反应详情

温度

-40 °C

Diisopropylamine (5.75 g, 56.8 mmol) and dry THF (58 mL) were added to a dry 500 mL 3 neck round bottom flask under nitrogen. The solution was cooled to −40° C. and nBuLi (39 mL, 47.4 mmol) was added slowly while keeping the internal temperature at −40° C. After 15 min, a suspension of 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbo-nyl)-amino]-thiophene-2-carboxylic acid methyl ester (10.0 g, 23.7 mmol) in THF (70 mL) was added dropwise while maintaining the internal temperature at −40° C. After 30 min at −40° C., 4,4-dimethyl-cyclohexanone (5.88 g, 47.7 mmol) was added in one portion and stirred at −40° C. for 30 min. The reaction mixture was quenched with saturated NH4Cl, partitioned and the aqueous phase extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered and evaporated to obtain crude 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(1-hydroxy-4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (14.4 g) which was used for the next step without any purification.

1. customat −40° C
2. additionwas added dropwise
3. temperaturewhile maintaining the internal temperature at −40° C
4. waitAfter 30 min at −40° C.
5. customThe reaction mixture was quenched with saturated NH4Cl
6. custompartitioned
7. extractionthe aqueous phase extracted with EtOAc
8. washThe combined organic phase was washed with brine
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. customevaporated