Dimethylformamide → 7-(3-Fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester

HRID 902532Notes

Reaction equation

HRID 902532 reaction equation
[H-].[Na+].[CH3:3][C:4]1[S:14][C:7]2[NH:8][C:9](=[O:13])O[C:11](=[O:12])[C:6]=2[CH:5]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.[CH2:24](C(CC)(C([O-])=O)C([O-])=O)[CH3:25].[C:35](=[O:38])([O-])[O-:36].[Na+].[Na+].[CH3:41]N(C=O)C>>[CH2:24]([O:36][C:35]([C:41]1[C:9](=[O:13])[N:8]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([F:15])[CH:17]=2)[C:7]2[S:14][C:4]([CH3:3])=[CH:5][C:6]=2[C:11]=1[OH:12])=[O:38])[CH3:25]

Participants

7

Reactant 6

HCID 6228DimethylformamideHCID 10340Sodium CarbonateHCID 24758Sodium hydrideHCID 680073-Fluorobenzyl bromideHCID 69515632,2-DiethylpropanedioateHCID 138498796-Methyl-2H-thieno[2,3-d][1,3]oxazine-2,4(1H)-dione

Product 1

HCID 597020997-(3-Fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl esterYield 97%

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% dispersion in mineral oil, 5.6 g, 0.140 mol) was added slowly to a solution of 6-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (68) (11.07 g, 0.060 mol) in anhydrous DMF stirred under argon at 0° C. The solution was stirred for 15 minutes before adding 3-fluoro benzylbromide (7.6 mL, 0.062 mol). The solution was allowed to come at room temperature and further stirred for 3 hours. The solution was cooled to −10° C. and diethylmalonate (9.36 mL, 0.061 mol) was added slowly. The solution was heated at 110° C. (TLC control). The reaction was cooled and poured into aqueous sodium carbonate (7.7 g, 0.072 mol) solution. The aqueous solution was washed with isopropyl ether and acidified to pH 2 with dil. HCl. The solids were filtered, washed by cold water and air dried to yield 16.9 g (97%) of 7-(3-fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (69). 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 2.40 (d, J=1.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.22 (s, 2H), 7.05-7.15 (m, 4H), 7.38 (m, 1H), 13.25 m/z 362 (M+1).

Workup

  1. stirringThe solution was stirred for 15 minutes
  2. customto come at room temperature
  3. stirringfurther stirred for 3 hours
  4. temperatureThe solution was cooled to −10° C.
  5. temperatureThe solution was heated at 110° C. (TLC control)
  6. temperatureThe reaction was cooled
  7. washThe aqueous solution was washed with isopropyl ether
  8. filtrationThe solids were filtered
  9. washwashed by cold water and air
  10. customdried

Sources & evidence

ORD record
ord-7e3c2ccc48354465ab0b567df65272da
Source dataset
uspto-grants-2008_04
Patent number
US07365200B2

Reaction notes

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