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[ CAS No. 406235-30-1 ]

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2D
Chemical Structure| 406235-30-1
Chemical Structure| 406235-30-1
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Product Details of [ 406235-30-1 ]

CAS No. :406235-30-1MDL No. :MFCD04972471
Formula : C11H21NO3 Boiling Point : 296.4°C at 760 mmHg
Linear Structure Formula :-InChI Key :N/A
M.W :215.29Pubchem ID :22730812
Synonyms :

Computed Properties of [ 406235-30-1 ]

TPSA : 49.8 H-Bond Acceptor Count : 3
XLogP3 : 1.2 H-Bond Donor Count : 1
SP3 : 0.91 Rotatable Bond Count : 2

Safety of [ 406235-30-1 ]

Signal Word:WarningClass:N/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 406235-30-1 ]

  • Upstream synthesis route of [ 406235-30-1 ]
  • Downstream synthetic route of [ 406235-30-1 ]

[ 406235-30-1 ] Synthesis Path-Upstream   1~9

  • 1
  • [ 406235-30-1 ]
  • [ 3970-68-1 ]
YieldReaction ConditionsOperation in experiment
99% With trifluoroacetic acid In dichloromethane at 20℃; for 1 h; 4-methyl-piperidin-4-ol (Intermediate 79b)A solution of Intermediate 79a (5.50 g, 25.6 mmol) in TFA (20 mL) and DCM (40 mL) was stirred at RT for 1 h. The reaction mixture was applied to SCX- 2 cartridges (2 70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (3.19 g, 99percent). NMR (400 MHz, CDC13): 1.24 (3H, s), 1.51-1.61 (4H, m), 2.75-2.87 (2H, m), 2.89-3.02 (2H, m).
93.46% With trifluoroacetic acid In dichloromethane at 20℃; for 1 h; Synthesis of compound 221.3. To a solution of 221.2 (1.3 g, 6.04 mmol, l .Oeq) in CH2C12 (10 mL) was added trifluoroacetic acid (5mL). The reaction was allowed to stir at room temperature for lh. After completion of reaction, solvent was evaporated under reduced pressure to obtain pure TFA salt of 221.3 (0.650g, 93.46percent). MS(ES): m/z 115.18 [M+H]+.
Reference: [1] Patent: WO2013/83604, 2013, A1, . Location in patent: Page/Page column 278
[2] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 001155; 001157
[3] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0604; 0605
  • 2
  • [ 75-16-1 ]
  • [ 79099-07-3 ]
  • [ 406235-30-1 ]
YieldReaction ConditionsOperation in experiment
97% at -10 - 20℃; for 2 h; Inert atmosphere a) tert-Butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (A 141) ferf-Butyl 4-oxopiperidine-1 -carboxylate (1.0 g, 5.0 mmol) was dissolved in anhydrous Et20 (10 mL) and cooled to -10°C under nitrogen. A solution of methylmagnesium bromide (3 M in Et20, 2.5 mL, 7.5 mmol) was added drop-wise and the mixture stirred for 5 minutes. The cooling bath was removed and the slurry was stirred at room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of ammonium chloride (10 mL) and then diluted with water (20 mL) and diethyl ether (20 mL). The aqueous phase was extracted with diethyl ether (2 χ 30 mL), the pooled organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (1.05 g, 97percent). H NMR (400 MHz, CDCI3) δ 3.76-3.64 (m, 2H), 3.29-3.16 (m, 2H), 1.66 (s, 1 H), 1.45 (s, 9H), 1.25 (s, 3H) 4H obscured by solvent.
97%
Stage #1: at -30 - 20℃; Inert atmosphere
Stage #2: With water; ammonium chloride In diethyl ether
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at -25 to -30 °C was added methyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 mL) was then added dropwise, followed by saturated ammonium chloride (20 mL) and the ether layer was separated. The aqueous phase was further extracted with ether (50 mL) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.09 g, 97percent). 1H NMR (CDCl3, 300MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).
90% at -25 - 20℃; for 2 h; Inert atmosphere Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°Cand quenched by the addition of sat. aq. ammonium chloride. Another 20 mL ofether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (4.30g, 18.0 mmol, 90 percent) as a colorless oil. ‘H NMR (400MHz, CDC13) ö 3.84 - 3.65 (m,2H), 3.34 -3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50- 1.45 (m,9H), 1.32- 1.27 (m, 3H).
90% at -25 - 20℃; for 2 h; Inert atmosphere Under an N2 atmosphere, a 3N solution in ether ofmethylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to oocand quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04 , filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percentEtOAc/hexane to obtain tert-butyl4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. 1H NMR (400MHz, CDCh) 8 3.84- 3.65 (m,2H), 3.34-3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61- 1.53 (m, 4H), 1.50- 1.45 (m,9H), 1.32- 1.27 (m, 3H).
90% at -25 - 20℃; for 2 h; Inert atmosphere Int rmediate 43 tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. 1H NMR (400MHz, CDC13) δ 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90% at -25 - 20℃; for 2 h; Inert atmosphere tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. 1H NMR (400MHz, CDC13) δ 3.84 - 3.65 (i 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90% at -25 - 20℃; Inert atmosphere Intermediate 9 (0109) tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 °C and quenched by the addition of sat. NH4CI. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent yield) as a colorless oil. 1H NMR (500 MHz, CDC13) δ 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
90% at -25 - 20℃; for 2 h; Inert atmosphere Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (−25° C.) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4 g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0° C. and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.84-3.65 (m, 2H), 3.34-3.18 (m, 2H), 2.59-2.39 (m, 1H), 1.61-1.53 (m, 4H), 1.50-1.45 (m, 9H), 1.32-1.27 (m, 3H).
90% at -25 - 20℃; for 2 h; Inert atmosphere Intermediate 1 (0119) tert-Butyl 4-hydroxy-4-methylpiperidine-l-carboxylate: Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-l-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 °C and quenched by the addition of sat. NH4CI. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgS04, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-l-carboxylate (4.30 g, 18.0 mmol, 90 percent yield) as a colorless oil. 1H NMR (500 MHz, CDC13) δ 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 - 2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
62% at 0 - 20℃; for 1 h; a. 4-Hydroxy-4-methyl-piperidine-l-carboxylic acid tert-butyl ester (Intermediate 79a) To a solution of l-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0°C was added methylmagnesium bromide (3.0 M in Et2O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10°C. The reaction mixture was allowed to warm to T over 1 h. The reaction was quenched by addition of sat. aq. NH4C1 solution, then the mixture was extracted with diethyl ether (2 x). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100percent EtOAc in cyclohexane, to give the title compound (6.76 g, 62percent). NMR (400 MHz, CDC13): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
62% at 0 - 20℃; for 1 h; To a solution of 1-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0° C. was added methylmagnesium bromide (3.0 M in Et2O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10° C. The reaction mixture was allowed to warm to RT over 1 h. The reaction was quenched by addition of sat. aq. NH4Cl solution, then the mixture was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100percent EtOAc in cyclohexane, to give the title compound (6.76 g, 62percent). 1H NMR (400 MHz, CDCl3): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
60.2% at -20 - 20℃; for 2 h; Inert atmosphere Synthesis of compound 221.2. To a solution of tert-butyl 221.1 (2.0g, 10.03 mmol, l .Oeq) in Et20 (20 ml) was added 1M MeMgBr in Et20 (1.196g, 10.03mmol, l .Oeq.) at - 20 °C under argon atmosphere. The reaction mixture was allowed to stir at room temperature for 2 hrs. After completion of reaction, mixture was poured in to satd. NH4C1 solution and product was extracted with EtOAc. Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified by column chromatography to get pure 221.2 (1.3g, 60.2 percent). MS(ES): m/z 215.29 [M+H]+.
19%
Stage #1: at -78 - 23℃; for 6 h;
Stage #2: With ammonium chloride In tetrahydrofuran; diethyl ether
Step-1: Preparation of intermediate-46a; To a stirred solution of intermediate 32b (500 mg, 2.70 mmol) in dry THF (15 mL) was added methyl magnesium bromide (3 M in diethyl ether, 0.90 mL, 2.70 mmol) at -78° C. The reaction mass was stirred at -78° C. for 4 h and then at 23° C. for 2 h. The reaction mass was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. The crude mass was purified by flash column chromatography to afford intermediate 46a (100 mg, 19percent).

