Phenyl chloroformate → 1-(3-Diethylaminopropyl)-3-[4-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]thioureido}phenoxy)pyridin-2-yl]-1-methylurea

To a solution of 1-[4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]-3-[(4-fluorophenyl)acetyl]thiourea (100 mg) in tetrahydrofuran (10 ml) was added triethylamine (0.101 ml), and then phenyl chloroformate (0.0454 ml) was added while stirring in an ice bath, followed by stirring under a nitrogen atmosphere for 10 min. The reaction mixture was concentrated under a reduced pressure to give a residue, to which N,N-dimethylformamide (2.0 ml) and N,N-diethyl-N′-methyl-1,3-propanediamine (151 mg) were then added, followed by stirring at room temperature for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (150 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated to give a solid, which was further purified by LC-MS. Fractions containing the target compound were concentrated to give a solid, to which a saturated aqueous solution of sodium hydrogencarbonate was then added to make it alkaline. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to provide the titled compound (2.7 mg, 1.9%) as a pale yellow oil.

1. stirringby stirring under a nitrogen atmosphere for 10 min
2. concentrationThe reaction mixture was concentrated under a reduced pressure
3. customto give a residue
4. stirringby stirring at room temperature for 2.5 hrs
5. washwashed with a saturated aqueous solution of sodium hydrogencarbonate
6. dry with materialdried over anhydrous sodium sulfate
7. customThe solvent was evaporated
8. customto give a residue, which
9. customwas then purified by silica gel column chromatography (FUJI Silysia NH, hexane
10. additionFractions containing the target compound
11. concentrationwere concentrated
12. customto give a solid, which
13. customwas further purified by LC-MS
14. additionFractions containing the target compound
15. concentrationwere concentrated
16. customto give a solid
17. extractionThe mixture was extracted with ethyl acetate
18. dry with materialthe organic layer was dried over anhydrous sodium sulfate
19. customThe solvent was evaporated

ORD record

ord-1f5e8733dadd493f8266386808acd495

Source dataset

uspto-grants-2009_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07531532B2