Thieno[2,3-c]pyridine-2-carboxylic acid, 4,5,6,7-tetrahydro-, Methyl ester synthesis

Yield:1259287-72-3 55%

Reaction Conditions:

Stage #1: methyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylatewith carbonochloridic acid 1-chloro-ethyl ester;N-ethyl-N,N-diisopropylamine in 1,4-dioxane at 0 - 20; for 3 h;
Stage #2: with methanol for 3 h;Reflux;

Steps:

1.3

Into a 1000-mL round-bottom flask containing methyl 6-methyl-4,5,6,7-tetrahydrothieno[2,3 c]pyridine-2-carboxylate (9.84 g, 46.6 mmol), and 1,4-dioxane (466 mL) was added N₁N- diisopropylethylamine (81.1 mL, 466 mmol). The solution was cooled to 0 ⁰C whereupon α-chloroethyl chloroformate (50.2 mL, 466 mmol) was added dropwise. Upon complete addition, the solution was warmed to room temperature and stirred for 3 h. The solvent was removed in vacuo and the residue obtained was dissolved in methanol (466 mL). The clear yellow solution heated to reflux for 3 h. Removal of the solvent under reduced pressure afforded a solid which was partitioned between dichloromethane and saturated aqueous NaHCO₃. The aqueous layer was further extracted with dichloromethane three times. The combined organic phases were washed with brine, dried over anhydrous MgSO₄ and concentrated. Purification via flash chromatography (50% EtOAc-hexanes to 1% triethylamine-99% EtOAc to 1% MeOH- 1% triethylamine-98% EtOAc) afforded methyl 4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxylate (5.08 g, 55%) as a brown solid. LCMS: (FA) ES+ 198; ¹H NMR (CDCl₃, 300 MHz) δ 7.50 (s, 1 H)₅ 4.04 (s, 2 H), 3.86 (s, 3 H), 3.12 (/, J = 6.0 Hz, 2 H), 2.66 (/, J = 6.0 Hz, 2 H).

References:

WO2010/151317,2010,A1 Location in patent:Page/Page column 98; 99; 100