Hydrochloric Acid → 7-Iodopyrazolo[1,5-a]pyridine-4-carboxylic acid

Temperature

0 °C

To a stirred suspension of pyrazolo[1,5-a]pyridine-4-carboxylic acid (29 g, 179 mmol) in anhydrous THF (1000 mL) cooled at 0° C. was added lithium hexamethyldisilazide solution (1M in THF, 200 mL, 200 mmol). After the mixture was stirred at 0° C. for 30 min, additional LHMDS solution (1M in THF, 320 mL, 320 mmol) was added at −4° C. After the mixture was stirred for 10 min, iodine (55 g, 215 mmol) was added in portions. The reaction mixture was stirred at −4° C. for 1.5 h, at rt for 1 h, and then cooled to 0° C. Aqueous HCl (5N, 40 mL) and NaS2O3 solution (10 g in 40 mL of H2O) were added. The mixture was stirred at 0° C. for 30 min, and then concentrated under reduced pressure. The residual mixture was mixed with sat. NaHCO3 solution (100 mL), ethyl ether (150 mL), and H2O (130 mL). The ether solution was separated and extracted with H2O (50 mL). The combined aqueous solutions were washed with ethyl ether (150 mL), acidified to pH=1 with saturated aqueous solution of KHSO4, heated in a steam bath, and then cooled. The solid was filtered, washed with H2O, and then dried to give compound 777C (50 g, 97%) as a yellow solid. HPLC: 100% at 2.88 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 289 [M+H]+.

1. stirringAfter the mixture was stirred for 10 min
2. stirringThe reaction mixture was stirred at −4° C. for 1.5 h, at rt for 1 h
3. temperaturecooled to 0° C
4. stirringThe mixture was stirred at 0° C. for 30 min
5. concentrationconcentrated under reduced pressure
6. additionThe residual mixture was mixed with sat. NaHCO3 solution (100 mL), ethyl ether (150 mL), and H2O (130 mL)
7. customThe ether solution was separated
8. extractionextracted with H2O (50 mL)
9. washThe combined aqueous solutions were washed with ethyl ether (150 mL)
10. temperatureheated in a steam bath
11. temperaturecooled
12. filtrationThe solid was filtered
13. washwashed with H2O
14. customdried

ORD record

ord-250f685001f7498f93e7e60be95cb229

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07470797B2