4-Methylmorpholine → tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4'-methyl-[1,1'-biphenyl]-4-carbonyl)hydrazine carbonyl)benzyl)benzamido)acetate

HRID 923591Notes

Reaction equation

HRID 923591 reaction equation
[C:1]([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:39])=[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)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([C:72]([NH:74][NH2:75])=[O:73])=[CH:68][CH:67]=2)=[CH:62][CH:61]=1>C1COCC1.CN(C=O)C.C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:43])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]([NH:75][NH:74][C:72]([C:69]4[CH:68]=[CH:67][C:66]([C:63]5[CH:64]=[CH:65][C:60]([CH3:59])=[CH:61][CH:62]=5)=[CH:71][CH:70]=4)=[O:73])=[O:39])=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:12]=2)=[O:31])=[C:20]([C:27]([F:29])([F:28])[F:30])[CH:21]=1

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 13935694'-Methyl-[1,1'-biphenyl]-4-carbohydrazide2×HCID 710768754-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid

Product 1

HCID 71111628tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4'-methyl-[1,1'-biphenyl]-4-carbonyl)hydrazine carbonyl)benzyl)benzamido)acetateYield 65%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

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 (157 mg, 0.26 mmol) and 4-methylmorpholine (63.0 μL, 0.58 mmol) in THF (3 mL) was added isobutyl chloroformate (34.0 μL, 0.26 mmol). After 1 h, the reaction mixture was added to a stirring solution of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazide INT-50 (65.0 mg, 0.29 mmol) in DMF (2 mL). After 2 h, additional 4′-methyl-[1,1′-biphenyl]-4-carbohydrazide INT-50 (12 mg, 0.05 mmol) was added. After stirring at room temperature for 18 h, the reaction mixture was diluted with DCM (4 mL), washed with NaHCO3 (10 mL) and split though a hydrophobic frit. The crude product was purified by column chromatography (EA/isohexanes) to yield 138 mg (65%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4′-methyl-[1,1′-biphenyl]-4-carbonyl)hydrazine carbonyl)benzyl)benzamido)acetate INT-51. LCMS-ESI (m/z) calculated for C45H43F3N4O7: 808; found 809 [M+H]+, tR=2.75 min (Method 5).

Workup

  1. waitAfter 2 h
  2. addition(12 mg, 0.05 mmol) was added
  3. washwashed with NaHCO3 (10 mL)
  4. customsplit though a hydrophobic frit
  5. customThe crude product was purified by column chromatography (EA/isohexanes)

Sources & evidence

ORD record
ord-6c4987a3778b468584a4d036d1a85fb7
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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