6-(2,6-Difluoro-4-methoxyphenyl)-5-fluoropicolinic acid → N-(5-((2S,5R,6R)-5-Amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinamide

HRID 521966Notes

Reaction equation

HRID 521966 reaction equation
[F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:28]=1[C:36]1[N:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[CH:38][C:37]=1[F:45]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:42](=[O:43])[C:40]2[CH:39]=[CH:38][C:37]([F:45])=[C:36]([C:28]3[C:29]([F:35])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[N:41]=2)[CH2:6][CH2:7]1

Participants

3

Reactant 2

HCID 592264666-(2,6-Difluoro-4-methoxyphenyl)-5-fluoropicolinic acidHCID 86713831tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate2×

Product 1

HCID 73437807N-(5-((2S,5R,6R)-5-Amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinamideYield 26%

Procedure

Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinic acid (see WO2010/56576) gave 187 as a white solid (22 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.31 (dd, J=8.6, 4.0 Hz, 1H), 8.21 (s, 1H), 7.71-7.63 (m, 1H), 6.64 (d, J=10.1 Hz, 2H), 4.84-4.73 (m, 2H), 4.07-3.89 (m, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.41 (dd, J=23.1, 9.5 Hz, 1H), 2.67 (br s, 1H), 2.15-2.08 (m, 1H), 2.08-1.94 (m, 1H), 1.95-1.84 (m, 1H), 1.85-1.73 (m, 1H). LCMS (ES+) m/z 494 (M+1).

Sources & evidence

ORD record
ord-6f6e1c89027d4adbab9047161837b1b7
Source dataset
uspto-grants-2016_05
Patent number
US09328106B2

Reaction notes

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