Reference: [1] Journal of the American Chemical Society, 2013, vol. 135, # 41, p. 15342 - 15345
[2] Patent: WO2014/128465, 2014, A1, . Location in patent: Page/Page column 156
[3] Patent: WO2009/151598, 2009, A1, . Location in patent: Page/Page column 148-149
[4] Patent: WO2014/164409, 2014, A1, . Location in patent: Page/Page column 32; 33
[5] Patent: WO2014/164428, 2014, A1, . Location in patent: Page/Page column 25
[6] Patent: WO2014/159959, 2014, A1, . Location in patent: Page/Page column 68; 69
[7] Patent: WO2014/159076, 2014, A1, . Location in patent: Page/Page column 41; 42
[8] Patent: WO2015/123182, 2015, A1, . Location in patent: Page/Page column 23; 24
[9] Patent: US2015/232481, 2015, A1, . Location in patent: Paragraph 0093
[10] Patent: WO2015/126758, 2015, A1, . Location in patent: Page/Page column 24
[11] Patent: WO2013/83604, 2013, A1, . Location in patent: Page/Page column 278
[12] Patent: US2013/150343, 2013, A1, . Location in patent: Paragraph 1050; 1051
[13] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 001155; 001156
[14] Patent: US2011/92475, 2011, A1, . Location in patent: Page/Page column 19
[15] Patent: WO2008/132502, 2008, A1, . Location in patent: Page/Page column 96
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  • [ 676-58-4 ]
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  • [ 406235-30-1 ]
YieldReaction ConditionsOperation in experiment
99% at -78 - 0℃; for 2 h; To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in dry THF (25 mL) was added methylmagnesium chloride (2.17 mL, 6.52 mmol) at -78° C.
The reaction mixture was slowly warmed to 0° C. with stirring for 2 hours and quenched with saturated aq. NH4Cl.
The mixture was extracted with EtOAc twice, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.08 g, >99percent) as a colorless oil, which was used for the next reaction without further purification. 1H-NMR (CDCl3, Varian, 400 MHz): δ 1.27 (3H, s), 1.46 (9H, s), 1.50-1.58 (4H, m), 3.20-3.27 (2H, m), 3.64-3.76 (2H, m).
93%
Stage #1: at -40 - 20℃; for 2.16667 h;
Stage #2: With water; ammonium chloride In tetrahydrofuran at 0℃;
Preparation of 4-Hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester; A solution of N-boc piperidin-4-one (3 g, 15 mmol) in dry THF (30 mL) was cooled to - 400C, 3M MeMgCI (21 mL, 60.24 mmol) was added slowly over 10 min. The reaction mixture was allowed to rt and maintained for 2h. The reaction mixture was cooled to O0C, sat. NH4CI was added and then was extracted with EtOAc (250 mL). The organic layer was washed with water (250 mL), brine solution, dried over anhydrous sodium sulfate and concentrated to obtain the crude product as yellow liquid (3 g, 93percent). 1HNMR(CDCI3): δ 3.56-3.8(m, 2H), 3.12-3.35(m, 2H), 1.5-1.62(m, 4H), 1.45(s, 9H) and 1.26(s, 3H).
66% at 0℃; for 1 h; PREPARATION /; SYNTHESIS OF 4-METHYL-4-(2-TRIFLUOROMETHYLPHENOXY)PIPERIDINEA.; To a stirred solution of 4-oxopiperidine-1-carboxylic acid terf-butyl ester (2.000 g, 10.04 mmol) in THF (30 mL) was added methyl magnesiumchloride (3.7 mL, 11.04 mmol) at 00C. The resulting mixture was stirred at 00C for 60 minutes. Ethyl acetate (40 mL) was added to the mixture and the organic solution was washed with water (20 mL), saturated NaCI (20 mL), dried over MgSO4 and then concentrated in vacuo. The crude product was purified by column chromatography to yield the desired product, 4-hydroxy-4-methylpiperidine-1-carboxylic acid terf-butyl ester, in 66percent yield (1.418 g). 1H NMR (300 MHz, CDCI3) δ 3.67-3.60 (m, 2H), 3.23-3.13 (m, 2H), 1.50-1.46 (m, 4H), 1.40 (s, 9H), 1.20 (s, 3H).
Reference: [1] Patent: US2016/168156, 2016, A1, . Location in patent: Paragraph 0602; 0603
[2] Patent: WO2008/84300, 2008, A1, . Location in patent: Page/Page column 105
[3] Patent: WO2006/34338, 2006, A1, . Location in patent: Page/Page column 47
[4] Patent: WO2013/134226, 2013, A1, . Location in patent: Page/Page column 91; 92
  • 4
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YieldReaction ConditionsOperation in experiment
