Sulfuric Acid → Methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate

Temperature

115 °C

A 2 L single-necked round-bottomed flask was charged with 6 (64.00 g, 0.198 mol) and MeOH (360 g) followed by the slow, careful, and dropwise addition of H2SO4 (240 g) and the resulting homogeneous solution stirred at reflux (115° C. oil bath) until the reaction was complete (25 h with 0.8% unreacted starting material) with 3.5% ArCH2CO2H. After brief cooling, MgSO4 (75 g) was added and the mixture swirled and allowed to stand an additional 45 min (composition now 96.3% product, 0.8% unreacted starting material, and 2.5% ArCH2CO2H). The reaction mixture was then added slowly to a rapidly stirred and cooled (ice-water bath) mixture of DCM (2 L) and a solution of K2CO3 (450 g) in H2O (600 mL). The resulting emulsion was allowed to stand overnight. The clear portions of organic solution were siphoned off and the remainder portions were treated iteratively with water and DCM, the clear organics being combined with the original portion that was siphoned off. The combined organics were dried (Na2SO4), filtered, and concentrated to a volume of 1.2 L followed by the addition of 300 mL of 5% EtOAc (in heptane) and then heptane (300 mL) and the mixture concentrated (rotovap with heat) again to remove the DCM. At this point 15 mL EtOAc was added and the hot mixture swirled until crystallization had begun, swirling continued until crystallization was near complete, and then allowed to stand and cool to room temperature for complete crystallization. The solid was then filtered, washed with 300 mL 5% EtOAc (in heptane) and heptane (100 mL) and then fully air dried to give 57.74 g (yield of 82%) of 7 as a light yellow solid (98.9% AUC). Another 3.94 g of clean product (97.9% AUC) was obtained from the filtrate (total yield of 87%).

1. additionThe reaction mixture was then added slowly to
2. stirringa rapidly stirred
3. temperaturecooled
4. waitto stand overnight
5. dry with materialThe combined organics were dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated to a volume of 1.2 L
8. additionfollowed by the addition of 300 mL of 5% EtOAc (in heptane)
9. concentrationheptane (300 mL) and the mixture concentrated
10. temperature(rotovap with heat) again
11. customto remove the DCM
12. additionAt this point 15 mL EtOAc was added
13. customthe hot mixture swirled until crystallization
14. customswirling continued until crystallization
15. temperaturecool to room temperature for complete crystallization
16. filtrationThe solid was then filtered
17. washwashed with 300 mL 5% EtOAc (in heptane) and heptane (100 mL)
18. customfully air dried

ORD record

ord-a061e8f275c949649d6a7dabae6d8a38

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07935697B2