4-Toluenesulfonyl chloride → Methyl 6-(chloromethyl)nicotinate

Methyl 6-methylnicotinate (10 g, 66.2 mmol) was dissolved in dichloromethane (150 ml). 3-Chloroperoxybenzoic acid (17 g, 112 mmol) was added and the mixture was stirred for 3 hours at room temperature. Saturated NaHCO3 solution (200 ml) was added and the mixture was stirred for an additional hour. The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (2×100 ml). The combined dichloromethane layers were washed with saturated NaHCO3 (aq) (100 ml), brine (100 ml) and dried (Na2SO4). After evaporation of the solvent methyl 6-(chloromethyl)nicotinate N-oxide (7.8 g, 51.0 mmol) was obtained as a creme colored solid, mp 90.4-90.8° C., which was combined with p-toluenesulfonyl chloride (10.7 g, 56.1 mmol) and dioxane (100 ml) under an Argon atmosphere. The reaction mixture was heated under reflux for 1 night. After cooling to room temperature the solvent was evaporated and the residue dissolved in dichloromethane (200 ml). The solution was washed with saturated Na2CO3 (aq) (2×100 ml), brine (50 ml) and dried (Na2SO4). After evaporation of the solvent the product was purified by column chromatography (SiO2, using hexane/ethyl acetate 10:2.5 as an eluens) to give methyl 6-(chloromethyl)nicotinate (5.71 g, 46% overall yield) as a slightly yellow solid. An analytically pure sample could be obtained by recrstallization from n-hexane, mp 63.5-63.8° C.; 1H-NMR (CDCl3) δ 3.94 (s, 3H) 4.70 (s, 2H), 7.58 (d, 1H, J=8.4 Hz), 8.30 (dd, 1H, J=8.1 Hz, J=2.2 Hz), 9.08 (d, 1H, J=1.5 Hz); Anal. Calcd. for C8H8ClNO2: C 51.77, H 4.34, N 7.55; found: C 51.50, H 4.23, N 7.46.

1. stirringthe mixture was stirred for an additional hour
2. customThe dichloromethane layer was separated
3. extractionthe aqueous layer was extracted with dichloromethane (2×100 ml)
4. washThe combined dichloromethane layers were washed with saturated NaHCO3 (aq) (100 ml), brine (100 ml)
5. dry with materialdried (Na2SO4)
6. customwas obtained as a creme colored solid, mp 90.4-90.8° C., which
7. temperatureThe reaction mixture was heated
8. temperatureunder reflux for 1 night
9. temperatureAfter cooling to room temperature the solvent
10. customwas evaporated
11. dissolutionthe residue dissolved in dichloromethane (200 ml)
12. washThe solution was washed with saturated Na2CO3 (aq) (2×100 ml), brine (50 ml)
13. dry with materialdried (Na2SO4)
14. customAfter evaporation of the solvent the product
15. customwas purified by column chromatography (SiO2

ORD record

ord-a129da9ae76843028bc187fbbfc1665b

Source dataset

uspto-grants-2003_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06617299B1