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Stage #1: With potassium osmate(VI); methanesulfonamide; water; potassium carbonate; potassium hexacyanoferrate(III) In <i>tert</i>-butyl alcohol at 0 - 20℃; for 22 h; Stage #2: With sodium sulfite In <i>tert</i>-butyl alcohol at 20℃; for 1 h;
A3a) 1-benzyl-4-hydroxymethyl-piperidin-4-ol A solution of 200 g AD-Mix-Alpha (Messrs Aldrich, Item no. 39,275-8) in 500 mL water and 300 mL tert-butanol was stirred for 20 min at RT, cooled to 0° C., combined with 13.7 g (144 mmol) methanesulphonic acid amide and 27.0 g (144 mmol) of 1-benzyl-4-methylene-piperidine and, after removal of the cooling bath, stirred for 22 h at RT. 59 g Na2SO3 were added to the reaction mixture and it was stirred for 1 h at RT. 2 L EtOAc and 500 mL saturated NaHCO3 solution were added, the organic phase was separated off and dried over Na2SO4 . After the desiccant and solvent had been eliminated the residue was dissolved in 150 mL EtOAc and filtered through Alox. The filtrate was discarded and the product was eluted from the Alox with 1 L MeOH. After the solvent had been eliminated the product was reacted further without purification. Yield: 26.0 g (82percent of theory) ESI-MS: (M+H)+=222 retention time (HPLC): 1.4 min (method B)
A solution of the epoxide (1.33 g, 6.54 mmol) in aqueous 0.2 M sulfuric acid (82 mL) was stirred at room temperature for 20 hours. The solution was cooled to 0 °C, and sodium carbonate was added until the pH of the aqueous mixture reached 12. The mixture was then diluted with water (20 ML), and extracted with ethyl acetate (3x 200 ML). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting white solid was purified via flash chromatography eluting with a gradient of dichloromethane : methanol (5: 1 to 1: 1) to deliver the title compound as a waxy solid (1.12 g, 77percent). MS (APCI) (M+1/Z) 221.1.
58%
at 20℃;
A mixture of Compound 2 (30.5 g, 150 mmol) in H2S04 (37.5 g, 380 mmol, 0.2 M) was stirred at rt overnight. The mixture was neutralized with Na2C03 to pHIO and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to give the desired product (20.0 g, 58percent). 1H NMR (400 MHz, CD3OD): δ ppm: 7.29-7.22(m, 5H), 3.50(s, 2H), 3.44(s, 2H), 3.31-3.27 (m, 2H), 2.61-2.58(m, 2H), 2.41-2.36(m, 2H), 1.69-1.64(m, 2H), 1.51-1.49(m, 2H).
A solution of the epoxide (1.33 g, 6.54 mmol) in aqueous 0.2 M sulfuric acid (82 mL) was stirred at room temperature for 20 hours. The solution was cooled to 0 C, and sodium carbonate was added until the pH of the aqueous mixture reached 12. The mixture was then diluted with water (20 ML), and extracted with ethyl acetate (3x 200 ML). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The resulting white solid was purified via flash chromatography eluting with a gradient of dichloromethane : methanol (5: 1 to 1: 1) to deliver the title compound as a waxy solid (1.12 g, 77%). MS (APCI) (M+1/Z) 221.1.
58%
With sulfuric acid; at 20℃;
A mixture of Compound 2 (30.5 g, 150 mmol) in H2S04 (37.5 g, 380 mmol, 0.2 M) was stirred at rt overnight. The mixture was neutralized with Na2C03 to pHIO and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and concentrated to give the desired product (20.0 g, 58%). 1H NMR (400 MHz, CD3OD): delta ppm: 7.29-7.22(m, 5H), 3.50(s, 2H), 3.44(s, 2H), 3.31-3.27 (m, 2H), 2.61-2.58(m, 2H), 2.41-2.36(m, 2H), 1.69-1.64(m, 2H), 1.51-1.49(m, 2H).
85% potassium hydroxide (40.6 g) was dissolved in water (615 mL) and was mixed with dioxane (103 mL). A solution of the compound (25.0 g) obtained in Step 1 in dioxane (103 mL) was added dropwise thereto at 90C under nitrogen atmosphere over sixty minutes, followed by stirring at the same temperature for twenty minutes. The reaction mixture was treated with concentrated hydrochloric acid under cooling with ice-water to be adjusted to pH 9, sodium chloride was added until the mixture was saturated, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from a mixture of hexane and ether, was collected by filtration to yield the titled compound (24.6 g) as crystals.
With potassium hydroxide; water; In 1,4-dioxane; at 90℃; for 1.33333h;
85% potassium hydroxide (40.6 g) was dissolved in water (615 mL) and mixed with dioxane (103 mL). A dioxane solution (103 mL) of the compound (25.0 g) obtained in Step 1 was added dropwise to the mixture at 90C over 60 minuites under nitrogen atmosphere and stirred at the same temperature for 20 minutes. With cooling the reaction solution with ice-water, the pH of the solution was adjusted to 9 with concentrated hydrochloric acid, the mixture was saturated with salt, and extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from hexane : ether and collected by filtration to obtain the titled compound (24.6 g) as crystals.
