Triisopropyl borate → 3-{5-[2-Methoxy-5-(2-methoxy-ethoxy)-phenyl]-pyridin-2-yloxy}-azetidine-1-carboxylic acid pyridazin-3-ylamide

A solution of 2-bromo-1-methoxy-4-(2-methoxy-ethoxy)-benzene (110 mg, 0.42 mmol) in anhydrous THF (2 mL) was cooled to −78° C. with a CO2— acetone bath under a nitrogen atmosphere. Triisopropyl borate (0.19 mL, 0.842 mmol) was added, followed by n-butyl lithium solution (2.5M in hexanes, 0.22 mL, 0.55 mmol). The mixture was allowed to warm to ambient temperature the solvents were removed in vacuo to afford a colourless solid. To the crude boronic acid was added 3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (Example 7, step 1) (150 mg, 0.38 mmol), 1N aqueous sodium bicarbonate solution (1.26 mL), DMF (7 mL) and 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (15 mg). Nitrogen gas bubbled through mix for 5 minutes and reaction mixture heated at 80° C. for 2 hr. Mix was allowed to cool, partitioned between ethyl acetate (30 mL) and water (30 mL). Organic phase was separated then washed with sat. aqueous sodium chloride solution (60 mL) and dried over sodium sulphate. Solvents were removed in vacuo to afford a crude oil which was purified by flash chromatography on silica gel, eluting with a gradient of 0-10% ethyl acetate in hexane to afford the title compound (77 mg, 41%) as a pale yellow foam.

1. customwere removed in vacuo
2. customto afford a colourless solid
3. customNitrogen gas bubbled
4. additionthrough mix for 5 minutes
5. customreaction mixture
6. temperatureheated at 80° C. for 2 hr
7. additionMix
8. temperatureto cool
9. custompartitioned between ethyl acetate (30 mL) and water (30 mL)
10. customOrganic phase was separated
11. washthen washed with sat. aqueous sodium chloride solution (60 mL)
12. dry with materialdried over sodium sulphate
13. customSolvents were removed in vacuo
14. customto afford a crude oil which
15. customwas purified by flash chromatography on silica gel
16. washeluting with a gradient of 0-10% ethyl acetate in hexane

ORDレコード

ord-5efd098085c94941b1e81c308e2a529a

出典データセット

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09006269B2