Example 1
Reaction of azacyclonol (Diphenyl(piperidin-4-yl)methanol, CAS: 115-46-8) (IV) with 2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile according to the coupling conditions described in Table 2 of Wang et al. (Org. Proc. Res. and Dev. 2010, 14, 1464-68).
The table depicted below lists the reaction conditions (solvent, base, temperature) set forth in Table 2 of Wang et al. for reacting azacyclonol with a compound of formula III (X is Br, Cl, OTs; R1 is nitril) to obtain a compound of formula II-A and, as side product, a compound of formula V-A. If this nitrile by-product V-A is tested under the reaction conditions mentioned by Wang it does not react with azacyclonol to compound II-A as described below for each entry in more detail.
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10.0 mmol) were dissolved in 9.4 ml THF, Azacyclonol (3.21 g, 12.0 mmol, 1.2 eq.) and Na2CO3 (1.06 g; 10.0 mmol; 1.0 eq.) were added before stirring the mixture at 60° C. for 8 hours.
The assay was performed by diluting an aliquot taken from the reaction mixture in the standard manner.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 20->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm): Rt (Standard II-A)=3.57 min
Product II-A was not detectable. Addition of an aliquot corresponding to 0.1% of II-A to the diluted reaction mixture leads to a detectable peak, showing that less than 0.1% were formed in the reaction.
Entry 2
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10.0 mmol) were dissolved in 9.4 ml THF, Azacyclonol (3.21 g, 12.0 mmol, 1.2 eq.) and NaHCO3 (0.84 g; 10.0 mmol; 1.0 eq.) were added before stirring the mixture at 60° C. for 8 hours.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 20->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm): Rt (Standard II-A)=3.57 min
Product II-A was not detectable. Addition of an aliquot corresponding to 0.1% of II-A to the diluted reaction mixture leads to a detectable peak, showing that less than 0.1% were formed in the reaction
Entry 3
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10.0 mmol) were dissolved in 9.4 ml DMF. Azacyclonol (3.21 g, 12.0 mmol, 1.2 eq.) and NEt3 (1.39 ml; 10.0 mmol; 1.0 eq) were added before stirring the mixture at 25° C. for 8 hours.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 20->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm): Rt (Standard II-A)=3.55 min
Product II-A was not detectable. Addition of an aliquot corresponding to 0.1% of II-A to the diluted reaction mixture leads to a detectable peak, showing that less than 0.1% were formed in the reaction
Entry 4
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10.0 mmol) were dissolved in 9.4 ml THF. Azacyclonol (3.21 g, 12.0 mmol, 1.2 eq.) and NEt3 (1.39 ml; 10.0 mmol; 1.0 eq.) were added before stirring the mixture at 25° C. for 8 hours.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 20->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm): Rt (Standard II-A)=3.56 min
Product II-A was not detectable. Addition of an aliquot corresponding to 0.1% of II-A to the diluted reaction mixture leads to a detectable peak, showing that less than 0.1% were formed in the reaction
Entry 5
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10.0 mmol) were dissolved in 9.4 ml THF. Azacyclonol (3.21 g, 12.0 mmol, 1.2 eq.) and DIPA (1.4 ml; 10.0 mmol; 1.0 eq.) were added before stirring the mixture at 25° C. for 8 hours.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 20->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm): Rt (Standard II-A)=3.61 min
Product II-A was not detectable. Addition of an aliquot corresponding to 0.1% of II-A to the diluted reaction mixture leads to a detectable peak, showing that less than 0.1% were formed in the reaction
Entry 6
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10.0 mmol) were dissolved in 9.4 ml acetone. Azacyclonol (3.21 g, 12.0 mmol, 1.2 eq.) and NaHCO3 (0.84 g; 10.0 mmol; 1.0 eq.) were added before stirring the mixture at 55° C. for 8 hours.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 20->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm): Rt (Standard II-A)=3.61 min
Product II-A was not detectable. Addition of an aliquot corresponding to 0.1% of II-A to the diluted reaction mixture leads to a detectable peak, showing that less than 0.1% were formed in the reaction
Entry 7
2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10.0 mmol) were dissolved in 9.4 ml acetone. Azacyclonol (3.21 g, 12.0 mmol, 1.2 eq.) and NEt3 (1.39 ml; 10.0 mmol; 1.0 eq.) were added before stirring the mixture at 55° C. for 8 hours.
HPLC (AUC, Merck Chromolith Performance RP18e, A: H2O/0.05% TFA, B: MeCN/0.05% TFA, 20->70% B in 7 min, 4 ml/min, 40° C., UV: 210 nm): Rt (Standard II-A)=3.61 min
Product II-A was not detectable. Addition of an aliquot corresponding to 0.1% of II-A to the diluted reaction mixture leads to a detectable peak, showing that less than 0.1% were formed in the reaction.
Catalyst evaluation based on a general procedure for preparing 2-[4-[4-[4-[hydroxy(diphenyl)methyl]-1-piperidyl]butanoyl]phenyl]-2-methyl-propanenitrile (480.7 g/mol) of formula II-A using azacyclonol (Diphenyl(piperidin-4-yl)methanol, CAS: 115-46-8) of formula IV, 2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A and different salts as catalysts, partly additionally a salt with different amounts:
Azacyclonol (2.67 g, 10.0 mmol) and 2-[4-(cyclopropanecarbonyl-)-phenyl]-2-methyl-propanenitrile of formula V-A (2.13 g, 10 mmol) were placed in 25 ml 3-neeked flask. Toluene (0.3 ml, 5 wt %) and the catalyst as specified below in the single experiments were added and the mixture was heated to 150° C. and stirred for 20 h. Conversion was followed by HPLC and LC-MS (vide infra). Samples were taken at 150° C. after 2 h and 20 h. 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).
Isolation: The mixture was cooled to 110° C., EtOH (17 ml) was added carefully and the mixture was allowed cooling down to rt with stirring. The solid was filtered and the filter cake was washed with cold EtOH to yield the title compound II-A as a white solid. The products were characterised by HPLC (vide supra) and 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).
