Ethylenediaminetetraacetic Acid → Butyl 2-(isoquinolin-6-yl)acetate

Temperature

80 °C

A dry, 25 mL, 1 neck round bottom flask was charged with a 0.5 M Et2O solution of Zincate 2 (10.00 ml, 5.0 mmol, Reike Metals), and concentrated in vacuo. The vacuum was released with nitrogen, and the flask was charged with a stirbar, 5 mL dry THF, fitted with a reflux condenser and an Ar inlet. Upon dissolution of the solids, 6-bromoisoquinoline (0.516 g, 2.5 mmol) and tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol) was added. The solution was heated with an 80° C. oil bath for 5 h, and cooled. The solution was treated with 30 mL of 10% aqueous EDTA (pH adjusted to 6.1 with NaOH), and stirred for 1 h. A precipitate had formed that was removed by filtration of the biphasic solution through a sintered glass funnel and discarded. The filtrate was concentrated to ˜35 mL, and extracted with DCM (4×30 mL). The combined extracts were washed with water (1×30 mL), and the water was back-extracted with DCM (1×10 mL). The DCM layers were dried over MgSO4, and the resultant slurry filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL DCM and treated with Si-carbonate (Silicycle, 5.5 g, 3.7 mmol). The slurry was swirled occasionally for 1 h, and filtered through a 0.22 uM PTFE membrane. The silica was washed with DCM (4×20 mL), and the combined filtrates were concentrated in vacuo. The residue was purified in three injections using a Waters Spherisorb S5 column (PN PSS830195, 20×250 mm, 60 Å pore, 5 μm particle size); flow=20 mL/min; A=DCE, B=EtOH; isocratic at 5% B. A band that eluted from 3.9 to 5.9 minutes was isolated. The solvent was removed in vacuo to afford ten-butyl 2-(isoquinolin-6-yl)acetate.

1. concentrationconcentrated in vacuo
2. additionthe flask was charged with a stirbar, 5 mL dry THF
3. customfitted with a reflux condenser
4. additionwas added
5. temperaturecooled
6. customA precipitate had formed
7. customthat was removed by filtration of the biphasic solution through a sintered glass funnel
8. concentrationThe filtrate was concentrated to ˜35 mL
9. extractionextracted with DCM (4×30 mL)
10. washThe combined extracts were washed with water (1×30 mL)
11. extractionthe water was back-extracted with DCM (1×10 mL)
12. dry with materialThe DCM layers were dried over MgSO4
13. filtrationthe resultant slurry filtered through a sintered glass funnel
14. concentrationThe filtrate was concentrated in vacuo
15. dissolutionThe residue was dissolved in 10 mL DCM
16. waitThe slurry was swirled occasionally for 1 h
17. filtrationfiltered through a 0.22 uM PTFE membrane
18. washThe silica was washed with DCM (4×20 mL)
19. concentrationthe combined filtrates were concentrated in vacuo
20. customThe residue was purified in three injections
21. washA band that eluted from 3.9 to 5.9 minutes
22. customwas isolated
23. customThe solvent was removed in vacuo

ORD record

ord-8e783ca65b9b46be8b81891df07a414a

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08524900B2