2,2-Diethoxyethylamine → 5-chloro-N-(2,2-diethoxyethyl)thiophene-2-carboxamide

Temperature

4 °C

Add 5-chlorothiophene-2-carboxylic acid (100 g, 0.60 mol) and dichloromethane (1000 mL) to a 3 L three-necked round bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel, and thermocouple. Stir the resulting solution under nitrogen while cooling to 4° C. Add via addition funnel 2,2-diethyoxyethylamine (88.5 ml, 0.60 mol) in dichloromethane (35 mL) over 12 min. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 g, 0.64 mol) to the chilled mixture. Add additional dichloromethane (165 mL) and stir the reaction mixture for 22 h at RT. Quench the reaction with water (1000 mL) and separate the resulting layers. Back extract the aqueous layer with dichloromethane (500 mL) and combine the organic layers. Dry over sodium sulfate and purify through a silica gel bed eluting with dichloromethane followed by a mixture of 1% MeOH in dichloromethane and then a mixture of 10% MeOH in dichloromethane to afford 108 g (65%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 6H), 3.48-3.57 (m, 4H), 3.68-3.74 (m, 2H), 3.68-3.74 (m, 2H), 6.37 (bs, 1H), 6.85 (d, J=3.5 Hz, 1H), 7.26 (d, J=3.5 Hz, 1H).

1. customequipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel
2. stirringstir the reaction mixture for 22 h at RT
3. customQuench
4. customthe reaction with water (1000 mL)
5. customseparate the resulting layers
6. extractionBack extract the aqueous layer with dichloromethane (500 mL)
7. dry with materialDry over sodium sulfate
8. custompurify through a silica gel bed
9. washeluting with dichloromethane
10. additionfollowed by a mixture of 1% MeOH in dichloromethane
11. additiona mixture of 10% MeOH in dichloromethane

ORD record

ord-b4cf19faca924c61b3381fac65130c40

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08101764B2