Formaldehyde → Ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate

Temperature

60 °C

Titanium(IV) isopropoxide (0.598 mL, 2.00 mmol) was added to ethyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (0.262 g, 1 mmol), and paraformaldehyde (0.120 g, 4.00 mmol) in ethanol (5 mL). The resulting solution was stirred at 60° C. under nitrogen for 30 mins. This was cooled to 20° C. and sodium borohydride (0.095 g, 2.5 mmol) was added in one portion. The solution was heated at 60° C. for 24 h. The reaction mixture was quenched with 0.880 ammonia (0.5 mL), filtered, washed with diethyl ether (2×5 mL) and the organic extracts were evaporated. The crude product was purified by silica column chromatography, eluting with a gradient of 0-5% MeOH in DCM containing 0.1% ammonia. Fractions were evaporated to dryness to afford an oil. This was dissolved in acetonitrile (20 ml), polymer supported isocyante resin (1 mmol/g, 2 g) was added and the suspension was stirred overnight. The resin was filtered off and the solution evaporated to dryness to give ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate (0.310 g, 112%) as a white solid. MS: m/z 278 (MH+).

1. temperatureThis was cooled to 20° C.
2. temperatureThe solution was heated at 60° C. for 24 h
3. customThe reaction mixture was quenched with 0.880 ammonia (0.5 mL)
4. filtrationfiltered
5. washwashed with diethyl ether (2×5 mL)
6. customthe organic extracts were evaporated
7. customThe crude product was purified by silica column chromatography
8. washeluting with a gradient of 0-5% MeOH in DCM containing 0.1% ammonia
9. customFractions were evaporated to dryness
10. customto afford an oil
11. additionwas added
12. stirringthe suspension was stirred overnight
13. filtrationThe resin was filtered off
14. customthe solution evaporated to dryness

ORD record

ord-0eb9efc3a32e43eaa7d2b42fa22e4fc5

Source dataset

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08129391B2