90% With methylmagnesium bromide In diethyl ether at 20℃; for 2 h; Inert atmosphere tert-Butyl 4-hydroxy-4-methylpiperidine-1-carboxylate: Under an N2 atmosphere, a 3N solution in ether of methylmagnesium bromide (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reactionmixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0°C and quenched by the addition of sat. aq. ammonium chloride. Another 20 mL of ether was added and the mixture was partitioned in a separatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporatedto obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (4.30 g, 18.0 mmol, 90 percent) as a colorless oil. ‘H NMR (400MHz, CDC13) ö 3.84 - 3.652H), 3.34 -3.18 (m, 2H), 2.59 -2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50- 1.45 (m, 9H), 1.32- 1.27 (m, 3H).
Reference: [1] Patent: WO2015/127003, 2015, A1, . Location in patent: Page/Page column 21
[2] Patent: US2002/86887, 2002, A1,
  • 5
  • [ 75-16-1 ]
  • [ 109384-19-2 ]
  • [ 406235-30-1 ]
YieldReaction ConditionsOperation in experiment
90% at -25 - 20℃; for 2 h; Inert atmosphere Under an N2 atmosphere, a 3N MeMgBr/ether (1.67 mL, 5.02 mmol) was added dropwise to a cooled (-25°C) solution of tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (4g, 20.08 mmol) in ether (20 mL). The reaction mixture was allowed to warm to rt and was stirred for 2 h. It was then cooled to 0 °C and quenched by the addition ofNH4C1. Another 20 mL of ether was added and the mixture was partitioned in aseparatory funnel. The organic phase was set aside and the aqueous phase was extracted with another 20 mL of ether. The combined ether extracts were dried over MgSO4, filtered and evaporated to obtain an oil, which was then purified by biotage, eluting with 0-50percent EtOAc/hexane to obtain tert-butyl 4-hydroxy-4- methylpiperidine-1-carboxylate (4.30 g, 18.0 mmol, 90 percent yield) as a colorless oil. NMR (500 MHz, CDCl3) 3.84 - 3.65 (m, 2H), 3.34 - 3.18 (m, 2H), 2.59 -2.39 (m, 1H), 1.61 - 1.53 (m, 4H), 1.50 - 1.45 (m, 9H), 1.32 - 1.27 (m, 3H).
Reference: [1] Patent: WO2014/28384, 2014, A1, . Location in patent: Page/Page column 78
[2] Patent: WO2015/126743, 2015, A1, . Location in patent: Paragraph 26
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  • [ 917-54-4 ]
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YieldReaction ConditionsOperation in experiment
94% at -78 - 20℃; for 1.5 h; 1)
4-Hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester
In an argon atmosphere, methyllithium (0.98M diethyl ether solution, 64.5 mL) was added dropwise to a suspension of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (12.0 g) in diethyl ether (120 mL) at -78°C over 15 minutes, and the mixture was stirred for 30 minutes, at 0°C for 15 minutes, and at room temperature for 30 minutes.
Water, saturated brine, and chloroform were added for partitioning the reaction mixture, and the organic layer was dried over sodium sulfate anhydrate.
After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate - hexane), to thereby give 4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester as an oily product (12.2 g, 94percent).
1H-NMR(400MHz,CDCl3)δ:1.26(3H,s), 1.46(9H,s), 1.49-1.55(4H,m), 3.20-3.27(2H,m), 3.69-3.72(2H,m).
EI-MSm/z:215 (M+).
Reference: [1] Patent: EP1762568, 2007, A1, . Location in patent: Page/Page column 49
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  • [ 24424-99-5 ]
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Reference: [1] Patent: US2009/192156, 2009, A1, . Location in patent: Page/Page column 27-28
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  • [ 15721-22-9 ]
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Reference: [1] Patent: US2002/55631, 2002, A1,
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Reference: [1] Patent: US2013/236468, 2013, A1, . Location in patent: Paragraph 0321
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tert-Butyl 4-hydroxypiperidine-1-carboxylate

