4-Methylmorpholine → (S)-3-cyclohexyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide

HRID 1925925Notes

Reaction equation

HRID 1925925 reaction equation
[CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.[CH3:28]N1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C([O:61][C@@H:62]([CH2:70][O:71][CH2:72][CH3:73])[CH2:63][N:64]1[CH:68]=[CH:67][C:66]([NH2:69])=[N:65]1)C>O1CCCC1.O>[CH:16]1([CH2:15][C@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[C:12]([NH:69][C:66]2[CH:67]=[CH:68][N:64]([CH2:63][C@@H:62]3[CH2:70][O:71][C:72]([CH3:73])([CH3:28])[O:61]3)[N:65]=2)=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67521459(S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acidHCID 675214731-((R)-2,3-diethoxy-propyl)-1H-pyrazol-3-ylamine

Product 1

HCID 67520957(S)-3-cyclohexyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamideYield 65.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (Example 7, step 2) (150 mg, 0.40 mmol), in tetrahydrofuran (5 mL) was treated with commercially available N-methylmorpholine (0.11 mL, 1.01 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (384 mg, 1.01 mmol) and 1-((R)-2,3-diethoxy-propyl)-1H-pyrazol-3-ylamine (96 mg, 0.48 mmol) (prepared following the procedure described in WO2009127546). The mixture was heated in a sealed tube was heated for 24 hours at 90° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-cyclohexyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionamide (145 mg, 65.3%), as a white solid.

Workup

  1. customprepared
  2. temperatureThe mixture was heated in a sealed tube
  3. extractionextracted with ethyl acetate (3×)
  4. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  5. concentrationconcentrated in vacuo
  6. washhexane-ethyl acetate gradient elution

Sources & evidence

ORD record
ord-f38d5be183d04a199bec9ec1ec7ba927
Source dataset
uspto-grants-2012_05
Patent number
US08178689B2

Reaction notes

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