Tetrahydrofuran → 3-{[3-{[(5-Chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide

Temperature

50 °C

To a solution of 5-chloro-N-[4-(methyloxy)-1H-indazol-3-yl]-N-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2-thiophenesulfonamide (for a preparation see Intermediate 8) (150 mg, 0.316 mmol) into DMF (2 mL) was added at ambient temperature potassium carbonate (87 mg, 0.63 mmol) and 3-(chloromethyl)benzamide (Maybridge)(64.4 mg, 0.380 mmol). The resulting mixture was stirred at 50° C. overnight, and then diluted with DCM (2 mL) and water (2 mL). The organic mixture was partitioned and the aqueous layer was further extracted with 2 mL of DCM. The organic solutions were combined together, dried over an hydrophobic frit and evaporated under a nitrogen stream in a blowdown unit. The crude product was judged by LCMS to be pure enough to be engaged in the next step without any further purification. LCMS (System A) RT=1.37 min, ES+ve m/z 607/609 (M+H)+. In a 2 to 5 mL Biotage microwave vial were added the crude indazole product and TBAF solution in THF (1M, 3.16 mL, 3.16 mmol). The reaction vessel was sealed and heated in a Biotage Initiator at 110° C. for 10 min (very high absorption level). The crude mixture was then diluted with 2 mL of DCM and 2 mL of water. The organic layer was separated and the aqueous layer was further extracted with 2 mL of DCM. The combined organic solutions were dried over an hydrophobic frit, and evaporated under a nitrogen stream in a blowdown unit. The residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus to give the title compound (76 mg, 50%). LCMS (System A) RT=0.97 min, ES+ve m/z 477/479 (M+H)+.

1. customThe organic mixture was partitioned
2. extractionthe aqueous layer was further extracted with 2 mL of DCM
3. customdried over an hydrophobic frit
4. customevaporated under a nitrogen stream in a blowdown unit
5. customto be engaged in the next step without any further purification
6. customThe reaction vessel was sealed
7. temperatureheated in a Biotage Initiator at 110° C. for 10 min (very high absorption level)
8. customThe organic layer was separated
9. extractionthe aqueous layer was further extracted with 2 mL of DCM
10. customThe combined organic solutions were dried over an hydrophobic frit
11. customevaporated under a nitrogen stream in a blowdown unit
12. dissolutionThe residue was dissolved in 1:1 MeOH
13. customDMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column)
14. washeluting with solvents A/B (A: Water+0.1% Formic acid, B
15. customThe solvent was removed under a stream of nitrogen in a Radleys blowdown apparatus

ORD record

ord-801e2838ce364046b3c850b24a28d5d6

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08357716B2