Example 2
Reaction of azacyclonol (Diphenyl(piperidin-4-yl)methanol, CAS: 115-46-8) (IV) with 2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile (V-A) according to coupling conditions described by Yovell et al. (J. Org. Chem. 42, 850-855, 1977, page 855) to obtain a compound of formula II-A (as indicated in WO2006/034092/AMR Techn.).
a) Reaction According to Yovell
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (1.07 g, 5.0 mmol) and azacyclonol (1.34 g, 5.0 mmol, 1.0 eq.) and 2.4 ml o-xylene were added to a 25 ml 3-neck flask. p-Toluenesulfonic acid monohydrate (95 mg, 0.5 mmol 0.1 eq, CAS: 6192-52-5) were added and the mixture was heated to reflux (bath temperature about 150° C.).
Monitoring the reaction by HPLC showed about 7% product II-A after 2 hours and about 46% after 20 hours.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 10->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm Rt=4.11 min
b) Use of an Increased Amount of pTsOH
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (1.07 g, 5.0 mmol) and azacyclonol (1.34 g, 5.0 mmol, 1.0 eq.) and 2.4 ml o-xylene were added to a 25 ml 3-neck-flask. P-Toluenesulfonic acid monohydrate (950 mg, 5.0 mmol, 1 eq, CAS: 6192-52-5) were added and the mixture was heated to reflux (bath temperature about 150° C.).
Conversion was monitored by HPLC and LC-MS (vide infra).
II-A can be detected only in small trace amounts.
The major product with 49% (by HPLC) is by HPLC comparison with authentic material and LC-MS 4-(Diphenylmethylene)piperidine (CAS: 50706-57-5), resulting from elimination of water from the tertiary alcohol.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O+0.05% TFA, B: MeCN/0.05% TFA, 10->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm) Rt=3.14 min LC-MS: (YMC J′ sphere ODS H 80×20×2.1 mm, 4 μm, A: H2O+0.05% TFA, B: MeCN, 4%->95% B in 2 min., 1 ml/min, 30° C., UV: 220 nm; MS: ESI) Rt=1.21 min, MH+ 250.
