Ethyl Thioglycolate → 4-Isobutyl-3-methylthiophene-2-carboxylic acid

温度

20 °C

KOtBu (44.2 g, 394 mmol) is added portionwise to ethanol (200 mL). The mixture is stirred for 30 min at 20° C. to dissolve all KOtBu. Mercapto-acetic acid ethyl ester (47.3 g, 394 mmol) is added and the temperature is maintained at 20° C. This solution is slowly added at 20° C. to a solution of the crude 4-chloro-3-isobutyl-but-3-en-2-one (31.6 g, 197 mmol) in THF (350 mL). The mixture is stirred at rt for 15 h before sodium ethylate (13.4 g, 197 mmol) is added and stirring is continued at reflux for 1 h. The mixture is cooled to rt, and the solvents are evaporated on a rotavap. The residue is diluted with diethyl ether (500 mL), washed with 1 M aq. NaH2PO4 (200 mL), 1 N aq. NaOH (2×100 mL), sat. aq. NaHCO3 (35 mL) containing 10% aq. NaOCl (15 mL) and brine (100 mL), dried over Na2SO4, filtered and evaporated. The resulting residue (36.3 g) is dissolved in EtOH (250 mL), 2 N aq. LiOH (100 mL) is added, and the mixture is stirred at rt for 48 h before it is extracted with diethyl ether (1×400 mL, 2×150 mL). The organic extracts are washed with 1 N aq. NaOH (3×100 mL). The aq. extracts are carefully acidified with 25% aq. HCl and then extracted with DCM (3×150 mL). The combined DCM extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by crystallisation from acetonitrile (150 mL) at 4° C. to give 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (16.0 g) as a beige-brown crystalline powder; LC-MS: tR=0.95 min; 1H NMR (CD3OD): δ 7.21 (s, 1H), 2.43 (s, 3H), 2.42 (d, J=7.0 Hz, 2H), 1.83 (m, J=7.0 Hz, 1H), 0.92 (d, J=7.0 Hz, 6H).

1. temperaturethe temperature is maintained at 20° C
2. additionis added
3. stirringstirring
4. temperatureat reflux for 1 h
5. temperatureThe mixture is cooled to rt
6. customthe solvents are evaporated on a rotavap
7. additionThe residue is diluted with diethyl ether (500 mL)
8. washwashed with 1 M aq. NaH2PO4 (200 mL), 1 N aq. NaOH (2×100 mL), sat. aq. NaHCO3 (35 mL)
9. additioncontaining 10% aq. NaOCl (15 mL) and brine (100 mL)
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. customevaporated
13. dissolutionThe resulting residue (36.3 g) is dissolved in EtOH (250 mL)
14. addition2 N aq. LiOH (100 mL) is added
15. stirringthe mixture is stirred at rt for 48 h before it
16. extractionis extracted with diethyl ether (1×400 mL, 2×150 mL)
17. washThe organic extracts are washed with 1 N aq. NaOH (3×100 mL)
18. extractionextracted with DCM (3×150 mL)
19. dry with materialThe combined DCM extracts are dried over MgSO4
20. filtrationfiltered
21. customevaporated
22. customThe crude product is purified by crystallisation from acetonitrile (150 mL) at 4° C.

ORDレコード

ord-f0e2750bd8644020a00e0aa1af39fecd

出典データセット

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08003800B2