* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
4-(3,4-Dimethoxy-phenyl)-2,6-dimethyl-1-(3-phenyl-propyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl] ester 5-methyl ester[ No CAS ]
4-(3,4-Dimethoxy-phenyl)-1-[3-(4-fluoro-phenoxy)-propyl]-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl] ester 5-methyl ester[ No CAS ]
EXAMPLE 9 Alternatively, 0.35 molar equivalents of one of the 1,3-dioxolane derivatives described in Examples 6 and 7, S(-)1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol; S(-) 1,2-cyclopentylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol; S(-)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diol; are added in portions to a 36% hydrochloric acid solution (36 mL) in 45 ml of water under stirring; the suspension is heated to 80 C. to obtain a clear solution, which is kept at this temperature for a further 30 minutes, then cooled to 20-25 C. and the aqueous phase is repeatedly is extracted with dichloromethane (3*15 ml), then added with n-butanol (0.5 l). The diphasic mixture is refluxed to distil the water n-butanol azeotrope, recovering about 300 ml of distillate, then cooled to promote the crystallization of (-)3-(4-phenyl-piperazin-1-yl)-propanediol hydrochloride (85 g). A solution of the hydrochloride in 125 ml of water is decolorized by heating at 50 C. with active charcoal (2.2 g) for 15 minutes, filtered then neutralized by addition of an ammonium hydroxide aqueous solution (30% w/w). After briefly heating to 50 C., crystallization is started by addition of (-) 3-(4-phenyl-piperazin-1-yl)-propanediol crystals. The suspension is left to spontaneously cool, then kept for 2 hours at +2-+4 C., finally filtered to yield 70-72 g of (-) 3-(4-phenyl-piperazin-1-yl)-1,2-propanediol.
a) Recovery of partially resolved R(+) isomer Mother liquor from salification is alkalinized to pH 11 with 10% sodium hydroxide and repeatedly extracted with methylene chloride. The oganic layers are dried and evaporated to dryness, yielding 280 g of dropropizine rich in R(+) isomer.
a) Recovery of partially resolved R(+) isomer. Mother liquor from salification is alkalinized to pH 11 with 10% sodium hydroxide and repeatedly extracted with methylene chloride. The oganic layers are dried and evaporated to dryness, yielding 280 g of dropropizine rich in R(+) isomer.
8
active charcoal[ No CAS ]
S(-)-1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol[ No CAS ]
S(-)-1,2-cyclopentylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol[ No CAS ]
(-) 3-(4-phenyl-piperazin-1-yl)-propanediol[ No CAS ]
(-) 3-(4-phenyl-piperazin-1-yl)-propanediol hydrochloride[ No CAS ]
S(-)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diol[ No CAS ]
[ 17692-31-8 ]
Yield
Reaction Conditions
Operation in experiment
With ammonium hydroxide; In hydrogenchloride; water;
EXAMPLE 8 Alternatively, 0.35 molar equivalents of one of the 1,3-dioxolane derivatives described in Examples 1-4, namely S(-)-1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol; S(-)-1,2-cyclopentylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol; S(-)-1,2-cyclohexylidene-3-(4phenyl-piperazin-1-yl)propane-1,2-diol; S(-)-1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, are added in portions to a 36% hydrochloric acid solution (36 ml) in 45 ml of water under stirring; the suspension is heated to 80 C. to obtain a clear solution which is kept at this temperature for a further 30 minutes, then cooled to 20-25 C. The aqueous phase is repeatedly extracted with dichloromethane (3*15 ml), then n-butanol (0.5 L) is added. The diphasic mixture is refluxed to distil the water-n-butanol azeotropic mixture, recovering about 300 ml of distillate, then cooled to promote crystallization of (-) 3-(4-phenyl-piperazin-1-yl)-propanediol hydrochloride (85 g). A solution of the hydrochloride in 125 ml of water is decolorized with active charcoal (2.2 g) by heating to 50 C. for 15 minutes, filtered and subsequently neutralized by addition of an ammonium hydroxide aqueous solution (30% w/w). After briefly heating to 50 C., crystallization is started by addition of (-) 3-(4-phenyl-piperazin-1-yl)-propanediol crystals. The suspension is left to spontaneously cool, then kept for 2 hours at +2+4 C., and filtered to yield 70-72 g of (-) 3-(4-phenyl-piperazin-1-yl)-1,2-propanediol.
Multi-step reaction with 3 steps
1: sodium hydroxide / water / 0.25 h / 75 °C
2: (2-hydroxyphenyl)diphenyl(propyl)phosphonium iodide / neat (no solvent) / 48 h / 45 °C / 7500.75 Torr / Autoclave
3: sodium hydroxide / water / 3 h / 23 °C
Multi-step reaction with 2 steps
1: (2-hydroxyphenyl)diphenyl(propyl)phosphonium iodide / neat (no solvent) / 48 h / 45 °C / 7500.75 Torr / Autoclave
2: sodium hydroxide / water / 3 h / 23 °C
With hydrogen; water-d2 at 140℃; for 24h; Autoclave;
General procedure for the deuteration reactions.
General procedure: In a 4 ml vial fitted with a magnetic stir bar and septum cap, iron catalyst (60 mg, 20 mol%) and substrate (0.25 mmol) were added. Then, a needle was inserted in the septum, allowing gaseous reagents to enter. After adding the solvent deuterium oxide (1.5 ml), the vials (up to eight) were set in an alloy plate and then placed into a 300 ml steel Parr autoclave. The autoclave was flushed with hydrogen six times at 10 bar and finally pressurized to the desired value (20 bar). Then, it was placed into an aluminium block and heated to the desired temperature. At the end of the reaction, the autoclave was quickly cooled down to r.t. with an ice bath and vented. Finally, the samples were removed from the autoclave, and ethyl acetate was added to the crude mixture. This mixture was centrifuged, and the organic layer was removed from the vials (three times). After removal of all volatiles in vacuo, the desired products were obtained. In case of anilines with deuterium labelling on the nitrogen, 1 ml H2O was added during work up and N-D was replaced by N-H.
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