反应详情

To a solution of 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholine (1.38 g, 2.82 mmol) in THF (55 mL) stirring at −78° C. under nitrogen was slowly added 2.5M BuLi (2.259 mL, 5.65 mmol) via syringe. Immediately after the addition of n-BuLi, trimethyl borate (1.262 mL, 11.29 mmol) was added via syringe and then the dry ice bath was removed and the reaction was allowed to warm to room temperature. After stirring at RT for 60 minutes the mixture was quenched with MeOH and the entire reaction mixture was concentrated in vacuo to leave 2.1 g of crude reaction products—containing both the desired boronic acid and the des-bromo analog by LCMS with the desired boronic acid as the major product. The crude material was combined with crude material from a second reaction. The entire mixture was purified on silica gel that had been pre-treated with 3 column volumes of 0.5M ammonium acetate in methanol prior to being washed and equilibrated with chloroform. The column was eluted sequentially with chloroform/hexane (1:1, 300 mL) followed by chloroform (500 mL), then (a 2N solution of ammonia in methanol)/chloroform (5:95, 2 L). The fractions corresponding to product were combined and concentrated in vacuo to provide partially purified desired product that was free of the des-bromo analog by HPLC. The material was subsequently purified by preparative chiral phase HPLC. The product fractions were concentrated to provide an oil. Next added 200 ml CHCl3 and 200 ml of aqueous 0.5 M K2HPO4 (pH 3.4) and mixed. Separated the two phases, and re-extracted the aqueous phase with 2×100 ml CHCl3. Washed CHCl3 layer with H2O, then dried the CHCl3 layer over Na2SO4, filtered and concentrated to leave a beige glassy solid. The solid was chased with ethyl acetate (2×50 ml), and then dried @ 50° C. under high vacuum (4.5 hr.) to give desired product (250 mg). MS (ES+) m/e: 453.1, 454.1 [M+H]+; C18 HPLC 99.5%; 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.51 (s, 3H) 3.05-3.22 (m, 4H) 3.70-3.93 (m, 4H) 5.67 (s, 2H) 6.19 (d, J=8.08 Hz, 1H) 6.84 (br. s., 1H) 7.02 (t, J=8.08 Hz, 1H) 7.19-7.30 (m, 1H) 7.34 (d, J=8.34 Hz, 1H).

1. additionwas added via syringe
2. customthe dry ice bath was removed
3. customwas quenched with MeOH
4. customthe entire reaction mixture
5. concentrationwas concentrated in vacuo
6. customto leave 2.1 g of crude
7. customreaction
8. customThe entire mixture was purified on silica gel that
9. additionhad been pre-treated with 3 column volumes of 0.5M ammonium acetate in methanol
10. washto being washed
11. washThe column was eluted sequentially with chloroform/hexane (1:1, 300 mL)
12. concentrationconcentrated in vacuo
13. customto provide partially
14. custompurified desired product that
15. customThe material was subsequently purified by preparative chiral phase HPLC
16. concentrationThe product fractions were concentrated
17. customto provide an oil
18. additionmixed
19. customSeparated the two phases
20. extractionre-extracted the aqueous phase with 2×100 ml CHCl3
21. dry with materialWashed CHCl3 layer with H2O, then dried the CHCl3 layer over Na2SO4
22. filtrationfiltered
23. concentrationconcentrated
24. customto leave a beige glassy solid
25. customdried @ 50° C. under high vacuum (4.5 hr.)