* 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.
With ammonium hydroxide In methanol at 80℃; for 16 h; Sealed tube
A 100-mL sealed tube fitted with a magnetic stir bar was charged with tert-Butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (300 mg, 1.28 mmol) and a solution of ammonium hydroxide in methanol (20 mL, 7M). The solution was stirred for 16 h at 80° C. in an oil bath and cooled to room temperature. The mixture was concentrated under vacuum to afford tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (350 mg, >95percent) used without further purification. LCMS (ESI) m/z 231 [M+H].
86%
With ammonia In methanol at 20℃; for 12 h;
To a stirred solution of tert-butyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.64 grams, 3.0 mmol, obtained in the above step) in methanol (4 mL) at room temperature, a solution of ammonia (NH3) in methanol (7M, 8 mL) was added and the reaction was stirred for12 hours. The volatiles were removed under reduced pressure to obtain the crude mass which was triturated with hexanes and ether which yielded the above titled compound (0.6 gram). Yield: 86 percent.‘H - NMR CDCI3 (6 ppm): 1.45 (9H, s), 1.35 - 1.60 (4H, m), 2.63 (2H, s), 3.10 - 3.25 (2H, m), 3.80 - 3.95 (2H, m).Mass (m/z): 231.5 (M+H)4.
86%
With ammonia In methanol at 20℃; for 12 h;
To a stirred solution of N-tert butyloxycarbonyl1-oxa-6-aza-spiro[2.5]octane 21 (0.64 g, 3.0 mmols) in methanol(4.0 mL) at r.t., a solution of ammonia (NH3)in methanol (7M, 8.0 mL) was added and the reaction was stirred for 12 hours.The volatiles were removed under reduced pressure to obtain the crude masswhich was triturated with hexanes and ether which yielded the above titledcompound 22c (0.6 g) in 86percent yield.1H - NMR CDCl3 (CDCl3): d 3.95 - 3.80 (m, 2H), 3.25 -3.10 (m, 2H), 2.63 (s, 2H), 1.35 - 1.60 (m, 4H), 1.45 (s, 9H). Mass (m/z): 231.5 (M+H)+. Anal. (C11H22N2O3) C, H, N
76%
With ammonia In methanol at 25 - 40℃; for 40 h;
tert-Butyl l-Oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole) was added to methanolic ammonia solution (20 mL, 14.83 percent w/v) at room temperature. Then reaction mass was stirred for 40 hours at room temperature in a closed vessel. The progress of the reaction was monitored by TLC. After completion of the reaction (TLC), the reaction mass was concentrated on rotavacuum to obtain the title compound. Yield: 0.41 gram (76percent). 'H-NMR(8 ppm): 1.35 - 1.69 (16H, m), 2.61 (2H, s), 3.10 - 3.20 (2H, m), 3.81 -3.90(2H, m); Mass (m/z): 231.3 (M+H)+.
76%
With ammonia In methanol at 20℃; for 40 h;
tert-Butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole, obtained in the step (i) of preparation 5) was added to methanolic ammonia solution (20 mL, 14.83 percent w/v) at RT. Then reaction mass was stirred for 40 hours at RT in a closed vessel. The reaction mass was concentrated under vacuum to obtain the title compound. Weight: 0.41 gram (Yield: 76 percent). (0385) - NMR (δ ppm): 1.35 - 1.69 (16H, m), 2.61 - 2.69 (2H, m), 3.10 - 3.20 (2H, m), 3.81 - 3.90 (2H, m); (0386) Mass (m/z): 231.3 (M+H)+ .
69%
With ammonia In methanol at 20℃;
Intermediate 2M: tert-butyl 4-(amiriomethyl)-4-hydroxypiperidine-1 -carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removedunder vacuum and the residue was purified by flash chromatography, silica gel, gradient dichioromethane to methanol:dichloromethane (1:4) to give the title compound (7.4 g, 69percent yield) as a white solid. HPLC retention time: 2.15 mm; MS:131 (M+H-100).
