反应详情

To a suspension of 3-[amino(3,4-dichlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid.HCl (186.0 mg, 0.4145 mmol, prepared according to Example 6) in methanol (8.09 mL, 0.101 mol) was added 10 M of formaldehyde in water (74.00 uL, 0.9119 mmol), and sodium cyanoborohydride (130 mg, 2.07 mmol). Stirred at rt under argon for 16 hours. Added 10 M of formaldehyde in water soln (74.00 uL, 0.919 mmol) and sodium cyanoborohydride (0.130 g, 2.07 mmol) and stirred at rt for 72 hours. Quenched reaction with saturated aqueous sodium bicarbonate solution, added EtOAc, separated layers, extracted again w/EtOAc, combined organics, washed organics with saturated sodium bicarbonate, brine, dried over Na2SO4, filtered, added Celite to filtrate, and concentrated in vacuo. Purification of dry load via silica gel column chromatography (gradient elution: 100% DCM to 8% MeOH in DCM) afforded racemic 4-cyano-3-[(3,4-dichlorophenyl)(dimethylamino)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid (134 mg, 68%) as an off-white solid. LC/MS: (FA) 440, 442, 444; 1H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76 (s, 3H), 2.42 (s, 3H). Combined with another batch of 134 mg racemate for chiral HPLC to obtain pure enantiomers. Purified on IC 4.6×250 mm with 90/10/0.1 HEX/ETOH/DEA 10 uL Injection at 1.0 mL/min for 70 min. CD AT 254 nm to obtain separated enantiomers as the diethylamine salts. Each compound Peak1 and Peak2 were separately dissolved in water, acidified to pH of 2 with aqueous 1N HCl solution, extracted w/EtOAc, 3×, combined organics and washed w/brine, dried over Na2SO4, filtered, concentrated in vacuo, added water, freeze-dried, lyophilized overnight to recover parent compound. Peak 1 (103 mg, tan solid, overall 27% yield) LC/MS: (FA) 440, 442, 444; 1H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76 (s, 3H), 2.42 (s, 3H). Peak 2 (80 mg, beige solid, overall 20% yield) LC/MS: (FA) 440, 442, 444; 1H NMR (400 MHz, DMSO) δ 7.80-7.76 (m, 2 H), 7.53 (dd, J=8.4, 2.1 Hz, 1H), 5.26 (s, 1H), 3.74-3.64 (m, 4H), 3.53-3.38 (m, 4H), 2.76 (s, 3H), 2.42 (s, 3H).

1. stirringstirred at rt for 72 hours
2. customQuenched
3. customreaction with saturated aqueous sodium bicarbonate solution
4. customseparated layers
5. extractionextracted again
6. washwashed organics with saturated sodium bicarbonate, brine
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. additionadded Celite to filtrate
10. concentrationconcentrated in vacuo
11. customPurification of dry load
12. washvia silica gel column chromatography (gradient elution: 100% DCM to 8% MeOH in DCM)