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

HRID 902492Notes

Reaction equation

HRID 902492 reaction equation
[NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])O[C:2]1=[O:11].[H-].[Na+].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.[CH2:23](C(CC)(C([O-])=O)C([O-])=O)[CH3:24].[C:34](=[O:37])([O-])[O-:35].[K+].[K+].[CH3:40]N(C=O)C>O>[CH2:23]([O:35][C:34]([C:40]1[C:2](=[O:11])[N:1]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4]=1[OH:10])=[O:37])[CH3:24]

Participants

8

Reactant 6

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 24758Sodium hydrideHCID 680073-Fluorobenzyl bromideHCID 27775521H,2H,4H-thieno(3,2-d)(1,3)oxazine-2,4-dioneHCID 69515632,2-Diethylpropanedioate

Product 1

HCID 693160674-(3-Fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl esterYield 73%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
-10 °C

Procedure

1H-Thieno[3,2-d][1,3]oxazine-2,4-dione (14) (40.0 g, 0.24 mol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 21.75 g, 0.54 mol) in 300 mL anhydrous DMF stirred under argon at −10° C. After stirring at −10° C. for 15 minutes, 3-fluorobenzylbromide (29.73 mL, 0.24 mol) was added to the solution. The solution was allowed to come to room temperature and further stirred for 3 hours. The solution was again cooled to −10° C., and diethylmalonate (36.62 mL, 0.24 mol) was added slowly. The solution was then heated at 110° C. for 45 minutes. A large amount of gas evolved very quickly once the solution was heated, so this heating step was done in a flask at least 5 times as large as the reaction volume, and a reflux condenser was used which was open to the air, and not sealed with a septum. The reaction mixture was cooled to room temperature, and poured into a solution of potassium carbonate (32.68 g, 0.24 mol) in 2.5 L of water. This aqueous solution was stirred for 5 minutes, and then it was extracted 2 times with 600 mL ethyl acetate and 2 times with 600 mL isopropyl ether. These organic phases were discarded. The aqueous solution was then acidified slowly to pH 2 with 4M HCl. The precipitated solid product was collected by vacuum filtration to yield 60.1 g (73% yield) of 4-(3-fluoro-benzyl)-7-hydroxy-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.36 (s, 2H), 7.06 (m, 3H), 7.33 (m, 2H), 8.15 (m, 1H), 13.37 (s, 1H) ppm, EIMS m/z 348 (M+1).

Workup

  1. stirringAfter stirring at −10° C. for 15 minutes
  2. customto come to room temperature
  3. stirringfurther stirred for 3 hours
  4. temperatureThe solution was again cooled to −10° C.
  5. temperatureThe solution was then heated at 110° C. for 45 minutes
  6. temperaturewas heated
  7. customso this heating step was done in a flask at least 5 times
  8. customnot sealed with a septum
  9. temperatureThe reaction mixture was cooled to room temperature
  10. stirringThis aqueous solution was stirred for 5 minutes
  11. extractionit was extracted 2 times with 600 mL ethyl acetate and 2 times with 600 mL isopropyl ether
  12. filtrationThe precipitated solid product was collected by vacuum filtration

Sources & evidence

ORD record
ord-99eba761c4524ed08c0fe88ee80c63fd
Source dataset
uspto-grants-2008_04
Patent number
US07365200B2

Reaction notes

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