Sodium borohydride → HCID 42643948, compound

Experimental procedure for synthesis of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile (D107) is the same as that described in synthesis of (D46). The reaction of 2-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (6) (2.71 g, 7.81 mmol) with NaBH4 (886 mg, 23.4 mmol) gave an orange oil containing D107 upon workup. The oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with 30% MeOH/CH2Cl2 (400 mL) followed by the addition of silica gel (80 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (160 g, 230-400 mesh) and eluted with 1:1:100 acetic acid:MeOH:CH2Cl2. The fractions containing D107 were collected and concentrated to give a light yellow coloured oil. The oil was freeze dried by first diluting with methanol (30 mL) followed by the addition of deionised water (400 mL), the resultant white suspension was frozen in a dry-ice acetone bath and placed overnight on freeze-dryer. A white solid of D107 was obtained (1.82 g, with 30 mol % pinacoldiol present as established by H NMR). To increase purity of D107, it was resubjected to column chromatography and freeze-dried following the same conditions as before to give D107 (402 mg, 17% isolated yield) as a white solid. 1H NMR 400 MHz (d6-DMSO) δ9.25 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.20 (dd, J=7.8, 2.0 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.99 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H); Mass Spectrum [M+H+]=297; HPLC purity 97.18% (Maxplot), 97.65% (220 nm).

1. customthat described in synthesis of (D46)
2. customgave an orange oil
3. additioncontaining D107 upon workup
4. customby dry-pack column chromatography
5. additionthe oil was diluted with 30% MeOH/CH2Cl2 (400 mL)
6. additionfollowed by the addition of silica gel (80 g, 230-400 mesh)
7. concentrationconcentrated to dryness
8. washeluted with 1:1:100 acetic acid
9. additionThe fractions containing D107
10. customwere collected
11. concentrationconcentrated
12. customto give a light yellow coloured oil
13. customdried
14. additionby first diluting with methanol (30 mL)
15. additionfollowed by the addition of deionised water (400 mL)
16. temperaturethe resultant white suspension was frozen in a dry-ice acetone bath
17. customA white solid of D107 was obtained (1.82 g, with 30 mol % pinacoldiol present as established by H NMR)
18. temperatureTo increase purity of D107, it
19. customfreeze-dried
20. customto give
21. customD107 (402 mg, 17% isolated yield) as a white solid

ORD record

ord-dfa8d7d45b7d4bd7bf804cd1941f9686

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09416146B2