Dichloromethane → HCID 70874109, compound

Temperature

65 °C

To a dry flask was added zinc dust (186 mg, 2.85 mmol) and the flask was heated using a heat gun for a few minutes. Then anhydrous DMA (15 ml) was added under nitrogen whilst stirring vigorously and heating to 65° C. TMSCl (44 μl, 0.34 mmol) and 1,2-dibromoethane (30 μl, 0.34 mmol) were added and the reaction was stirred at 65° C. for 30 mins followed by the dropwise addition of N-Boc-3-iodoazetidine (624 mg, 2.20 mmol) as a solution in anhydrous DMA (5 ml). The reaction was then cooled to room temperature methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (470 mg, 1.32 mmol) was added as a solution in anhydrous DMA (10 ml). The resulting solution was degassed with nitrogen for 10 mins after which Pd(dppf)Cl2.DCM (32 mg, 0.04 mmol) and copper (I) iodide (15 mg, 0.08 mmol) were added as solids. The reaction was heated to 80° C. for 60 min and then cooled to room temperature followed by the addition of distilled water (50 ml) and saturated NH4Cl solution (10 ml). The aqueous phase was extracted with EtOAc (3×50 ml) and then the combined organics were washed with brine (20 ml), dried with Na2SO4, filtered and evaporated to dryness followed by heptane azeotrope to remove any residual DMA. The residue was purified over a 10 g Isolute column using 0%-25% EtOAc in heptane as the eluent to afford the title compound as a pale brown oil (565 mg). LC-MS 100%, 2.12 min (3.5 minute LC-MS method), m/z=433.2. To this oil was added DCM (4 ml) followed by TFA (1 ml) and the solution was stirred at room temperature for 2 h after which the solvent was evaporated and saturated aqueous NaHCO3 was added until pH7-8. The aqueous phase was extracted with DCM (3×30 ml), washed with brine (30 ml), dried with MgSO4, filtered and evaporated to afford the title compound yellow oil (440 mg). LC-MS 100%, m/z=333.1.

1. temperaturethe flask was heated
2. customfor a few minutes
3. stirringthe reaction was stirred at 65° C. for 30 mins
4. customThe resulting solution was degassed with nitrogen for 10 mins after which Pd(dppf)Cl2
5. temperatureThe reaction was heated to 80° C. for 60 min
6. temperaturecooled to room temperature
7. extractionThe aqueous phase was extracted with EtOAc (3×50 ml)
8. washthe combined organics were washed with brine (20 ml)
9. dry with materialdried with Na2SO4
10. filtrationfiltered
11. customevaporated to dryness
12. customto remove any residual DMA
13. customThe residue was purified over a 10 g Isolute column

ORD record

ord-c23d2bab950e43e680aa1f59994405f8

Source dataset

uspto-grants-2016_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09376422B2