Acetic Acid → HCID 69349529, compound

A solution of lithium hexamethyldisilazide in THF (1M, 0.25 ml, 0.25 mmol) was added at 0–5° C. to a solution of allyl (2S)-4-(2-mercapto-1,3-thiazol-4-yl)-2-isopropyl-3,6-dihydro-1(2H)-pyridinecarboxylate (80 mg, 0.25 mmol) in THF (4.3 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 0.94 g, 0.50 mmol) and the solution was allowed to stand in a refrigerator for 12 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was dissolved in THF (5.65 ml) and thereto were added at 0° C. water and 1N hydrochloric acid to adjust pH about 3. The solution was stirred for 1 hour. To the reaction mixture was added an aqueous sodium hydrogen carbonate and the solution was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (5 ml). To the solution were added at 0° C. acetic acid (36 μl, 0.63 mmol) and tributyltin hydride (0.67 ml, 2.5 mmol) and then was added at room temperature bis(triphenylphosphine)palladium chloride(II) (17.5 mg, 0.025 mmol). The mixture was stirred at the same temperature for 10 minutes. The reaction mixture was poured into a mixture of ice (5 g) and phosphate buffer (pH7.0, 5 ml). After separation with a separating funnel, the organic layer was extracted twice with water. The organic solvent in the aqueous layer was removed in vacuo and was purified by polymer chromatography (CHP-20P). The fractions eluted with an 3–8% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(6S)-6-isopropyl-1,2,5,6-tetrahydro-3-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (29.9 mg, 17%) as a white amorphous.

1. waitto stand in a refrigerator for 12 hours
2. extractionthe reaction mixture was extracted with ethyl acetate
3. washThe organic layer was washed with a saturated aqueous sodium chloride solution
4. dry with materialdried over anhydrous sodium sulfate
5. customAfter removal of the solvent in vacuo
6. dissolutionthe residue was dissolved in THF (5.65 ml)
7. additionwere added at 0° C. water and 1N hydrochloric acid
8. stirringThe solution was stirred for 1 hour
9. additionTo the reaction mixture was added an aqueous sodium hydrogen carbonate
10. extractionthe solution was extracted twice with ethyl acetate
11. washThe organic layer was washed with a saturated aqueous sodium chloride solution
12. dry with materialdried over anhydrous sodium sulfate
13. customthe solvent was removed in vacuo
14. dissolutionThe residue was dissolved in dichloromethane (5 ml)
15. stirringThe mixture was stirred at the same temperature for 10 minutes
16. customAfter separation with a separating funnel
17. extractionthe organic layer was extracted twice with water
18. customThe organic solvent in the aqueous layer was removed in vacuo
19. customwas purified by polymer chromatography (CHP-20P)
20. washThe fractions eluted with an 3–8% aqueous THF solution

ORD record

ord-a75cc35a092b460f995ae2fec4977fb8

Source dataset

uspto-grants-2007_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07163936B2