Acetyl chloride → 1-[(Pyridin-4-yl)methyl]-1,4-diazepane

Temperature

25 °C

A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved in anhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution of homopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reaction mixture was heated to reflux for 1 h, cooled to 25° C. and a solution of 4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) in EtOH (40 mL) was added. The reaction mixture was heated to reflux for 16 h, cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with CH2Cl2 (300 mL) and was washed with 2N KOH (1×300 mL). The aqueous layer was extracted with CH2Cl2 (1×300 mL) and the organic phase was washed with 2N KOH (150 mL), dried (MgSO4) and concentrated. Chromatography (SiO2, 5% H2O-5% NH4OH—1PrOH) afforded the desired product (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC Rf 0.45 (5% H2O-5% NH4OH—1PrOH): 1H NMR (CDCl3, 300 MHz) δ 8.77 (d, J=5.9 Hz, 2H), 7.53 (d, J=5.7 Hz, 2H), 3.91 (s, 2H), 3,19 (m, 4H), 2.92 (m, 4H), 2.04 (m, 2H).

1. temperatureThe reaction mixture was heated
2. temperatureto reflux for 1 h
3. temperatureThe reaction mixture was heated
4. temperatureto reflux for 16 h
5. temperaturecooled to 25° C.
6. customthe solvent was removed under vacuum
7. additionThe residue was diluted with CH2Cl2 (300 mL)
8. washwas washed with 2N KOH (1×300 mL)
9. extractionThe aqueous layer was extracted with CH2Cl2 (1×300 mL)
10. washthe organic phase was washed with 2N KOH (150 mL)
11. dry with materialdried (MgSO4)
12. concentrationconcentrated

ORD record

ord-7b8633d4bcee4172a9d18447621a20ff

Source dataset

uspto-grants-2004_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06686353B1