Hydrochloric Acid → HCID 23587486, compound

Temperature

75 °C

A solution of (±)-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutanone O-methyl-oxime (438 mg, 1.43 mmol) in THF (13 mL) under Ar was treated dropwise with 1 M BH3.THF complex in THF (8.6 mL, 8.6 mmol) and stirred at room temperature for 3 h and at 75° C. for 20 h. The reaction was cooled to 0° C. and treated carefully with 6 N HCl (1 mL) until the pH ˜2. The THF was evaporated and a solution of the residue in EtOH (9 mL) and 6 N HCl (1 mL) was stirred at 75° C. for 1 h. It was then allowed to cool to room temperature, basified with 8 N NaOH (4 mL) until the pH ˜10, diluted with H2O (5 mL) to dissolve the resulting white precipitate, and concentrated. The residue was partitioned between CH2Cl2 and 1 N NaOH, the aqueous phase was extracted with CH2Cl2, and the extracts were dried and concentrated. Chromatography of the residue with 90:9.5:0.5–60:38:2 CH2Cl2:MeOH:NH4OH gave, in order of elution, 70 mg of the desired product (80% pure by 1H NMR) as a colorless oil which was used without further purification, 48 mg (12%) of pure desired product as a colorless oil, and 125 mg of a mixture of desired product, stereoisomeric (±)-trans-2-[4-(4-chlorobenzyl)piperidin-1-yl]-cyclobutylamine, and an unidentified impurity. Product: 1H NMR δ 1.19–1.70 (m, 8H), 1.89–2.05 (m, 3H), 2.50 (d, J=6.9 Hz, 2H), 2.56 (m, 1H), 2.78 (m, 2H), 3.44 (m, 1H), 7.60 (m, 2H), 7.23 (m, 2H); 13C NMR δ 24.39, 25.56, 31.63, 31.76, 38.01, 42.61, 49.17, 49.63, 51.74, 62.51, 128.25, 130.42, 131.50, 139.16; MS m/z 279.2 (M+1)+.

1. temperatureThe reaction was cooled to 0° C.
2. customThe THF was evaporated
3. stirringa solution of the residue in EtOH (9 mL) and 6 N HCl (1 mL) was stirred at 75° C. for 1 h
4. temperatureto cool to room temperature
5. additiondiluted with H2O (5 mL)
6. dissolutionto dissolve the resulting white precipitate
7. concentrationconcentrated
8. customThe residue was partitioned between CH2Cl2 and 1 N NaOH
9. extractionthe aqueous phase was extracted with CH2Cl2
10. customthe extracts were dried
11. concentrationconcentrated

ORD record

ord-b66bf0585d6444a1aa7beda63733a69b

Source dataset

uspto-grants-2006_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07019007B2