Acetic Acid → 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-N-(2-methylpropoxy)picolinamide

HRID 43244

Reaction equation

Cl.[CH2:2]([O:6][NH2:7])[CH:3]([CH3:5])[CH3:4].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25](O)=[O:26])[C:10]=1[Cl:28].Cl.C(N=C=NCCCN(C)C)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCCl>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25]([NH:7][O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:26])[C:10]=1[Cl:28]

Participants

Conditions

Temperature: 23 °C

Procedure

O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+).

Workup

customprepared as in Balko et al., U.S
customat 23° C
concentrationconcentrated by a nitrogen stream

Sources & evidence

ORD record: ord-464b6be03b7d42e0b654d9a41c40fae6
Source dataset: uspto-grants-2013_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08536331B2

Linked notes

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