69%
With ammonia In methanol at 20℃;
A solution of intermediate 1A (10.0 g, 46.9 mmol) in ammonia (201 ml_, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69percent yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
69%
With ammonia In methanol at 20℃;
Intermediate 2A: fert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69percent yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
60.5%
With ammonia In ethanol; waterInert atmosphere
A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml*3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5percent) as a white solid. MS m/z (ESI): 231 [M+1]
60.5%
With ammonia In ethanol
A stirred solution of l-oxa-6-aza-spiro [2.5] octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol(60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml><3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane: methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (5.87 g, 60.5percent) as a white solid. MS m/z (ESI): 231[M+1] ,
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7458 - 7461
[2] Patent: US2016/185786, 2016, A1, . Location in patent: Paragraph 0679
[3] Patent: WO2015/92804, 2015, A1, . Location in patent: Page/Page column 21
[4] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 289 - 301
[5] Patent: WO2014/147636, 2014, A1, . Location in patent: Page/Page column 35; 36
[6] Patent: WO2016/128990, 2016, A1, . Location in patent: Page/Page column 36-37
[7] Patent: WO2015/185207, 2015, A1, . Location in patent: Page/Page column 173
[8] Patent: WO2015/185208, 2015, A1, . Location in patent: Page/Page column 138
[9] Patent: WO2015/185209, 2015, A1, . Location in patent: Page/Page column 78-79
[10] Patent: US2010/4239, 2010, A1, . Location in patent: Page/Page column 93
[11] Patent: WO2007/85188, 2007, A1, . Location in patent: Page/Page column 155
[12] Patent: US2005/43334, 2005, A1, . Location in patent: Page/Page column 25
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: With water; sodium sulfate In tetrahydrofuran at 20℃; for 5 h;
Step 2. tert-Butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate To a suspension of lithium alminium hydride (84 mg, 2.2 mmol) in THF (5 mL), a solution of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (200 mg, 0.88 mmol, step 1 of Example 22) in THF (1 mL) was added dropwise at 0° C. The mixture was stirred for 1 h at that temperature and Na2SO4.10H2O (400 mg) was added slowly, and the mixture was stirred for 5 h at room temperature. The mixture was filtered though a pad of Celite, washed with CH2Cl2 (20 mL*2), the filtrate was concentrated to give clear colorless oil. The residue was chromatographed on a column of silica gel eluding with CH2Cl2/MeOH/NH4OH (14:1:0.1) to give 120 mg (59percent) of the title compound as white solid. 1H-NMR (CDCl3) δ: 3.98-3.75 (2H, m), 3.17 (2H, t, J=10.8 Hz), 2.56 (2H, s), 1.46 (9H, s), 1.60-1.25 (4H, m). Signals due to O and N were not observed.
With ammonium hydroxide; In methanol; at 80℃; for 16h;Sealed tube;
A 100-mL sealed tube fitted with a magnetic stir bar was charged with tert-Butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (300 mg, 1.28 mmol) and a solution of ammonium hydroxide in methanol (20 mL, 7M). The solution was stirred for 16 h at 80 C. in an oil bath and cooled to room temperature. The mixture was concentrated under vacuum to afford tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (350 mg, >95%) used without further purification. LCMS (ESI) m/z 231 [M+H].
86%
With ammonia; In methanol; at 20℃; for 12h;
To a stirred solution of tert-butyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.64 grams, 3.0 mmol, obtained in the above step) in methanol (4 mL) at room temperature, a solution of ammonia (NH3) in methanol (7M, 8 mL) was added and the reaction was stirred for12 hours. The volatiles were removed under reduced pressure to obtain the crude mass which was triturated with hexanes and ether which yielded the above titled compound (0.6 gram). Yield: 86 %.?H - NMR CDCI3 (6 ppm): 1.45 (9H, s), 1.35 - 1.60 (4H, m), 2.63 (2H, s), 3.10 - 3.25 (2H, m), 3.80 - 3.95 (2H, m).Mass (m/z): 231.5 (M+H)4.
86%
With ammonia; In methanol; at 20℃; for 12h;
To a stirred solution of N-tert butyloxycarbonyl1-oxa-6-aza-spiro[2.5]octane 21 (0.64 g, 3.0 mmols) in methanol(4.0 mL) at r.t., a solution of ammonia (NH3)in methanol (7M, 8.0 mL) was added and the reaction was stirred for 12 hours.The volatiles were removed under reduced pressure to obtain the crude masswhich was triturated with hexanes and ether which yielded the above titledcompound 22c (0.6 g) in 86% yield.1H - NMR CDCl3 (CDCl3): d 3.95 - 3.80 (m, 2H), 3.25 -3.10 (m, 2H), 2.63 (s, 2H), 1.35 - 1.60 (m, 4H), 1.45 (s, 9H). Mass (m/z): 231.5 (M+H)+. Anal. (C11H22N2O3) C, H, N
76%
With ammonia; In methanol; at 25 - 40℃; for 40h;
tert-Butyl l-Oxa-6-aza-spiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole) was added to methanolic ammonia solution (20 mL, 14.83 % w/v) at room temperature. Then reaction mass was stirred for 40 hours at room temperature in a closed vessel. The progress of the reaction was monitored by TLC. After completion of the reaction (TLC), the reaction mass was concentrated on rotavacuum to obtain the title compound. Yield: 0.41 gram (76%). 'H-NMR(8 ppm): 1.35 - 1.69 (16H, m), 2.61 (2H, s), 3.10 - 3.20 (2H, m), 3.81 -3.90(2H, m); Mass (m/z): 231.3 (M+H)+.
76%
With ammonia; In methanol; at 20℃; for 40h;
tert-Butyl l-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.5 grams, 2.34 mmole, obtained in the step (i) of preparation 5) was added to methanolic ammonia solution (20 mL, 14.83 % w/v) at RT. Then reaction mass was stirred for 40 hours at RT in a closed vessel. The reaction mass was concentrated under vacuum to obtain the title compound. Weight: 0.41 gram (Yield: 76 %). (0385) - NMR (delta ppm): 1.35 - 1.69 (16H, m), 2.61 - 2.69 (2H, m), 3.10 - 3.20 (2H, m), 3.81 - 3.90 (2H, m); (0386) Mass (m/z): 231.3 (M+H)+ .
