1-Hydroxybenzotriazole → HCID 23153146, compound

To (4-benzoylpiperazin-1-yl)acetic acid ethyl ester (8.19 g) were added methanol (300 ml) and water (50 ml), and lithium hydroxide (1.34 g) was added thereto in an ice water bath, followed by stirring for 10 min. The reaction mixture was allowed to warm up to room temperature and stirred for 24 hr. After addition of 1N hydrochloric acid (55.9 ml), the reaction mixture was concentrated under reduced pressure, and ethanol (200 ml) was added to the resultant residue. Precipitated insoluble matter was filtered through celite. The filtrate was concentrated to provide a crude product of (4-benzoylpiperazin-1-yl)acetic acid as a white solid (8.6 g). To (4-benzoylpiperazin-1-yl)acetic acid (2 g) was added N,N-dimethylformamide (80 ml) under a nitrogen atmosphere at room temperature, and azetidine hydrochloride (1.51 g), triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added thereto in this order, followed by stirring at room temperature for 66 hr. Liquid-liquid separation was carried out after addition of ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, the resultant residue was suspended in diethyl ether (10 ml). The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (731.5 mg).

1. customLiquid-liquid separation
2. additionafter addition of ethyl acetate (100 ml)
3. washThe organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order
4. dry with materialdried over anhydrous sodium sulfate
5. customThe solvent was removed under reduced pressure
6. customthe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate)
7. additionFractions containing the target compound
8. concentrationwere concentrated under reduced pressure
9. filtrationThe solid was collected by filtration
10. customdried under aeration

ORD record

ord-f3a296bed22b4c1cb6b4f61e76f2917b

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08288538B2