4-Methylmorpholine → HCID 178490477, compound

HRID 923577Notes

Reaction equation

HRID 923577 reaction equation
C([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)(C)(C)C.CN1CCOCC1.ClC(O[CH2:55][CH:56]([CH3:58])[CH3:57])=O.[CH3:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([C:72](=[N:74][NH2:75])[NH2:73])=[CH:68][CH:67]=2)=[CH:62][CH:61]=1>O1CCOCC1.CN(C=O)C>[C:56]([CH:7]([N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]2[N:73]=[C:72]([C:69]3[CH:68]=[CH:67][C:66]([C:63]4[CH:64]=[CH:65][C:60]([CH3:59])=[CH:61][CH:62]=4)=[CH:71][CH:70]=3)[NH:74][N:75]=2)=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:28])([F:30])[F:29])=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:43])([CH3:58])([CH3:57])[CH3:55]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 68606274'-Methyl-[1,1'-biphenyl]-4-carbohydrazonamideHCID 710768754-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid

Product 1

HCID 178490477HCID 178490477, compoundYield 9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Procedure

To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (216 mg, 0.360 mmol) in dioxane (4 mL) were added N-methylmorpholine (79.0 μl, 0.719 mmol) and isobutyl chloroformate (49.0 μl, 0.378 mmol). After stirring at room temperature for 1 h, the reaction mixture was added drop wise through a frit to a stirred solution of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazonamide INT-39 (89.0 mg, 0.396 mmol) in DMF (2 mL). After 30 min, the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to room temperature then poured onto water (50 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed successively with citric acid (10 mL, 0.1 M aqueous solution) and NaHCO3 (10 mL) then dried over MgSO4 and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and treated with TFA (2 mL). The reaction mixture was allowed to stir at room temperature for 2 h then concentrated and purified by preparative HPLC to afford 24 mg (9%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,4-triazol-3-yl)benzyl)benzamido)acetic acid 361. LCMS-ESI (m/z) calculated for C41H34F3N5O5: 733; found 734 [M+H]+, tR=7.72 min (Method 9). 1H NMR (400 MHz, DMSO) δ 14.54 (s, 1H), 12.84 (s, 1H), 10.34 (s, 1H), 8.25-8.13 (m, 2H), 8.08 (d, J=7.9 Hz, 2H), 7.94-7.73 (m, 2H), 7.70-7.59 (m, 4H), 7.57-7.35 (m, 5H), 7.32 (d, J=7.9 Hz, 2H), 7.25-7.14 (m, 2H), 4.73 (s, 1H), 4.65 (s, 1H), 4.03 (s, 1H), 3.93 (s, 1H), 3.90-3.76 (m, 5H), 2.37 (s, 3H).

Workup

  1. waitAfter 30 min
  2. temperaturethe reaction mixture was heated to 120° C. for 1 h
  3. temperatureto cool to room temperature
  4. additionthen poured onto water (50 mL)
  5. extractionextracted with DCM (3×20 mL)
  6. washThe combined organic extracts were washed successively with citric acid (10 mL, 0.1 M aqueous solution) and NaHCO3 (10 mL)
  7. dry with materialthen dried over MgSO4
  8. customevaporated
  9. customThe crude material was purified by column chromatography (EA/isohexanes)
  10. dissolutionThe isolated material was dissolved in DCM (2 mL)
  11. additiontreated with TFA (2 mL)
  12. stirringto stir at room temperature for 2 h
  13. concentrationthen concentrated
  14. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-35720be7adf34beb9f66973cae050b68
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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