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Chemical Structure| 181269-70-5

[ 181269-70-5 ]

1-Boc4-hydroxy-3-methylpiperidine

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Chemical Structure| 392331-66-7

[ 392331-66-7 ]

1-Boc-4-(Aminomethyl)-4-hydroxypiperidine

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Chemical Structure| 236406-33-0

[ 236406-33-0 ]

tert-Butyl 4-(2-hydroxyethyl)-4-methylpiperidine-1-carboxylate

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Chemical Structure| 89151-44-0

[ 89151-44-0 ]

N-Boc-4-Piperidineethanol

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Related Parent Nucleus of
[ 406235-30-1 ]

Piperidines

Chemical Structure| 109384-19-2

[ 109384-19-2 ]

tert-Butyl 4-hydroxypiperidine-1-carboxylate

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Chemical Structure| 181269-70-5

[ 181269-70-5 ]

1-Boc4-hydroxy-3-methylpiperidine

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Chemical Structure| 1209319-87-8

[ 1209319-87-8 ]

tert-Butyl 2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane-9-carboxylate

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Chemical Structure| 146093-46-1

[ 146093-46-1 ]

4-(Aminoethyl)-1-N-Boc-piperidine

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Chemical Structure| 173405-78-2

[ 173405-78-2 ]

tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate

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