69%
With ammonia; In methanol; at 20℃;
Intermediate 2M: tert-butyl 4-(amiriomethyl)-4-hydroxypiperidine-1 -carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removedunder vacuum and the residue was purified by flash chromatography, silica gel, gradient dichioromethane to methanol:dichloromethane (1:4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 mm; MS:131 (M+H-100).
69%
With ammonia; In methanol; at 20℃;
A solution of intermediate 1A (10.0 g, 46.9 mmol) in ammonia (201 ml_, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
69%
With ammonia; In methanol; at 20℃;
Intermediate 2A: fert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate A mixture of intermediate 1A (10.0 g, 46.9 mmol) and ammonia solution (201 mL, 7 M solution in methanol, 1.4 mol) was stirred at r.t. overnight. The solvent was removed under vacuum and the residue was purified by flash chromatography, silica gel, gradient dichloromethane to methanokdichloromethane (1 :4) to give the title compound (7.4 g, 69% yield) as a white solid. HPLC retention time: 2.15 min; MS: 131 (M+H-100).
60.5%
With ammonia; In ethanol; water;Inert atmosphere;
A stirred solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol (60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml*3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid. MS m/z (ESI): 231 [M+1]
60.5%
With ammonia; In ethanol;
A stirred solution of l-oxa-6-aza-spiro [2.5] octane-6-carboxylic acid tert-butyl ester (9.0 g, 42.2 mmol) in ethanol(60 ml) was added with ammonia (100 ml). The resulting mixture was stirred under a nitrogen atmosphere overnight. The mixture was concentrated under reduced pressure. The residue was added with water (50 ml) and extracted with ethyl acetate (150 ml><3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane: methanol (20:1) as eluents to give 4-aminomethyl-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (5.87 g, 60.5%) as a white solid. MS m/z (ESI): 231[M+1] ,
With ammonia; In methanol; water; at 0 - 20℃; for 7h;
4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is prepared from 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (Bourrain et al Bioorg. Med. Chem. Lett. 9(23):3369-3374 (1999)). Concentrated aqueous NH4OH (6 mL) is added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0 C. The reaction mixture is removed from the cooling and allowed to warm to room temperature. After 7 hours, the reaction mixture is concentrated under reduced pressure to afford desired product as a white solid.
With ammonium hydroxide; In methanol; at 0 - 20℃; for 16h;
aqueous ammonia (6mL)was added to a solution of tert-butyl 1-oxa-6-azaspiro[2.5]octan-6-carboxylate (500mg, 2mmol) in methanol (4mL) at0C. The reaction solution warmed to room temperature and was stirred for 16 hours, then concentrated under reduced pressure to give a colorless oil (530mg, 2.3mmol) with a yield of 100%, which was used directly in the next step withoutpurification.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
Triethylamine (0.0373 mol, 5.2 ml) then ethyl chloroformate (0.0373 mol) were added dropwise at a temperature between 0C and 5C to a mixture of intermediate (8) (0.0373 mol) in DCM (100 ml) under nitrogen flow. The mixture was stirred at this temperature for 45 minutes (first mixture). Triethylamine (0.0373 mol, 5. 2ml) was added at room temperature to a mixture of intermediate (52) (0.0373 mol) in DCM (100 ml). The mixture was stirred at room temperature for 45 minutes, then added dropwise at a temperature between 0C and 5C to the first mixture. The reaction mixture was stirred at this temperature for 1 hour, then brought to room temperature, stirred for 1 hour and poured out into ice water. DCM was added. The mixture was extracted with DCM. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2CL2/CH30H/NH40H 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 12 g of intermediate (53).
With hydrogen;palladium 10% on activated carbon; In methanol; at 14℃;
A mixture of intermediate (51) (0.058 mol) and acetic acid (12 ml) in methanol (250 ml) was hydrogenated at 14 C with palladium-on-carbon (10%, 1 G) as a catalyst. After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice/water, then alkalized with potassium hydroxide and salted out with K2CO3. This mixture was extracted twice with DCM. The separated organic layer was dried, filtered and the solvent evaporated. The residue was suspended in DIPE, filtered off, washed and dried, yielding 7.5 g of intermediate (52)
A mixture of intermediate (64) (0.058 mol) and acetic acid (12 ml) in methanol (250 ml) was hydrogenated at 14C with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of hydrogen (3 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice/water, then alkalized with potassium hydroxide and salted out with K2CO3. This mixture was extracted twice with DCM. The separated organic layer was dried, filtered and the solvent evaporated. The residue was suspended in DIPE, filtered off, washed and dried, yielding 7.5 g of intermediate (65).
With hydrogen;palladium(II) hydroxide/carbon; In ethanol; under 2068.65 Torr; for 120h;
A mixture of tert-butyl 4-hydroxy-4-(nitromethyl)piperidine-l -carboxylate (20.42 g, 78.4 mmol) and 20% palladium hydroxide on carbon (1.21 g) in ethanol (250 mL) was hydrogenated at 40 psi (2.8 x 105 Pa) for 3 d on a Parr apparatus. More 20% palladium hydroxide on carbon (1.0 g) was added and the hydrogenation was continued for 2 more days. The mixture was filtered through CELITE filter agent and the filtrate was concentrated to provide tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-l -carboxylate, which was concentrated from toluene (200 mL) to remove residual ethanol before use in the next reaction.
