4-Methylmorpholine → 4-{2-[2-(Benzyloxycarbonyl-methyl-amino)-propionylamino]-3,3-dimethyl-butyryl}-3-(3,4-difluoro-phenoxy)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester

HRID 1965179Notes

Reaction equation

HRID 1965179 reaction equation
[C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:49]([O:53][C:54]([N:56]1[CH2:60][CH:59]([O:61][C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=2)[CH:58]2[N:70]([C:73](=[O:80])[CH:74]([NH2:79])[C:75]([CH3:78])([CH3:77])[CH3:76])[CH2:71][CH2:72][CH:57]12)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN1C(=O)CCC1.CCOC(C)=O.CCOCC>[C:49]([O:53][C:54]([N:56]1[CH2:60][CH:59]([O:61][C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=2)[CH:58]2[N:70]([C:73](=[O:80])[CH:74]([NH:79][C:14](=[O:16])[CH:12]([N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH3:17])[CH3:13])[C:75]([CH3:78])([CH3:77])[CH3:76])[CH2:71][CH2:72][CH:57]12)=[O:55])([CH3:52])([CH3:50])[CH3:51]

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 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 675179964-(2-Amino-3,3-dimethyl-butyryl)-3-(3,4-difluoro-phenoxy)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester

Product 1

HCID 676065094-{2-[2-(Benzyloxycarbonyl-methyl-amino)-propionylamino]-3,3-dimethyl-butyryl}-3-(3,4-difluoro-phenoxy)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl esterYield 89.2%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent2×

Procedure

To a solution Cbz-N(Me)-Ala-OH (1.2 g, 4.8 mmol) and HATU (2.0 g, 5.3 mmol) in NMP (30 mL) was added NMM (0.7 mL) followed by a solution of compound 33 (1.8 g, 4.0 mmol crude) in NMP (30 mL) at ambient temperature. After 16 h, the reaction mixture was diluted with 10% EtOAc in Et2O, washed successively with water, 1N HCl, 1N NaOH, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by RP-HPLC (2″ Dynamax® C18; 10-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 2.4 g of compound 34 as white solid. Mass spectrum, m/z [673.0] (M+H)+.

Workup

  1. washwashed successively with water, 1N HCl, 1N NaOH, and brine
  2. dry with materialdried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude residue was purified by RP-HPLC (2″ Dynamax® C18
  6. wait10-100% ACN/water containing 0.1% HOAc over 30 min

Sources & evidence

ORD record
ord-4c3a30ed854548abb8fc709b39d002ea
Source dataset
uspto-grants-2013_04
Patent number
US08415486B2

Reaction notes

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