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

HRID 1923548Notes

Reaction equation

HRID 1923548 reaction equation
[CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li][CH2:12]CCC.[CH2:16]([C:20]1[C:24]([CH2:25]Cl)=[C:23]([CH3:27])[O:22][N:21]=1)[CH2:17][CH2:18][CH3:19].C[Si](C=[N+]=[N-])(C)C>C1COCC1.CO.C(OCC)C>[CH3:12][O:9][C:8]([C:4]1[S:3][C:2]([CH2:1][CH2:25][C:24]2[C:20]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:21][O:22][C:23]=2[CH3:27])=[N:6][C:5]=1[CH3:7])=[O:10]

Participants

8

Reactant 4

HCID 167693TrimethylsilyldiazomethaneHCID 736488Dimethyl-1,3-thiazole-5-carboxylic acidHCID 66643618HCID 66643618, compoundHCID 178418339Butyllithium

Product 1

HCID 666436812-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid methyl esterYield 63%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of 2,4-dimethylthiazole-5-carboxylic acid (1.26 g, 8.0 mmol) in THF (60 mL) at −78° C. and under argon was added BuLi (1.6M in hexanes, 10 mL, 16.0 mmol) dropwise. After 2 h at −75° C. a solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (1.5 g, 8.0 mmol) in THF (10 mL) was added dropwise. After 3.5 h the reaction mixture was quenched with citric acid solution (5%, 30 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give the intermediate acid compound as a yellow oil. To a solution of intermediate acid in MeOH (30 mL) and diethylether (14 mL) was added trimethylsilyldiazomethane (2M in diethylether, 12 mL, 24 mmol) under ice cooling. Then the reaction mixture was quenched by addition of acetic acid (conc., 0.7 mL), evaporated and extracted with ethyl acetate. The combined extracts were washed with NaOH (2 N), water, dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, 0 to 4% methanol in dichloromethane) afforded the title compound (1.51 g, 63%) as a yellow oil. MS: m/e=323.4 [M+H]+.

Workup

  1. customAfter 3.5 h the reaction mixture was quenched with citric acid solution (5%, 30 mL)
  2. extractionextracted with ethyl acetate
  3. customThe combined extracts were dried
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give the intermediate acid compound as a yellow oil
  7. customThen the reaction mixture was quenched by addition of acetic acid (conc., 0.7 mL)
  8. customevaporated
  9. extractionextracted with ethyl acetate
  10. washThe combined extracts were washed with NaOH (2 N), water
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customPurification by chromatography (silica, 0 to 4% methanol in dichloromethane)

Sources & evidence

ORD record
ord-e4aef79cc64a4334832d0a7993b054a9
Source dataset
uspto-grants-2012_05
Patent number
US08178522B2

Reaction notes

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