With palladium 10% on activated carbon; hydrogen; acetic acid; In methanol; at 20℃;
The mixture of tert-butyl 4-hydroxy-4- (nitromethyl) piperidine-1-carboxylate (15.0 g, 0.058 mol) and acetic acid (12 mL) in methanol (180 mL) was hydrogenated at rt with palladium-on-carbon (10, 1.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice water, alkalized with potassium hydroxide, extracted twice with EtOAc, dried over Na2SO4, filtered and concentrated to give tert-butyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate.
With palladium on activated charcoal; hydrogen; acetic acid; In methanol; at 20℃;
The mixture of tert- butyl 4-hydroxy-4-(nitromethyl)piperidine-l-carboxylate (15.0 g, 0.058 mol) and acetic acid (12 mL) in methanol (180 mL) was hydrogenated at rt with palladium-on-carbon (10 %, 1.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up into ice water, alkalized with potassium hydroxide, extracted twice with EtOAc, dried over Na2S04, filtered and concentrated to give tert-butyl 4-(aminomethyl)-4- hydroxypiperidine- 1 -carboxylate.
Step 2. tert-Butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate To a suspension of lithium alminium hydride (84 mg, 2.2 mmol) in THF (5 mL), a solution of tert-butyl 4-cyano-4-hydroxypiperidine-1-carboxylate (200 mg, 0.88 mmol, step 1 of Example 22) in THF (1 mL) was added dropwise at 0 C. The mixture was stirred for 1 h at that temperature and Na2SO4.10H2O (400 mg) was added slowly, and the mixture was stirred for 5 h at room temperature. The mixture was filtered though a pad of Celite, washed with CH2Cl2 (20 mL*2), the filtrate was concentrated to give clear colorless oil. The residue was chromatographed on a column of silica gel eluding with CH2Cl2/MeOH/NH4OH (14:1:0.1) to give 120 mg (59%) of the title compound as white solid. 1H-NMR (CDCl3) delta: 3.98-3.75 (2H, m), 3.17 (2H, t, J=10.8 Hz), 2.56 (2H, s), 1.46 (9H, s), 1.60-1.25 (4H, m). Signals due to O and N were not observed.
3-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoyl}-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethylmorpholine;; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;
(iii) 3-{3-[2-(2,4-Dichloro-Phenyl)-Ethoxy]-4-Methyl-Benzoyl}-1-Oxa-3,8-Diaza-Spiro[4.5]decane-8-carboxylic acid tert-butyl ester 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (300 mg, 0.922 mmol) and crude <strong>[392331-66-7]4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester</strong> (212.5 mg, 0.922 mmol) was dissolved in 5 ml DMF. After cooling to -15 C. HATU (386 mg, 1 mmol) and N-ethylmorpholine (318.9 mg, 2.77 mmol) were added. The mixture was stirred at 0 C. for 2 hours and at room temperature for 15 hours, evaporated and purified on RP18 (5mum) (gradient acetonitrile water 90:10 to 0:100). The fractions containing the product were evaporated and lyophilised. The product was obtained as its trifluoroacetate salt.
4-Cyano-4-trimethylsilanyloxy-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
[ 392331-66-7 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In tetrahydrofuran;
(ii) 4-Aminomethyl-4-Hydroxy-Piperidine-1-Carboxylic Acid Tert-Butyl Ester 4-Cyano-4-trimethylsilanyloxy-piperidine-1-carboxylic acid tert-butyl ester (7.5 g) was dissolved in 100 ml of tetrahydro-furan under an argon atmosphere. A solution of lithium aluminium hydride in tetrahydro-furan (30 ml, 1 molar) was dropwise added at 0 C. After stirring for 15 hours at room temperature, a sodium hydroxide solution (20%) was slowly added under cooling. The solid was filtered after dilution with ethyl acetate and the organic layer evaporated. The crude material contains a mixture of the desired product (MS: 231.2 (M+H)+) and the corresponding trimethylsiliyl ether (MS: 303.1 (M+H)+) and was used without further purification.
With triethylamine; In dichloromethane; at 0 - 20℃;
Under a nitrogen atmosphere a solution of tert-butyl 4-(aminomethyl)-4- hydroxypiperidine-1 -carboxylate (38.9 g, 169 mmol, prepared according to Parts A and B of Example 4) in dichloromethane (420 mL) was cooled to 0 0C. Triethylamine (23.6 mL, 169 mmol) was added followed by the portionwise addition of 4-chloro-3- nitronaphthyridine (30.8 g, 147 mmol). The reaction mixture was stirred at ambient temperature overnight and then diluted with saturated aqueous sodium bicarbonate (200 mL). The layers were separated and the aqueous was extracted with dichloromethane (3 x 100 mL). The combined organics were concentrated under reduced pressure to provide a dark yellow solid. This material was triturated with saturated aqueous sodium bicarbonate, isolated by filtration, rinsed well with water, and then dried in a vacuum oven at 70 C overnight to provide 58.85 g of tert-butyl 4-hydroxy-4-[(3- nitro[l,5]naphthyridin-4-yl)amino]methyl}piperidine-l-carboxylate as a yellow solid.
