Dimethyl-1,3-thiazole-5-carboxylic acid → 2-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl ester

To a stirred solution of 2,4-dimethyl-thiazole-5-carboxylic acid (7.52 g, 47.8 mmol) in THF (400 mL) at −78° C. and under argon was added n-butyllithium (59.8 mL of a 1.60M solution in hexane, 95.7 mmol) dropwise. After 1.5 h, a solution of 3-butyl-5-methyl-isoxazole-4-carbaldehyde (8.0 g, 47.8 mmol) in THF (200 mL) was added dropwise over 30 min. After 3 h the reaction mixture was quenched with HCl (1 N, 80 mL) and water (100 mL), warmed to room temperature, then the reaction mixture was adjusted to pH 6 with 10% aqueous citric acid. The reaction mixture was concentrated to remove most of the THF then was extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated. The resultant oil was redissolved in methanol (400 mL) and ether (200 mL) then (trimethylsilyl)diazomethane (71.8 ml, of a 2M solution in ether, 144 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (71.8 mL of a 2M solution in ether, 144 mmol) was added. After 30 min, the reaction mixture was quenched with acetic acid then saturated aqueous sodium bicarbonate (200 mL) added. The mixture was filtered and the filtrates concentrated to ˜200 mL then extracted with in ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 10 to 40% ethyl acetate in heptane) to give the title compound (12.8 g, 79%) as a yellow solid. MS: m/e=321.2 [M+H—H2O]+.

1. customAfter 3 h the reaction mixture was quenched with HCl (1 N, 80 mL) and water (100 mL)
2. concentrationThe reaction mixture was concentrated
3. customto remove most of the THF
4. extractionthen was extracted with ethyl acetate
5. customThe combined extracts were dried
6. filtrationfiltered
7. concentrationconcentrated
8. dissolutionThe resultant oil was redissolved in methanol (400 mL)
9. additionether (200 mL) then (trimethylsilyl)diazomethane (71.8 ml, of a 2M solution in ether, 144 mmol) was added dropwise
10. waitAfter 30 min
11. additionfurther (trimethylsilyl)diazomethane (71.8 mL of a 2M solution in ether, 144 mmol) was added
12. waitAfter 30 min
13. customthe reaction mixture was quenched with acetic acid
14. additionsaturated aqueous sodium bicarbonate (200 mL) added
15. filtrationThe mixture was filtered
16. concentrationthe filtrates concentrated to ˜200 mL
17. extractionthen extracted with in ethyl acetate
18. customThe combined organic extracts were dried
19. filtrationfiltered
20. concentrationconcentrated
21. customthen purified by chromatography (silica, 10 to 40% ethyl acetate in heptane)

ORD record

ord-928451f5bf3c4de3976df4f2d9dee404

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08178522B2