With hydrogen;palladium 10% on activated carbon; In methanol; at 50℃; under 2250.23 Torr; for 4h;
A3b) 4-hydroxymethyl-piperidin-4-ol A suspension of 26.0 g (117 mmol) <strong>[92197-36-9]1-benzyl-4-hydroxymethyl-piperidin-4-ol</strong> and 5.0 g 10% Pd/C in 500 mL MeOH was hydrogenated at 50 C. and 3 bar hydrogen pressure until the theoretical hydrogen uptake had occurred (4 h). The catalyst was filtered off and washed with MeOH. After the solvent had been eliminated the residue was reacted further without purification. Yield: 15.4 g (100% of theory) ESI-MS: (M+H)+=132 retention time (HPLC): 0.5 min (method B)
98%
With 10 wt% Pd(OH)2 on carbon; hydrogen; In methanol; under 775.743 Torr;
To a solution of Compound 3 (20 g, 90 mmol) in CH3OH (800 mL) was added dry Pd(OH)2 (2 g). The formed mixture was hydrogenated under H2 atmosphere of 15 Psi pressure overnight. The catalyst was filtered and the filtrate was concentrated to give the desired product (12 g, 98%).
95 - 100%
With hydrogen;palladium(II) hydroxide/carbon; In methanol; under 2585.81 Torr; for 3h;
A mixture of the benzylamine (1.05 g, 4.75 mmol) and 20% Pd (OH) 2/C (0.15 g) in methanol (50 mL) was hydrogenated at 50 psi for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to deliver the title compound as a white solid (Yield 593 mg, 95%). MS (APCI) (M+1/Z) = 132.0
100 ml water and 10 ml perchloric acid were added to 100 ml solution of 6.8 g of this 6-benzyl-1-oxo-6-azaspiro[2.5]octane in tetrahydrofuran, and the mixture was stirred at room temperature for 7 hr. The mixture was ice-cooled, and aqueous sodium carbonate was added thereto to adjust the pH thereof to 7, and then the mixture was evaporated. Ethyl acetate was added to the residue, and the insoluble mattters were removed by filtration. The filtrate was evaporated, and then purified by silica gel column chromatography to give 4 g of 1-benzyl-4-(hydroxymethyl)-4-piperidinol.
7
[ 109105-86-4 ]
[ 92197-36-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
A3a) 1-benzyl-4-hydroxymethyl-piperidin-4-ol A solution of 200 g AD-Mix-Alpha (Messrs Aldrich, Item no. 39,275-8) in 500 mL water and 300 mL tert-butanol was stirred for 20 min at RT, cooled to 0 C., combined with 13.7 g (144 mmol) methanesulphonic acid amide and 27.0 g (144 mmol) of 1-benzyl-4-methylene-piperidine and, after removal of the cooling bath, stirred for 22 h at RT. 59 g Na2SO3 were added to the reaction mixture and it was stirred for 1 h at RT. 2 L EtOAc and 500 mL saturated NaHCO3 solution were added, the organic phase was separated off and dried over Na2SO4 . After the desiccant and solvent had been eliminated the residue was dissolved in 150 mL EtOAc and filtered through Alox. The filtrate was discarded and the product was eluted from the Alox with 1 L MeOH. After the solvent had been eliminated the product was reacted further without purification. Yield: 26.0 g (82% of theory) ESI-MS: (M+H)+=222 retention time (HPLC): 1.4 min (method B)
60% sodium hydride (0.30 g) was added to a solution of the compound (1.66 g) obtained in Step 2 in anhydrous dimethylformamide (8 mL) under cooling with ice-water, and stirred at room temperature for thirty minutes under nitrogen atmosphere. 4-fluorobenzonitrile (0.91 g) was added to the mixture and stirred at room temperature for two days. The resulting mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH)(eluent; ethyl acetate : hexane = 1 : 1) to obtain the titled compound (2.2 g).
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃;
Step 1 4-(Hydroxymethyl)piperidin-4-ol hydrochloride 500 mg of <strong>[92197-36-9]1-benzyl-4-(hydroxymethyl)piperidin-4-ol</strong> (synthesized according to the method described in J. Med. Chem., 1988, 486-491) was dissolved in 10 ml of ethanol, 300 mg of 10% palladium carbon and 0.38 ml of concentrated hydrochloric acid were added thereto, and the mixture was subjected to hydrogenation at room temperature overnight. The reaction mixture was filtrated to remove precipitates, the precipitates were wasted with ethanol and water, and the filtrate was concentrated under reduced pressure. The obtained residue was turned into powder by adding diethylether to obtain 374 mg of the objective compound as white powder.
With hydrogenchloride; palladium on activated charcoal; In ethanol; water; at 20℃;
step 1 4- (hydroxymethyl) piperidin-4-ol hydrochloride1-benzyl-4- (hydroxymethyl) piperidin-4-ol 500 mg (J. Med. Chem., was dissolved in ethanol 10ml synthesis) according to 1988,486-491, 10% palladium-carbon 300mg and concentrated hydrochloric acid 0.38ml was added and overnight hydrogenated at room temperature.Insoluble matter was separated by filtration, and washed with ethanol and water, and the filtrate was concentrated under reduced pressure.To the residue was powdered addition of diethyl ether, the desired product was obtained 374mg as a white powder.
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