Diethyl Carbonate → (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester

To a cold solution of (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester (25 g, 130 mmol) and diethylcarbonate (33.79 g, 286 mmol) in tetrahydrofuran (62.5 ml) under nitrogen at −10° C. was added lithium diisopropylamide in tetrahydrofuran (158.9 ml, 1.8M, 286 mmol) dropwise over 1 hr 10 min. After stirring for an additional 30 mins at −10° C. a solution of 4-nitrobenzonitrile (29.78 g, 195 mmol) in tetrahydrofuran (175 ml) is added dropwise and stirring continued for 3 hrs. The reaction mixture was poured into a cold aqueous hydrochloric solution (375 ml, 2M) at 0° C.; after warming to room temperature the acidic aqueous layer was separated and washed with tert-butyl methyl ether (200 ml). The acidic aqueous layer was cooled in an ice bath and tert-butyl methyl ether (500 ml) was added. The mixture was then made basic (pH 9) by addition of sodium carbonate solution (55 ml, 25 w/w %). The mixture was then warmed to room temperature and the organic phase separated; the basic aqueous phase was extracted with tert-butyl methyl ether (250 ml). The combined organic layer was treated with Celite® (12.5 g), then filtered and the filtrate concentrated in vacuo to give (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester crude (28.58 g, 51% w/w %). The crude material was dissolved in ethanol (300 ml) then heated to 40° C. and a solution of hydrochloric acid in isopropanol (8 ml, 4.95M, 20.7 mmol) was added followed by addition of seeds (90 mg) and the solution cooled to −10° C. over 10 hrs. The crystals were filtered and washed with tert-butyl methyl ether. After drying at 40° C. under vacuum gave 14.51 g, 25% yield of (5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester hydrochloride salt as red wine crystals. Characterisation data were in accordance with example 7.

1. additionis added dropwise
2. customwas separated
3. washwashed with tert-butyl methyl ether (200 ml)
4. temperatureThe acidic aqueous layer was cooled in an ice bath
5. additiontert-butyl methyl ether (500 ml) was added
6. additionby addition of sodium carbonate solution (55 ml, 25 w/w %)
7. temperatureThe mixture was then warmed to room temperature
8. customthe organic phase separated
9. extractionthe basic aqueous phase was extracted with tert-butyl methyl ether (250 ml)
10. additionThe combined organic layer was treated with Celite® (12.5 g)
11. filtrationfiltered
12. concentrationthe filtrate concentrated in vacuo

ORD record

ord-737d3d36c3654fe6b0d79d101ae653b7

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08101750B2