Lithium hydride → 4-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylic acid methyl ester

HRID 15918

反応式

HRID 15918 の反応式
[H-].[Li+].[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[NH:9][CH:8]=1)=[O:6].Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](=[O:23])[N:9]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:8]=1)=[O:6]

参加物

5

反応物 3

HCID 62714Lithium hydrideHCID 127070373-(Bromomethyl)pyridine hydrobromideHCID 666735074-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester

生成物 1

HCID 666742304-(4-Bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylic acid methyl ester

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

Lithium hydride (14 mg, 1.64 mmol) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.190 g, 0.529 mmol) in DMF (5 mL) at 0° C. After stirring for 30 minutes, 3-bromomethyl-pyridine hydrobromide (0.14 g, 0.53 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. After quenching with ice water, the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography (1% MeOH in methylene chloride) yielded 4-(4-bromo-2-fluorophenylamino)-5-fluoro-6-oxo-1-pyridin-3-ylmethyl-1,6-dihydropyridine-3-carboxylic acid methyl ester. The methyl ester was dissolved in 4:1 THF:MeOH (5 mL) and 1 M LiOH solution (1.1 mL) was added. After 1 hour, the reaction mixture was acidified to pH 1 with 10% aqueous HCl solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Trituration with diethyl ether gave 0.160 g (69% two step yield) clean desired product. MS APCI (−) m/z 434, 436 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 9.40 (bs, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.51 (d, 1H), 7.74 (d, 1H), 7.58 (d, 1H), 7.39 (m, 1H), 7.34 (s, 1H), 7.16 (m, 1H), 0.525 (s, 1H).

後処理

  1. stirringstirred for 16 hours
  2. customAfter quenching with ice water
  3. extractionthe reaction mixture was extracted with ethyl acetate
  4. dry with materialThe combined organic extracts were dried (MgSO4)
  5. concentrationconcentrated under reduced pressure
  6. customPurification by flash column chromatography (1% MeOH in methylene chloride)

出典と根拠

ORDレコード
ord-de40c9ab3d954d63bc0d4741d43f1d89
出典データセット
uspto-grants-2010_06
特許番号
US07732616B2

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