Hydrochloric Acid → Hydrochloric Acid

Temperature

-20 °C

Stir a solution of 4-((1R,3S)-1-formylaminomethyl-5-isopropoxy-6-methyl-isochroman-3-yl)-piperidine-1-carboxylic acid isopropyl ester directly from the previous step in of 5% methanolic hydrochloric acid (4 mL) at room temperature for 2 days. Remove the solvent to give yellow oil. Purify the oil on a 2 g SCX column. The resulting residue was redissolved in 4 mL of anhydrous dichloromethane, cooled to −20° C., and 6 equivalents of BCl3 (using 1M BCl3 in dichloromethane) was added slowly into the solution. After the addition, the reaction mixture was stirred at −20° C. for 2 hours and 0° C. for 1 hour. It was then cooled to −20° C. and quenched with 0.5 mL anhydrous CH3OH. The resulting solution was warmed to room temperature and concentrated. The crude product was purified by 2 g SCX column, followed by 1 g silica gel column (eluted by 7N NH3 in methanol:ethyl acetate=1:10) and the hydrochloride was formed with 2M HCl in diethyl ether. CIMS 363.2 (MH+), tR (min)=2.65.

1. customRemove the solvent
2. customto give yellow oil
3. customPurify the oil on a 2 g SCX column
4. dissolutionThe resulting residue was redissolved in 4 mL of anhydrous dichloromethane
5. additionAfter the addition
6. temperatureIt was then cooled to −20° C.
7. customquenched with 0.5 mL anhydrous CH3OH
8. temperatureThe resulting solution was warmed to room temperature
9. concentrationconcentrated
10. customThe crude product was purified by 2 g SCX column
11. washfollowed by 1 g silica gel column (eluted by 7N NH3 in methanol:ethyl acetate=1:10)

ORD record

ord-85a22c28502b46859a086b11c1fb0566

Source dataset

uspto-grants-2011_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07919508B2