Diisopropylethylamine → 3-(2-Ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid tert-butyl ester

HRID 2047312노트

반응식

HRID 2047312 반응식
[CH2:1]([N:3]([CH3:14])[C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:7]([OH:9])=O)[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72](=[NH:75])[NH:73]O)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C.O.C([O-])(O)=O.[Na+].O1CCOCC1>[C:57]([O:61][C:62](=[O:78])[CH2:63][CH2:64][C:65]1[C:70]([CH3:71])=[CH:69][C:68]([C:72]2[N:73]=[C:7]([C:6]3[CH:10]=[C:11]([CH3:13])[N:12]=[C:4]([N:3]([CH2:1][CH3:2])[CH3:14])[CH:5]=3)[O:9][N:75]=2)=[CH:67][C:66]=1[CH2:76][CH3:77])([CH3:60])([CH3:59])[CH3:58]

참가 물질

9

반응물 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 584180642-(Ethyl-methyl-amino)-6-methyl-isonicotinic acidHCID 178436624tert-butyl 3-[2-ethyl-4-[(Z)-N'-hydroxycarbamimidoyl]-6-methylphenyl]propanoate

생성물 1

HCID 685784423-(2-Ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid tert-butyl ester

시약·촉매·용매 4

HCID 962Water용매HCID 6228Dimethylformamide용매HCID 312751,4-Dioxane용매HCID 516892Sodium Bicarbonate용매

실험 절차

To a solution of 2-(ethyl-methyl-amino)-6-methyl-isonicotinic acid (106 mg, 0.459 mmol) and DIPEA (178 mg, 1.38 mmol) in DMF (2 mL) is added PyBOP (253 mg, 0.486 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid tert-butyl ester (140 mg, 0.459 mmol) is added. Stirring is continued for 1 h at 0° C. The reaction mixture is diluted with water (2 mL) and sat. aq. NaHCO3-solution and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxyamidine ester intermediate; LC-MS: tR=0.92 min; [M+1]+=483.22. This material is dissolved in dioxane and then stirred at 80° C. for 15 h. The solvent is removed in vacuo to give crude 3-(2-ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid tert-butyl ester; LC-MS: tR=1.03 min; [M+1]+=463.31. The crude ester is dissolved in 6 N aq. HCl (10 mL) and stirred at 65° C. for 18 h. The mixture is concentrated and the crude product is purified by prep. TLC using DCM containing 11% of methanol as eluent to give 3-(2-ethyl-4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (5 mg) as a yellow resin; LC-MS: tR=0.89 min; [M+1]+=409.19.

후처리

  1. additionis added
  2. extractionextracted three times with diethyl ether
  3. dry with materialextracts are dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give the crude hydroxyamidine ester intermediate
  7. stirringstirred at 80° C. for 15 h
  8. customThe solvent is removed in vacuo

출처 및 근거

ORD 기록
ord-0b3b9757e3694ddbb2ef1948e4c44c68
출처 데이터셋
uspto-grants-2013_11
특허 번호
US08592460B2

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