With triethylamine; In dichloromethane; for 2h;Heating / reflux;
To a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidme-l -carboxylate (78.4 mmol, prepared as described above) in dichloromethane (300 mL) was added triethylamine (11 mL, 79 mmol) and 4-chloro-3-nitroquinoline (12.7 g, 61.2 mmol). The mixture was stirred at rt for 1 h, then heated at reflux for 1 h. The solution was transferred to a separatory funnel and extracted with water (100 mL). The organic layer was isolated and upon standing a precipitate formed. The solid was isolated by filtration and washed with dichloromethane and water and dried. Additional solid precipitated from the mother liquor and was isolated. The two yellow solids were combined and dried to yield tert- butyl 4-hydroxy-4-[(3-nitroqumolin-4-yl)amino]methyl}piperidine4 ^ (20.23 g, 82%).
A stirred mixture of <strong>[392331-66-7]4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester</strong> (529 mg, 2.3 mmol) in tetrahydrofuran (15 ml) was added slowly with lithium aluminum hydride (0.88 g, 23 mmol) while maintaining the temperature at 0~5 C. Upon completion of the addition, the mixture was stirred at 80 C. in oil bath overnight. The mixture was added with potassium sodium tartrate tetrahydrate (6.3 g, 22.3 mmol) and stirred for 8 hours at room temperature. The mixture was filtered and washed with tetrahydrofuran (10 ml*3). The combined organic extracts were concentrated under reduced pressure to give 4-aminomethyl-1-methyl-piperidin-4-ol (245 mg, 74%) as a white oil which was used as such. MS m/z (ESI): 145 [M+1]
74%
A stirred mixture of 4-aminomethyl-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (529 mg, 2.3 mmol) in tetrahydrofuran (15 ml) was added slowly with lithium aluminum hydride (0.88 g, 23 mmol) while maintaining the temperature at 0-~5C. Upon completion of the addition, the mixture was stirred at 80 C in oil bath overnight. The mixture was added with potassium sodium tartrate tetrahydrate (6.3 g, 22.3 mmol) and stirred for 8 hours at room temperature. The mixture was filtered and washed with tetrahydrofuran (10 mlx3). The combined organic extracts were <n="157"/>concentrated under reduced pressure to give 4-aminomethyl-l-methyl-piperidin-4-ol (245 mg, 74%) as a white oil which was used as such. MS m/z (ESI): 145[M+1]A solution of 2-carboxvmethyl
Step 1 : To a solution of t-butyl-4-(aminomethyl)-4-hydroxypiperidine-l-carboxylate (2.0 g, 8.69 mmol) in THF, were added DMAP (110 mg, 0.86 mmol) and ethyl 2,2,2-trifluoroacetate (1.5 g, 10.43 mmol). The reaction mixture was heated at 70 C and stirred for 6 h then was diluted with ethyl acetate. The organic layer was washed in turn with IN HCl (2x10 mL) and brine then, dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, eluent n-Hexane/EtOAc 70:30) to afford tert-butyl 4- hydroxy-4-((2,2,2-trifluoroacetamido)methyl)piperidine-l-carboxylate (2.00 g, 84%) as an oil. 1H NMR (400 MHz, CDC13) delta 6.90 (bs, 1H), 3.79 (bs, 2H), 3.41 (bs, 2H), 3.25-3.18 (m, 4H), 1.57 (bs, 4H), 1.48 (s, 9H); MS (ESI) m/z 327 [C13H21F3N204+ H]+.
84%
With dmap; In tetrahydrofuran; at 70℃; for 6h;
To a solution of <strong>[392331-66-7]t-butyl-4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate</strong> (2.0 g, 8.69 mmol) in THF, were added DMAP (110 mg, 0.86 mmol) and ethyl 2,2,2-trifluoroacetate (1.5 g, 10.43 mmol). The reaction mixture was heated at 70 C. and stirred for 6 h then was diluted with ethyl acetate. The organic layer was washed in turn with 1N HCl (2*10 mL) and brine then, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, eluent n-Hexane/EtOAc 70:30) to afford tert-butyl 4-hydroxy-4-((2,2,2-trifluoroacetamido)methyl)piperidine-1-carboxylate (2.00 g, 84%) as an oil. 1H NMR (400 MHz, CDCl3) delta 6.90 (bs, 1H), 3.79 (bs, 2H), 3.41 (bs, 2H), 3.25-3.18 (m, 4H), 1.57 (bs, 4H), 1.48 (s, 9H); MS (ESI) m/z 327 [C13H21F3N2O4+H]+.
