4-Methylmorpholine → 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid

HRID 923581노트

반응식

HRID 923581 반응식
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: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)(C)(C)C.CN1CCOCC1.ClC(OCC(C)C)=O.O[N:60]=[C:61]([NH2:69])[C:62]1[CH:67]=[CH:66][C:65]([CH3:68])=[CH:64][CH:63]=1>O1CCOCC1.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:12]=[CH:11][C:10]([C:9]([N:8]([CH2:7][C:6]([OH:5])=[O:43])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]4[O:39][N:69]=[C:61]([C:62]5[CH:67]=[CH:66][C:65]([CH3:68])=[CH:64][CH:63]=5)[N:60]=4)=[CH:41][CH:42]=3)=[O:32])=[CH:15][CH:14]=2)=[O:31])=[C:20]([C:27]([F:29])([F:28])[F:30])[CH:21]=1

참가 물질

8

반응물 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 209113N'-Hydroxy-4-methylbenzenecarboximidamideHCID 710768754-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid

생성물 1

HCID 711116292-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid수율 14%

시약·촉매·용매 3

HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 312751,4-Dioxane용매

실험 절차

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 (141 mg, 0.235 mmol) and 4-methylmorpholine (57.0 μl, 0.52 mmol) in dioxane (4 mL) was added isobutyl chloroformate (31.0 μl, 0.24 mmol). After 1 h, the reaction mixture was added through a frit to a stirred solution of N′-hydroxy-4-methylbenzimidamide (38.8 mg, 0.258 mmol) in DMF (2 mL). After stirring at room temperature for 1 h, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM (4 mL), washed with NaHCO3 (10 mL), split through a hydrophobic frit and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was taken up in DCM (2 mL), treated with TFA (2 mL) and allowed to stir for 2 h. The solvents were evaporated and the residue purified by preparative HPLC to afford 22 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 363 as a white solid. LCMS-ESI (m/z) calculated for C35H29F3N4O6: 658; found 659 [M+H]+, tR=8.01 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 10.34 (s, 1H), 8.32-8.11 (m, 2H), 8.11-7.86 (m, 2H), 7.71-7.52 (m, 4H), 7.50-7.29 (m, 5H), 7.26-7.16 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.99 (s, 1H), 3.92-3.76 (m, 5H), 2.42 (s, 3H).

후처리

  1. temperaturethe reaction mixture was heated to 120° C. for 2 h
  2. temperatureto cool to room temperature
  3. washwashed with NaHCO3 (10 mL)
  4. customsplit through a hydrophobic frit
  5. customevaporated
  6. customThe crude material was purified by column chromatography (EA/isohexanes)
  7. additiontreated with TFA (2 mL)
  8. stirringto stir for 2 h
  9. customThe solvents were evaporated
  10. customthe residue purified by preparative HPLC

출처 및 근거

ORD 기록
ord-c5dfe59a882947669ccebe37989925f4
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09278910B2

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