Acetic Acid → 1-(4-Cyanobenzyl)azetidine-3-carboxylic acid

A mixture of 4-formylbenzonitrile (2.88 g, 22.0 mmol), azetidine-3-carboxylic acid (2.02 g, 20 mmol), and acetic acid (1.15 mL, 20.0 mmol) in dichloromethane (20 mL) and methanol (80 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (6.78 g, 32.0 mmol) was added and stirring was continued at room temperature for 18 hr. The volatiles were removed under reduced pressure, and the residue was partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous phase was washed with diethyl ether (50 mL) and was then concentrated to dryness. The residue was dissolved in water (20 mL) and loaded onto a 2.5×20 cm HP-20 column [Preparation of HP-20 Gel: ˜400 ml of dry, unused MCI CHP-20 Gel (75-150 micron) was swelled in methanol for 24 hrs. The gel was filtered and rinsed with 1 liter of methanol. It was then transferred to a bottle for storage under methanol. Immediately before use, the desired amount of gel was rinsed thoroughly with 20 volumes of water]. The column was eluted with 240 mL of water and 400 mL of methanol. The product containing fractions were concentrated and co-evaporated from ethanol and ethyl acetate/heptane to afford 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol, 75% yield) as a white solid. MS: (M+H)=217.18. 1H NMR (400 MHz, MeOD) δ ppm 3.39 (m, 1H), 4.08 (m, 4H), 4.32 (s, 2H), 7.63 (d, J=8.3 Hz, 2H), and 7.82 (d, J=8.3 Hz, 2H).

1. stirringstirring
2. waitwas continued at room temperature for 18 hr
3. customThe volatiles were removed under reduced pressure
4. customthe residue was partitioned between water (50 mL) and diethyl ether (50 mL)
5. washThe aqueous phase was washed with diethyl ether (50 mL)
6. concentrationwas then concentrated to dryness
7. dissolutionThe residue was dissolved in water (20 mL)
8. customcolumn [Preparation of HP-20 Gel
9. custom˜400 ml of dry
10. waitunused MCI CHP-20 Gel (75-150 micron) was swelled in methanol for 24 hrs
11. filtrationThe gel was filtered
12. washrinsed with 1 liter of methanol
13. washImmediately before use, the desired amount of gel was rinsed thoroughly with 20 volumes of water]
14. washThe column was eluted with 240 mL of water and 400 mL of methanol
15. additionThe product containing fractions
16. concentrationwere concentrated

ORDレコード

ord-93d2b528ea634561a82c3c704bca3792

出典データセット

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08822510B2