6-chloro-5-nitro-N-[4-hydroxy-1-(tert-butoxycarbonyl)-4-piperidinyl]methyl}quinoline-8-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
A solution of ' 6-chloro-5-nitro quinoiine-8-carboxylic acid (0.37 grams, 1.46 mmole) and carbonyldiimidazole (0.28 grams, 1.72 mmole) in dichloromethane (15 mL) was stirred for 3 hours at room temperature. Then added a solution of tert-butyl 4-aminomethyl-4-hydroxy piperidine-l-carboxylate (0.4 grams, 1.73 mmole) in dichloromethane (10 ml). The reaction mass was stirred over night (12 hours) at RT under nitrogen atmosphere, while monitoring the progress of the reaction by TLC. After completion of the reaction (TLC), the reaction mass was washed with chilled water (10 mL), brine solution (10 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated on rotavacuum to afford the title compound. Yield: 0.68 grams (100%). - NMR (delta ppm): 1.46 - 1.72 (11H, m), 2.60 - 2.65 (2H, m), 3.17 - 3.23 (2H, m), 3.66 - 3.85 (4H, m), 7.70 - 7.73 (1H, m), 8.16 - 8.19 (1H, m), 8.93 (IH, s), 9.05 - 9.07 (IH, m), 11.23 - 11.27 (IH, t); Mass (m/z): 465.1 (M+H)+, 467.1(M+H)+.
2-isopropyl-2H-indazole-7-carboxylic acid[ No CAS ]
N-[(1-tert-butyloxycarbonyl-4-hydroxypiperidin-4-yl)methyl]-2-isopropyl-2H-indazole-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
To a stirred solution of 2-isopropyl-2H-indazole-7-carboxylic acid (0.209 gram, 1.02 mmol, obtained in the preparation 1) in DCM (4 mL) cooled at 0 C was added DIPEA (0.26mL, 1.5 mmol) and TBTU (0.35 gram, 1.1 mmol). After stirring for 15 minutes, tert-butyl 4- aminomethyl-4-hydroxy piperidine- 1 -carboxylate (0.27 gram, 1.18 mmol, obtained in the preparation 4) was added. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM and water. The two layers were separated, the organic layer was washed with brine, dried over anhydrous Na2SO4 andthe volatiles were removed under reduced pressure and the crude mass was purified by silica gel column chromatography to obtain the titled compound (0.41 gram). Yield: 100 % 111 - NMR CDCI3 (8 ppm): 1.45 (9H, s), 1.55 - 1.80 (1 1H, m), 3.20 - 3.35 (211, rn), 3.60 - 3.95(4H, m), 4.75 -4.90 (111, m), 7.21 (IH, t,J 7.5 Hz), 7.84(111, d, J 8.2 Hz), 8.08 (1H, s),8.23 (IH, d, 3 = 7.0 Hz), 9.57 (1H, bs).Mass (rn/i): 417.4 (M+H)+.
3-(1-methylethyl)imidazo[1,5-a]pyridine-1-carboxylic acid[ No CAS ]
N-[N-tert-butyloxycarbonyl-4-hydroxypiperidin-4-ylmethyl]-3-isopropyl-imidazo[1,5-a]pyridine-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: General Procedure 2: To a stirred solution of 3-isopropylimidazopyridine carboxylic acid 11 (1.0 mmol) in DCM (6.0 mL) at r.t.,diisopropylethylamine (2.0 mmols) and Boc-protected amines 22 (1.05 mmols) were added. After 5 minutes, TBTU (500.0 mg, 1.05mmols) was added in portions over a period of 5 minutes. The reaction mixturewas stirred for 4 h before it was diluted with ice cold water and DCM. The twolayers were separated. The organic layer was washed with brine solution, driedover anhydrous Na2SO4 and the solvent was removed under reduced pressure. Thecrude compound was purified by silica gel column chromatography to obtaincompounds 23
tert-butyl 4-[(chloroacetyl)amino]methyl}-4-hydroxypiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium carbonate; In water; ethyl acetate; at 0 - 25℃; for 16h;Large scale;
A solution of potassium carbonate (1.32 kg, 9.55 mol) in water (11 L) was added to a solution of te/ -butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (1.10 kg, 4.78 mol) in ethyl acetate (11 L). The mixture was cooled to 0 C, and then treated in a drop-wise manner with chloroacetyl chloride (595 g, 5.27 mol). After completion of the addition, the reaction mixture was warmed to 25 C and allowed to stir for 16 hours. The aqueous layer was extracted with ethyl acetate (3 x 10 L), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; trituration of the residue with fe/f-butyl methyl ether (10 L) afforded the product (1040 g). The filtrate from the trituration was concentrated and triturated with a mixture of fe/f-butyl methyl ether and petroleum ether (1 :1 ; 300 mL) to provide additional product (123 g) as a white solid. Combined yield: 1.16 kg, 3.78 mol, 79%. 1H NMR (400 MHz, CDCI3) delta 7.02 (br t, J=5 Hz, 1 H), 4.09 (s, 2H), 3.88-3.70 (br m, 2H), 3.43-3.28 (br s, 2H), 3.20 (br dd, J=11 , 11 Hz, 2H), 2.71 (s, 1 H), 1.62-1.46 (m, 4H), 1.45 (s, 9H).
