6-(4-(2-((Tert-butyldimethylsilyl)oxy)ethoxy)-2,6-difluorophenyl)-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-(2-hydroxyethoxy)phenyl)-5-fluoropicolinamide

HRID 521969Notes

Reaction equation

HRID 521969 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.[Si]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]2[N:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:39]([F:54])[CH:38]=1)(C(C)(C)C)(C)C>>[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:50](=[O:51])[C:48]2[CH:47]=[CH:46][C:45]([F:53])=[C:44]([C:40]3[C:41]([F:43])=[CH:42][C:37]([O:36][CH2:35][CH2:34][OH:33])=[CH:38][C:39]=3[F:54])[N:49]=2)[CH2:6][CH2:7]1

Participants

3

Reactant 2

HCID 666520856-(4-(2-((Tert-butyldimethylsilyl)oxy)ethoxy)-2,6-difluorophenyl)-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 73437753N-(5-((2S,5R,6R)-5-Amino-6-fluorooxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2,6-difluoro-4-(2-hydroxyethoxy)phenyl)-5-fluoropicolinamideYield 62%

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-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinic acid (see US2012/225062) gave 190 as a white solid (29 mg, 62%). 1H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.40 (dd, J=8.6, 3.9 Hz, 1H), 8.27 (dd, J=8.6, 8.6 Hz, 1H), 8.10 (s, 1H), 7.15 (d, J=10.5 Hz, 2H), 5.09 (dd, J=8.4, 3.6 Hz, 1H), 4.86-4.83 (d, J=48 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 4.12-3.92 (m, 2H), 3.92-3.86 (m, 5H), 3.70-3.38 (br s, 1H), 3.36-3.24 (m, 1H), 2.33-2.25 (m, 1H), 2.02-1.87 (m, 1H), 1.87-1.75 (m, 1H), 1.75-1.63 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 524 (M+1).

Sources & evidence

ORD record
ord-72807ba32ab5419bb3b15b13329d4b83
Source dataset
uspto-grants-2016_05
Patent number
US09328106B2

Reaction notes

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