反应详情

温度

100 °C

A solution of 2-methyl-4-thiophen-2-yl-butan-2-ol (340 mg, 2 mmol)—synthesis see Step A of Example 1—in 20 ml of THF was treated with LDA (2M in THF/heptane/ethylbenzene, 5 ml, 10 mmol) at −78° C. under nitrogen and the mixture was stirred for 5 minutes. Then, trimethylborate (1.1 ml, 10 mmol) was added in one portion and the cooling bath was removed. After 15 minutes, the mixture was quenched with 50 ml of saturated ammonium chloride solution and extracted twice with ether. The aqueous layer was then acidified with 2N-HCl and extracted once more with ether. The combined organic extracts were washed with brine and evaporated. This crude boronic acid was redissolved in 10 ml of DME and added to a stirred suspension 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (190 mg, 1 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 20 ml of DME and 3 ml of a 10% solution of sodium bicarbonate. This mixture was then kept at reflux (100° C. heat bath) for 90 minutes. After cooling, most of the DME was evaporated and the crude was partitioned between water and ether. The organic layer was separated, washed with 0.2N-HCl, water and brine, dried over sodium sulfate and evaporated. The crude was purified by chromatography on silicagel (EtOAc/hexane:1/1) to give 4-[5-(5-methoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol. Yield: 275 mg (85%).

1. customthe cooling bath was removed
2. waitAfter 15 minutes
3. customthe mixture was quenched with 50 ml of saturated ammonium chloride solution
4. extractionextracted twice with ether
5. extractionextracted once more with ether
6. washThe combined organic extracts were washed with brine
7. customevaporated
8. dissolutionThis crude boronic acid was redissolved in 10 ml of DME
9. temperatureat reflux
10. customwas evaporated
11. customthe crude was partitioned between water and ether
12. customThe organic layer was separated
13. washwashed with 0.2N-HCl, water and brine
14. dry with materialdried over sodium sulfate
15. customevaporated
16. customThe crude was purified by chromatography on silicagel (EtOAc/hexane:1/1)