79%
With potassium carbonate; In water; ethyl acetate; at 0 - 25℃; for 16h;Large scale;
A solution of potassium carbonate (1.32 kg, 9.55mol) in water (11 L) was added to a solution of tert-butyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (1.1 0kg, 4.78 mol) in ethyl acetate (11 L). The mixture was cooledto oo C., and then treated in a drop-wise manner withchloroacetyl chloride (595 g, 5.27 mol). After completion ofthe addition, the reaction mixture was warmed to 25 C. andallowed to stir for 16 hours. The aqueous layer was extractedwith ethyl acetate (3x10 L), and the combined organic layerswere dried over sodium sulfate, filtered, and concentrated invacuo; trituration of the residue with tert-butyl methyl ether(10 L) afforded the product (1040 g). The filtrate from thetrituration was concentrated and triturated with a mixture oftert-butyl methyl ether and petroleum ether (1:1; 300 mL) toprovide additional product (123 g) as a white solid. Combinedyield: 1.16 kg, 3.78 mol, 79%. 1H NMR (400 MHz,CDC13 ) o7.02 (brt, 1=5 Hz, lH), 4.09 (s, 2H), 3.88-3.70 (brm, 2H), 3.43-3.28 (br s, 2H), 3.20 (br dd, 1=11, 11 Hz, 2H),2.71 (s, lH), 1.62-1.46 (m, 4H), 1.45 (s, 9H).
With potassium carbonate; In water; ethyl acetate; at 0℃; for 0.5h;
Step 1. tert-Butyl 4-((2-chloroacetamido)methyl )-4-hydroxypiperidine- 1 -carboxylate:To a solution of intermediate 2M (1.0 g, 4.34 mmol) in ethyl acetate (9 mL), a solution of K2C03 (1.67 g, 12.11 mmol) in water (7 mL) was added. After cooling to 0 C, chioroacetyl chloride (0.47 mL, 5.91 mmol) was added dropwise. The reaction mixturewas stirred at 0 C for 30 mm, the layers were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness to give the title compound (1.1 g). HPLC retention time: 2.90 mm; MS: 207 (M+H-100).
With potassium carbonate; In water; ethyl acetate; at 0℃; for 0.5h;
To a solution of intermediate 2A (1.0 g, 4.34 mmol) in ethyl acetate (9 ml_), a solution of K2C03 (1.67 g, 12.11 mmol) in water (7 mL) was added. After cooling to 0 C, chloroacetyl chloride (0.47 mL, 5.91 mmol) was added dropwise. The reaction mixture was stirred at 0 C for 30 minutes, then the layers were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over MgS04, filtered and concentrated to dryness to give the title compound (1.1 g). HPLC retention time: 2.90 min; MS: 207 (M+H-100).
With potassium carbonate; In water; ethyl acetate; at 0℃; for 1h;
The mixture of tert-butyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate (10.0 g, 45 mmol) , chloroacetyl chloride (6 mL, 64 mmol) and K2CO3 (14.0 g, 95 mmol) in EtOAc/H2O (100 mL/100 mL) was stirred for 1 h at 0 . The crude mixture was extracted with EtOAc (2×300 mL) . The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4- ( (2-chloroacetamido) methyl) -4- hydroxypiperidine-1-carboxylate. 1H NMR (300 MHz, CDCl3) delta : 1.45 (s, 9H) , 1.53 (d, 4H) , 2.59 (s, 1H) 3.21 (s, 2H) 3.35 (s, 2H) , 3.78 (d, J 18.0 Hz, 2H) 4.13 (s, 2H) , 6.99 (s, 1H) .
With potassium carbonate; In water; ethyl acetate; at 0℃; for 1h;
The mixture of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-l -carboxylate (10.0 g, 45 mmol), chloroacetyl chloride (6 mL, 64 mmol) and K2C03 (14.0 g, 95 mmol) in EtOAc/H20 (100 mL/100 mL) was stirred for 1 h at 0 C. The crude mixture was extracted with EtOAc(2x300 mL). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to give tert-butyl 4-((2-chloroacetamido)methyl)-4-hydroxypiperidine-l-carboxylate. 1H MR (300 MHz, CDC13) delta: 1.45 (s, 9H), 1.53 (d, 4H), 2.59 (s, 1H) 3.21 (s, 2H) 3.35 (s, 2H), 3.78 (d, J= 18.0 Hz, 2H) 4.13 (s, 2H), 6.99 (s, 1H).
tert-butyl 4-((4-chlorobenzamido)methyl)-4-hydroxypiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; for 2h;
A solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine- 1 -carboxylate (0.25 g, 1.086 mmol) and 4-chlorobenzoic acid (0.204 g, 1.303 mmol) in DMF (2 mL)was treated with triethylamine (0.454 mL, 3.26 mmol) followed by BOP (0.576 g, 1.303 mmol). The reaction was stirred for 2h then quenched with dil. aq. HOAc. This resulted in the formation of a precipitate, so the mixture was filtered and rinsed with water. It was then suspended in dil. aq. sodium bicarbonate, sonicated, then filtered, rinsed with water, and air-dried to afford tert-butyl 4-((4-chlorobenzamido)methyl)-4-hydroxypiperidine- 1-carboxylate (0.38 g, 90% yield) as a colorless solid, mp 172-173 C. MS(ES): m/z = 369 [M+H]. tR = 0.93 mm (Method A).
