Cesium carbonate → (S)-2-sec-Butylamino-6-difluoromethoxy-isonicotinic acid ethyl ester

HRID 1436599Notes

Reaction equation

C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([OH:17])[N:14]=[C:13]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:12]=1)[CH3:8].COC(=O)[C:27](Cl)([F:29])[F:28]>CC(=O)CC>[CH2:7]([O:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([O:17][CH:27]([F:29])[F:28])[N:14]=[C:13]([NH:18][C@H:19]([CH2:21][CH3:22])[CH3:20])[CH:12]=1)[CH3:8]

Participants

Conditions

Temperature: 70 °C

Procedure

Add cesium carbonate (0.352 g, 1.08 mmol) to (S)-2-sec-butylamino-6-hydroxy-isonicotinic acid ethyl ester (0.172 g, 0.72 mmol) in butan-2-one (10 mL) ((Bioorg. Med. Chem. Lett., 12, 2149-2152 (2002)). Heat at 70° C. for 30 min and add chlorodifluoroacetic acid methyl ester (0.24 mL, 2.16 mmol) in three equal portions over 3 h. Heat for 3 days at 70° C. Add again chlorodifluoroacetic acid methyl ester (0.24 mL, 2.16 mmol) in three equal portions over 3 h and stir at room temperature for 24 h. Concentrate and dissolve the crude mixture in ethyl acetate and filter. Purify (silica gel chromatography, eluting with 2:98 to 6:92 ethyl acetate:hexanes) to give the title compound (0.135 g, 65%). MS (ES): m/z=289 [M+H].

Workup

temperatureHeat for 3 days at 70° C
concentrationConcentrate
dissolutiondissolve the crude mixture in ethyl acetate
filtrationfilter
customPurify
wash(silica gel chromatography, eluting with 2:98 to 6:92 ethyl acetate:hexanes)

Sources & evidence

ORD record: ord-546af9a563174cbeb7a29c6624741295
Source dataset: uspto-grants-2009_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07618978B2

Reaction notes

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