685b9d73b94b63
Source dataset
uspto-grants-2013_04
Patent number
US08415486B2

Reaction notes

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