tert-butyl 4-hydroxy-4-[(2-nitrobenzylamino)methyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With methanol; sodium cyanoborohydride; at 20℃; for 12h;
Step 1: Ter<strong>[392331-66-7]t-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate</strong> (3.1 g, 13 mmol) obtained by the method described in WO2005/000837 was dissolved in methanol (150 mL), and 2-nitrobenzaldehyde (2.0 g, 13 mmol) and sodium cyanoborohydride (1.3 g, 26 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby tert-butyl 4-hydroxy-4-[(2-nitrobenzylamino)methyl]piperidine-1-carboxylate (2.2 g, yield: 40%) was obtained. (0297) 1H-NMR (400 MHz, CDCl3, delta): 7.97 (dd, J=8.0, 0.8 Hz, 1H), 7.64-7.45 (m, 3H), 5.32 (s, 1H), 4.10 (s, 2H), 3.86 (br s, 2H), 3.18 (t, J=12 Hz, 2H), 2.59 (s, 2H), 1.55-1.40 (m, 13H)
1-amino-2-p-tolyl-1H-imidazole-5-carboxylic acid[ No CAS ]
tert-butyl 4-([[1-amino-2-(4-methylphenyl)-1H-imidazol-5-yl]formamido]methyl)-4-hydroxypiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;
A 100-mL round-bottom flask fitted with a magnetic stir bar was charged with 1-amino-2-p-tolyl-1H-imidazole-5-carboxylic acid (100 mg, 0.45 mmol, 1.00 equiv), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (262 mg, 0.69 mmol), ethyldiisopropylamine (178 mg, 1.38 mmol), N,N-dimethylformamide (10 mL), <strong>[392331-66-7]ter<strong>[392331-66-7]t-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate</strong></strong> (127 mg, 0.55 mmol). The solution was stirred for 1 h at room temperature and quenched with water (30 mL). The product was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:4 v/v) to afford tert-butyl 4-([[1-amino-2-(4-fluorophenyl)-1H-imidazol-5-yl]formamido] methyl)-4-hydroxypiperidine-1-carboxylate (150 mg, 77%) as a light yellow oil. LCMS (ESI) m/z 430 [M+H].
5-amino-6-chloro-N-[4-hydroxy-1-(tert-butoxycarbonyl)-4-piperidinyl]methyl}chroman-8-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of 5-amino-6-chloro chroman-8-carboxylic acid (0.200 grams, 0.878 mmole, obtained in the preparation 1) and carbonyldiimidazole (CDI) (0.170 grams, 1.054 mmole) in DCM (6 mL) was stirred for 2 hours at RT. Then a solution of tert-butyl 4- aminomethyl-4-hydroxy piperidine-l-carboxylate (0.222 grams, 0.967 mmole) in DCM (4 mL) was added. Reaction mass was 'stirred overnight at RT under nitrogen atmosphere. The reaction mass was washed with chilled water (10 mL), brine solution (10 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated on rotavacuum to obtain the crude residue, which was further purified by flash chromatography using EtOAc:n-hexane (30:70) to afford the title compound. (0423) Weight: 0.266 grams (Yield: 69 %). (0424) - NMR (delta ppm): 1.24 - 1.32 (4H, m), 1.36 (9H, s), 1.54 - 1.70 (2H, m), 1.87 - 1.95 (2H, m), 2.41 - 2.46 (2H, m), 3.09 - 3.13 (2H, m), 3.34 - 3.36 (2H, d), 3.86 - 3.94 (2H, m), 4.80 (1H, s), 5.56 (2H, bs), 7.54 (1H, s), 7.92 - 7.94 (1H, t); (0425) Mass (m/z): 440.1 (M+H)+, 442.3(M+H)+.
4-amino-5-chloro-N-[4-hydroxy-1-(tert-butoxycarbonyl)-4-piperidinylmethyl]benzofuran-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
A solution of 4-amino-5-chloro benzofuran-7-carboxylic acid (0.050 grams, 0.236 mmole, obtained in the preparation 2) and CDI (0.042 grams, 0.259 mmole) in DCM (3 mL) was stirred for 2 hours at RT. Then added a solution of tert-butyl 4-aminomethyl-4- hydroxy piperidine-l-carboxylate (0.081 grams, 0.354 mmole, obtained in preparation 6) in DCM (2 mL). The reaction mass was stirred overnight (12 hours) at RT under nitrogen atmosphere, while monitoring the progress of the reaction by TLC. The reaction mass was washed with chilled water (10 mL) and brine solution (10 mL) and dried over anhydrous Na2S04. The organic phase was concentrated on rotavacuum to obtain the crude residue, which was further purified by flash chromatography using EtOAc : n-hexane (70:30) to afford the title compound. (0473) Weight: 0.064 grams (Yield: 64 %). (0474) - NMR (delta ppm): 1.14 - 1.28 (2H, m), 1.36 (9H, s), 1.40 - 1.46 (2H, m), 3.08 - 3.1 1 (2H, m), 3.34 - 3.36 (2H, d), 3.59 - 3.62 (2H, m), 4.79 (1H, s), 6.47 (2H, bs), 7.2 (1H, d, J = 1.95 Hz), 7.64 (1H, s), 7.66 - 7.69 (1H, t), 7.95 (1H, d, J = 1.83 Hz); (0475) Mass (m/z): 424.2 (M+H)+, 426.3 (M+H)+.
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