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0 °C

A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.6 g) and thiophene-2,5-dicarboxylic acid (1.7 g) in DMF (10 mL) was treated with triethylamine (2.75 mL) and cooled to 0° C. HATU (1.013 g) was added and the mixture stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and brine containing acetic acid (2 mL), the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 1% acetic acid in ethyl acetate as solvent. This material was dissolved in THF (30 mL), treated with carbonyldiimidazole (0.332 g) and the mixture was allowed to stand at 45° C. for 1 hour. Methanol (20 mL) was added and the reaction heated at 50° C. for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 40% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.45 g.

1. customThe mixture was partitioned between ethyl acetate and brine
2. additioncontaining acetic acid (2 mL)
3. washthe organic layer was washed twice with brine
4. dry with materialdried over sodium sulphate
5. filtrationfiltered
6. customthe solvent evaporated under reduced pressure
7. customThe residue was purified by flash silica chromatography
8. dissolutionThis material was dissolved in THF (30 mL)
9. additiontreated with carbonyldiimidazole (0.332 g)
10. waitto stand at 45° C. for 1 hour
11. additionMethanol (20 mL) was added
12. temperaturethe reaction heated at 50° C. for 30 minutes
13. customThe solvent was removed under reduced pressure
14. customthe residue was partitioned between ethyl acetate and brine
15. dry with materialThe organic layer was dried over sodium sulphate
16. filtrationfiltered
17. customthe solvent evaporated under reduced pressure
18. customThe crude product was purified by flash silica chromatography
19. customPure fractions were evaporated to dryness