4-Chloropyridine → HCID 59135228, compound

A solution of 2-(dimethylamino)ethanol (471 mg, 531 mL, 5.28 mmol) in dry hexanes (3.3 mL) was cooled to −5° C. and n-butyllithium (1.6 M in hexanes, 6.60 mL, 10.6 mmol) was added dropwise under N2. After 30 min at 0° C., the solution was cooled to −78° C. and a solution of 4-chloropyridine (obtained by washing a solution of the corresponding HCl salt (264 mg, 1.76 mmol) in CH2Cl2 (20 mL) with saturated K2CO3 (10 mL), then back extracting with CH2Cl2 (2×20 mL), combining the organic layers, drying (Na2SO4) and concentrating in vacuo) in hexanes (3.3 mL) was added dropwise by cannula. The solution became dark red in color and after 1 h at −78° C., a solution of the electrophile (prepared by adding isopropylmagnesium chloride (2M in THF, 1.29 mL, 2.59 mmol) to a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (702 mg, 2.64 mmol) in dry THF (3.5 mL) at −15° C. under N2 and stirring for 15 min) was added by cannula. The reaction was allowed to warm slowly to room temperature overnight. Water (25 mL) and saturated NH4Cl (50 mL) were added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-30% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate. Rf=0.46 (20% EtOAc in hexanes). LCMS calc.=319.1; found=319.3 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=5.0 Hz, 1H), 8.04 (s, 1H), 7.47 (dd, J=5.2, 2.0 Hz, 1H), 7.35-7.30 (m, 5H), 5.78 (s, 1H), 5.72 (m, 1H), 5.11 (m, 2H), 1.47 (d, J=7.0 Hz, 3H).

1. extractionback extracting with CH2Cl2 (2×20 mL)
2. dry with materialdrying (Na2SO4)
3. concentrationconcentrating in vacuo) in hexanes (3.3 mL)
4. additionwas added dropwise by cannula
5. customa solution of the electrophile (prepared
6. additionwas added by cannula
7. extractionthe mixture was extracted with EtOAc (3×50 mL)
8. dry with materialThe combined extracts were dried (MgSO4)
9. concentrationconcentrated in vacuo
10. customto give the crude product
11. customThis was purified by flash chromatography (Si, 40×160 mm, 0-30% EtOAc in hexanes gradient)

ORD record

ord-c63906ede8814fa699019a90db2605f3

Source dataset

uspto-grants-2010_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07652049B2