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 → 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

HRID 2047313Notes

Reaction equation

C([O:5][C:6](=[O:34])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:30][CH3:31])[CH3:29])[CH:22]=3)[O:18][N:17]=2)=[CH:11][C:10]=1[CH2:32][CH3:33])(C)(C)C>Cl>[CH2:32]([C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]([CH2:30][CH3:31])[CH3:29])[CH:22]=3)[O:18][N:17]=2)[CH:13]=[C:14]([CH3:15])[C:9]=1[CH2:8][CH2:7][C:6]([OH:34])=[O:5])[CH3:33]

Participants

Conditions

Temperature: 65 °C

Procedure

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.

Workup

concentrationThe mixture is concentrated
customthe crude product is purified by prep

Sources & evidence

ORD record: ord-9051af1e7b094304b0ffbaa6097b08aa
Source dataset: uspto-grants-2013_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08592460B2

Reaction notes

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