Hydrochloric Acid → HCID 67516443, compound

In an Ace pressure tube, a solution of tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (280 mg, 0.415 mmol) was treated with concentrated HCl (8 mL) and stirred at room temperature. After 10 min the tube was sealed, and the mixture was heated to ˜118° C. for 16 h. After cooling to room temperature, the solution was carefully diluted with water (20 mL) and washed with methylene chloride (2×15 mL). The aqueous phase was concentrated under reduced pressure, and the resulting residue purified by reverse phase HPLC. Product fractions (mixture of diastereomers) were pooled and concentrated. The residue was reconstituted in 1 M HCl and re-concentrated. The resulting residue was diluted with deionized water and lyophilized to give (3R,4S)-3-amino-1-[(7-chloro-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-4-[3-(dihydroxyboryl)propyl]-pyrrolidine-3-carboxylic acid trihydrochloride (mixture of 2 diastereomers, each a racamate) (102 mg, 49%) as a faint yellow amorphous solid. 1H NMR (0.1M DCl in D2O, 400 MHz) δ 7.23 (m, 1 H), 7.15 (m, 2 H), 4.37 (s, 2 H), 4.00 (m, 3 H), 3.84 (m, 2 H), 3.69 (m, 1 H), 3.43 (m, 1 H), 3.22 (m, 1 H), 2.98 (m, 1 H), 2.68 (m, 1 H), 1.60 (m, 1 H), 1.25 (m, 3 H), 0.64 (m, 2 H). ESI+ MS found for C18H27BClN3O4 m/z 378.1 (M−18+H), 360.1 (M−36+H); ESI− MS m/z 376.2 (M−18−H).

1. customAfter 10 min the tube was sealed
2. temperaturethe mixture was heated to ˜118° C. for 16 h
3. temperatureAfter cooling to room temperature
4. washwashed with methylene chloride (2×15 mL)
5. concentrationThe aqueous phase was concentrated under reduced pressure
6. customthe resulting residue purified by reverse phase HPLC
7. additionProduct fractions (mixture of diastereomers)
8. concentrationconcentrated
9. concentrationre-concentrated
10. additionThe resulting residue was diluted with deionized water

ORD record

ord-b09c29cd856c4d1bbcfb9e4746c51e6e

Source dataset

uspto-grants-2016_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09233985B2