4-Methylmorpholine → HCID 86705898, compound

HRID 339258Notes

Reaction equation

HRID 339258 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][C:47]([CH3:104])([CH3:103])[C@H:48]([NH:92][C:93](=[O:102])[O:94][CH2:95][C:96]1[CH:101]=[CH:100][CH:99]=[CH:98][CH:97]=1)[C:49](=[O:91])[N:50]1[CH2:54][C@@H:53]([C:55]2[CH:64]=[C:63]3[C:58]([CH2:59][C@@H:60]([C:65](=[O:77])[NH:66][C@H:67]4[C:76]5[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=5)[CH2:70][CH2:69][CH2:68]4)[NH:61][CH2:62]3)=[CH:57][CH:56]=2)[CH2:52][C@H:51]1[C:78](=[O:90])[NH:79][C@H:80]1[C:89]2[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=2)[CH2:83][CH2:82][CH2:81]1.CN1CCOCC1>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[CH2:95]([O:94][C:93]([NH:92][C@@H:48]([C:47]([CH3:104])([CH3:103])[CH3:46])[C:49]([N:50]1[C@H:51]([C:78](=[O:90])[NH:79][C@H:80]2[C:89]3[C:84](=[CH:85][CH:86]=[CH:87][CH:88]=3)[CH2:83][CH2:82][CH2:81]2)[CH2:52][C@H:53]([C:55]2[CH:64]=[C:63]3[C:58]([CH2:59][C@@H:60]([C:65](=[O:77])[NH:66][C@H:67]4[C:76]5[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=5)[CH2:70][CH2:69][CH2:68]4)[N:61]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([S:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:15])[CH3:14])[CH2:62]3)=[CH:57][CH:56]=2)[CH2:54]1)=[O:91])=[O:102])[C:96]1[CH:97]=[CH:98][CH:99]=[CH:100][CH:101]=1

Participants

8

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 86705895HCID 86705895, compound2×HCID 86705897HCID 86705897, compound

Product 1

HCID 86705898HCID 86705898, compoundYield 82.7%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-((2-methoxy-2-oxoethyl)thio)-3-methylbutanoic acid (0.19 g, 0.58 mmol) in DMF (4 mL) was added HATU (0.24 g, 0.62 mmol) at ice bath temperature. The reaction mixture was stirred at 0° C. for 10 min, followed by addition of a solution of benzyl ((S)-3,3-dimethyl-1-oxo-1-((2S,4R)-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-4-((S)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyrrolidin-1-yl)butan-2-yl)carbamate (Compound A, 0.35 g, 0.44 mmol) in DMF (2 mL) and NMM (0.08 mL, 0.71 mmol). The resulting mixture was stirred at rt for 4 h. The reaction mixture was poured into a separatory funnel containing EtOAc and brine. The organic layer was separated and washed with sat. aq. NaHCO3 solution and brine successively. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (gradient elution from 0 to 60% EtOAc/DCM) to afford the title compound (0.40 g, 82%) as a white foam. MS (ESI+) m/z 1099.6 (M+H)+.

Workup

  1. stirringThe resulting mixture was stirred at rt for 4 h
  2. additionThe reaction mixture was poured into a separatory funnel
  3. customThe organic layer was separated
  4. washwashed with sat. aq. NaHCO3 solution and brine successively
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated in vacuo
  8. customThe residue was purified by flash chromatography (gradient elution from 0 to 60% EtOAc/DCM)

Sources & evidence

ORD record
ord-edd856de613f4182bca8a7ade41e1a3b
Source dataset
uspto-grants-2014_11
Patent number
US08889712B2

Reaction notes

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