反应详情

温度

100 °C

A solution of 2-(4-methoxy-butyl)-thiophene (527 mg, 3.1 mmol) in 10 ml of THF was treated with LDA (2.3 ml of 1.5M solution in cyclohexane, 3.4 mmol) at −78° C. under nitrogen and the mixture was stirred for 5 minutes. Then, trimethylborate (0.379 ml, 3.4 mmol) was added in one portion and the cooling bath was removed. After 15 minutes, the mixture was quenched with 10 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 water and brine and evaporated. This crude boronic acid was redissolved in 5 ml of DME and added to a stirred suspension of (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (416 mg, 1.55 mmol), Pd(PPh3)4 (36 mg, 0.031 mmol), 10 ml of DME and 5 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 2N-HCl and ether. The aqueous layer was separated, made basic with 2N-NaOH and extracted twice with ether and once with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate and evaporated. The crude oil was purified by preparative HPLC and converted into its hydrochloride salt by addition of excess of 3M-HCl solution in EtOAc. Yield: 494 mg (73%).

1. customthe cooling bath was removed
2. waitAfter 15 minutes
3. customthe mixture was quenched with 10 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 water and brine
7. customevaporated
8. dissolutionThis crude boronic acid was redissolved in 5 ml of DME
9. temperatureat reflux
10. customwas evaporated
11. customthe crude was partitioned between 2N-HCl and ether
12. customThe aqueous layer was separated
13. extractionextracted twice with ether and once with DCM
14. washThe combined organic layers were washed with water and brine
15. dry with materialdried over sodium sulfate
16. customevaporated
17. customThe crude oil was purified by preparative HPLC
18. additionconverted into its hydrochloride salt by addition of excess of 3M-HCl solution in EtOAc