Pyrimidine derivatives as cftr modulators

Synthesis of 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-4-ylmethoxy)pyrimidin-5-yl)picolinamide hydrochloride (1)

[0056]

(1) tert-butyl 4-(((5-aminopyrimidin-4-yl)oxy)methyl)piperidine-1-carboxylate (C1)

[0057]

[0058]At room temperature, NaH (67 mg, 2.79 mmol) was added to a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (B1) (500 mg, 2.32 mmol) in THF (tetrahydrofuran) (10 mL) and stirred for 1 hour. 4-chloropyrimidin-5-amine (A) (346 mg, 2.67 mmol) was then added. The reaction mixture was then heated to 100° C. under nitrogen and stirred for 4 hours, cooled to room temperature (20-30° C.) and concentrated in vacuo. The residue was purified with flash column (eluent: 10-30% ethyl acetate / petroleum ether) to obtain the product C1 (308 mg, 1.0 mmol).

(2) Synthesis of tert-butyl 4-(((5-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyrimidin-4-yl)oxy)methyl)piperidine-1-carboxylate (E1)

[0059]

[0060]Compound (C1) (49 mg, 0.16 mmol), 6-(2,6-difluorophenyl)-5-fluoropicolini

Synthesis of N-(4-(azetidin-3-ylmethoxy)pyrimidin-5-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide hydrochloride (2)

[0063]

[0064]Following the procedure described in Example 1, and substituting compound B1 in Step (1) with tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (B2), the title compound 2 was obtained.

Synthesis of 6-(2,6-difluorophenyl)-5-fluoro-N-(4-(piperidin-4-yloxy)pyrimidin-5-yl)picolinamide hydrochloride (3)

[0065]

[0066]Following the procedure described in Example 1, and substituting compound B1 in Step (1) with tert-butyl 4-hydroxypiperidine-1-carboxylate (B3), the title compound 3 was obtained.