Carbonic acid sodium salt (1:2) → 5-(2-Chloro-pyrimidin-4-yl)-2-methoxy-nicotinonitrile

温度

100 °C

To a stirred solution of 5-bromo-2-methoxy-nicotinonitrile (10 g, 46.9 mmol) and bis(pinacolato)diboron (17.9 g, 70.4 mmol) in 1,4-dioxane (300 mL) was added potassium acetate (13.8 g, 140.8 mmol). The reaction mixture was deoxygenated with argon, Pd(dppf)Cl2 was added and the mixture deoxygentated for a further 20 min. The resulting mixture was heated at 100° C. for 1.5 h. The reaction mixture was cooled to rt, diluted with water (100 mL) and filtered through Celite. The filtrate was extracted with EtOAc (2×150 mL), the combined organic layer dried over Na2SO4 and evaporated to obtained a crude mixture containing an approximate 1:1 mixture of boronic ester and boronic acid (12 g). The crude material was dissolved in 1,4-dioxane (100 mL) and 2,4 dichloropyrimidine (8.4 g, 56.2 mmol) was added followed by a solution sodium carbonate (17.9 g, 168.5 mmol) in water (25 mL). The reaction mixture was deoxygenated with argon gas, Pd(PPh3)4 was added and again deoxygenated for 30 min. The resulting mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to rt, diluted with water (100 mL), extracted with EtOAc (3×100 mL), the combined organic layer was dried (Na2SO4) and evaporated. The crude compound was purified by flash column chromatography (100-200 mesh silica gel), eluting with 30% EtOAc/pet ether to obtain the desired compound (6 g, 51% (over two steps)) as a white solid; Rf: 0.3 (40% EtOAc/pet ether); (m/z): 247[M+1]+; 1H NMR (300 MHz, DMSO-d6): δ 9.24 (1H, d, J=2.4 Hz), 8.98 (1H, d, J=2.1 Hz), 8.89 (1H, d, J=5.1 Hz), 8.21 (1H, d, J=5.1 Hz), 4.04 (3H, s). 2-Methoxy-5-[2-(6-morpholin-4-ylmethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-nicotinonitrile (17)

1. customThe reaction mixture was deoxygenated with argon, Pd(dppf)Cl2
2. additionwas added
3. temperatureThe reaction mixture was cooled to rt
4. additiondiluted with water (100 mL)
5. filtrationfiltered through Celite
6. extractionThe filtrate was extracted with EtOAc (2×150 mL)
7. dry with materialthe combined organic layer dried over Na2SO4
8. customevaporated
9. customto obtained a crude mixture
10. additioncontaining
11. customThe reaction mixture was deoxygenated with argon gas, Pd(PPh3)4
12. additionwas added
13. customagain deoxygenated for 30 min
14. temperatureThe resulting mixture was heated at 100° C. for 3 h
15. temperatureThe reaction mixture was cooled to rt
16. additiondiluted with water (100 mL)
17. extractionextracted with EtOAc (3×100 mL)
18. dry with materialthe combined organic layer was dried (Na2SO4)
19. customevaporated
20. customThe crude compound was purified by flash column chromatography (100-200 mesh silica gel)
21. washeluting with 30% EtOAc/pet ether

ORD记录

ord-2c9a8704ff9040b799b42e1d196eab7c

来源数据集

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

专利号

US09433622B2