Pyridine → HCID 178498464, compound

HRID 889656Notes

Reaction equation

HRID 889656 reaction equation
[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=O)[CH:10]=1)=[O:4].Cl.[NH2:23][OH:24].N1C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=[N:23][OH:24])[CH:10]=1)=[O:4]

Participants

5

Reactant 3

HCID 1049PyridineHCID 443297Hydroxyamine hydrochlorideHCID 596121066-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester

Product 1

HCID 178498464HCID 178498464, compoundYield 83.7%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16, 5.19 g, 16.5 mmol) was slurried in methanol (160 mL). Hydroxylamine hydrochloride (3.35 g, 48.3 mmol) was added, followed by pyridine (10.0 mL, 123 mmol). The reaction mixture was stirred at reflux for 120 min. Methanol was evaporated under vacuum. H2O (200 mL) was added, and the residue was extracted into ether (4×150 mL). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (18; 4.54 g, 80%) as a white solid: mp 136-138° C. A 1:1 mixture of syn and anti isomers was observed by NMR spectroscopy and HPLC. 1H NMR (400 MHz, C6D6) δ 8.34 (br, 1H, NOH), 8.25 (br, 1H, NOH), 7.00 (s, 1H, H3), 6.71 (dd, JF-H=1.5 Hz, JH-H=9 Hz, 1H, aromatic), 6.69 (dd, JF-H=1.8 Hz, JH-H=9 Hz, 1H, aromatic), 6.57 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 6.53 (s, 1H, H3), 6.50 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 4.72 (s, 1H, NH), 4.52 (s, 1H, NH), 4.38 (dd, JH-H=3.6, 10.2 Hz, 1H, H6, isomer A), 4.23 (dd, JH-H=3.9, 11.4 Hz, 1H, H6, isomer B), 3.53 (s, 6H, CO2Me), 3.24 (s, 3H, OMe), 3.23 (s, 3H, OMe), 3.30 (dd, JH-H=4.2, 16.8 Hz, 1H, H5, isomer B), 2.63 (dd, JH-H=4.2, 15.3 Hz, 1H, H5, isomer A), 2.44 (dd, JH-H=10.5, 15.3 Hz, 1H, H5, isomer A), 2.33 (dd, JH-H=11.1, 16.8 Hz, 1H, H5, isomer B); 13C{1H} NMR (CDCl3) δ 164.2 (CO2Me), 163.9 (CO2Me), 153.7 (d, JF-C=250 Hz, C2′), 153.6 (d, JF-C=251 Hz, C2′), 152.6 (C4), 149.6 (C4), 144.3 (d, JF-C=3 Hz, C3′), 144.1 (d, JF-C=3 Hz, C3′), 139.2, 138.3, 128.6 (d, JF-C=12 Hz), 127.9 (d, JF-C=11 Hz), 127.8 (d, JF-C=3 Hz), 127.7 (d, JF-C=3 Hz), 125.3, 121.7, 101.7 (C3), 92.6 (C3), 61.42, 61.38, 52.7, 52.6, 49.3, 48.3, 33.6 (C5), 28.7 (C5). HRMS-ESI (m/z) calcd for C14H14ClFN2O4, 328.0621. found, 328.0620. Anal. Calcd for C14H14ClFN2O4: C, 51.15; H, 4.29; N, 8.52. Found: C, 51.31; H, 4.34; N, 8.40.

Workup

  1. temperatureat reflux for 120 min
  2. customMethanol was evaporated under vacuum
  3. additionH2O (200 mL) was added
  4. extractionthe residue was extracted into ether (4×150 mL)
  5. washThe combined extracts were washed with brine
  6. dry with materialdried (MgSO4)
  7. customevaporated under vacuum

Sources & evidence

ORD record
ord-fc302b3f205f47829e84864ad7e9a03b
Source dataset
uspto-grants-2012_08
Patent number
US08252938B2

Reaction notes

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