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

To a stirred solution of 2-methyl-thiazole-5-carboxylic acid (215 mg, 1.50 mmol) in THF (10 mL) at −78° C. and under argon was added n-butyllithium (1.88 mL of a 1.60M solution in hexane, 3.0 mmol) dropwise. After 1 h, a solution of 3-butyl-5-methyl-isoxazole-4-carbaldehyde (251 mg, 1.50 mmol) in THF (10 mL) was added dropwise. After 2 h the reaction mixture was quenched with 10% aqueous citric acid (10 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was redissolved in methanol (15 mL) and ether (7 mL) then (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added. After 30 min, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and the residue redissolved in ethyl acetate and washed with NaOH (2 N). The organic phase was dried, filtered and concentrated then purified by chromatography (silica, 0 to 4% methanol in dichloromethane) to give the title compound (49 mg, 10%) as a brown oil. MS: m/e=307.3 [M+H]+.

1. customAfter 2 h the reaction mixture was quenched with 10% aqueous citric acid (10 mL)
2. extractionThe reaction mixture was extracted with ethyl acetate
3. customthe combined extracts were dried
4. filtrationfiltered
5. concentrationconcentrated
6. dissolutionThe resultant oil was redissolved in methanol (15 mL)
7. additionether (7 mL) then (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added dropwise
8. waitAfter 30 min
9. additionfurther (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added
10. waitAfter 30 min
11. customthe reaction mixture was quenched with acetic acid (3 drops)
12. concentrationthen was concentrated
13. dissolutionthe residue redissolved in ethyl acetate
14. washwashed with NaOH (2 N)
15. customThe organic phase was dried
16. filtrationfiltered
17. concentrationconcentrated
18. customthen purified by chromatography (silica, 0 to 4% methanol in dichloromethane)

ORD record

ord-34892e0d88e344a395a9683705ca5dbc

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08178522B2