4-Methylmorpholine → tert-butyl 2-(4-((tert-butoxycarbonyl)amino)-N-(4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate

HRID 923605Notes

Reaction equation

HRID 923605 reaction equation
[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=O)=[CH:28][CH:27]=1)[C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[OH:51]/[N:52]=[C:53](/[C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)\[NH2:54]>O1CCOCC1.CN(C=O)C.CC(=O)OCC>[C:20]([O:19][C:17]([NH:16][C:13]1[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:35])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]3[O:51][N:52]=[C:53]([C:55]4[CH:56]=[CH:57][C:58]([C:61]5[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=5)=[CH:59][CH:60]=4)[N:54]=3)=[CH:33][CH:34]=2)=[O:24])=[CH:11][CH:12]=1)=[O:18])([CH3:21])([CH3:23])[CH3:22]

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 18693170N-Hydroxy-4'-methyl-[1,1'-biphenyl]-4-carboximidamideHCID 711120664-((N-(2-(tert-butoxy)-2-oxoethyl)-4-((tert-butoxycarbonyl)amino)benzamido)methyl)benzoic acid

Product 1

HCID 71111627tert-butyl 2-(4-((tert-butoxycarbonyl)amino)-N-(4-(3-(4'-methyl-[1,1'-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetateYield 30%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

Prepared from INT-62 and INT-40. To a stirred solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-((tert-butoxycarbonyl)amino)benzamido)methyl)benzoic acid INT-62 (1.57 g, 3.24 mmol) in dioxane (40 mL) and 4-methylmorpholine (0.712 mL, 6.48 mmol) was added isobutyl carbonochloridate (0.420 mL, 3.24 mmol) dropwise. After 30 min the reaction mixture was added to a solution of (Z)—N′-hydroxy-4′-methyl-[1,1′-biphenyl]-4-carboximidamide INT-40 (0.733 g, 3.24 mmol) in DMF (4 mL). After 30 mins the reaction was heated at 110° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with EA (150 mL) and washed with brine (200 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (MeCN/DCM) to afford 659 mg (30%) of tert-butyl 2-(4-((tert-butoxycarbonyl)amino)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-63 as a viscous oil. LCMS-ESI (m/z) calculated for C40H42N4O6: 674; no m/z observed, tR=3.29 min (Method 10).

Workup

  1. customPrepared from INT-62 and INT-40
  2. temperatureThe reaction mixture was cooled to room temperature
  3. washwashed with brine (200 mL)
  4. customThe organics were pre-absorbed onto silica gel
  5. custompurified by chromatography (MeCN/DCM)

Sources & evidence

ORD record
ord-10f8a4fb5b864a29928d16a3b3c1c2ce
Source dataset
uspto-grants-2016_03
Patent number
US09278910B2

Reaction notes

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