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Chemistry
Heterocyclic Building Blocks
Piperidines
tert-Butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate
Chemistry
Heterocyclic Building Blocks
Organic Building Blocks
Piperidines
Amides Alcohols Alkenes

[ CAS No. 198892-80-7 ] {[proInfo.proName]}

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Chemical Structure| 198892-80-7
Chemical Structure| 198892-80-7
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CAS No. :198892-80-7 MDL No. :MFCD09910236
Formula : C12H21NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 227.30 Pubchem ID :-
Synonyms :

Safety of [ 198892-80-7 ]

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Precautionary Statements: UN#:
Hazard Statements: Packing Group:

Application In Synthesis of [ 198892-80-7 ]

* 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.

  • Downstream synthetic route of [ 198892-80-7 ]

[ 198892-80-7 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 135716-08-4 ]
  • [ 198892-80-7 ]
YieldReaction ConditionsOperation in experiment
88% With diisobutylaluminium hydride; In n-heptane; toluene; at -77℃; for 2.83333h;Inert atmosphere; A solution of tert-butyl 4-(2-ethoxy-2-oxoeth- ylidene)piperidine- 1 -carboxylate (4.99 g, 18.5 mmol) in toluene (75 ml) was placed under nitrogen in a 500 mE round- bottom flask and cooled on a dry ice/acetone bath at -77 C. Diisobutylaluminum hydride (1.0 M in heptane, 40 ml, 40.0 mmol) was added dropwise by syringe over 20 mm. The solution was stirred for 2.5 hours before adding saturated aqueous NH4C1 (12.5 mE) dropwise over 8 mm. The sample warmed to 23C. and stirred for 16 h. The mixture was shaken with water (100 mE). The resulting emulsion was filtered on a l3uchner thnnel and the filter cake was washed with EtOAc (50 mE). The layers were separated. The product was extracted with EtOAc (2x50 mE), then the combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to provide an oil. The material was dissolved in hexanes-EtOAc and purified by l3iotage MPEC (100 g silica gel colunm, 10 to 60% EtOAc in hexanes) to provide tert-butyl 4-(2-hydroxyethylidene)piperidine-1 - carboxylate (3.71 g, 88%). ?H NMR (300 MHz, CHEOROFORM-d) oe 5.50 (t, J=7.04 Hz, 1H), 4.15-4.23 (m, 2H), 3.36-3.50 (m, 4H), 2.27 (dd, J=5.70 Hz, 2H), 2.19 (dd, J=5.70 Hz, 2H), 1.48 (s, 9H). ECMS: (ESI) mlz 250 [M+Na].
75% Intermediate 16; 4-(2-Hydroxyethylidene)piperidine-l-carboxylic acid terf-butyl ester; To a solution of 4-ethoxycarbonylmethylenepiperidine-l-carboxylic acid tert-butyl ester (3.5g, B.Olmmol) in toluene (3OmL) at -780C was added DIBAL (33mL of a IM solution in toluene, 33.0mmol) dropwise. The mixture was stirred at -780C for Ih then treated with MeOH (0.5mL) and allowed to warm to rt. Water was added and the precipitate removed by filtration. The filtrate was concentrated in vacuo and the crude mixture purified by flash chromatography with 33% EtOAc / Hexane as eluent to afford the title compound as a yellow oil (2.2g, 75%): deltaH (CDCl3) 1.30 (9H, s), 2.02 (2H, m), 2.10 (2H, m), 3.22 (4H, m), 4.01 (2H, m), 5.35 (IH, t).
With diisobutylaluminium hydride; t-Butyl 4-(2-HVDROXYETHVIIDENE) PIPERIDINVL-1-CARBOXYLATE (25) was prepared according the procedure described in Sato et. al Heterocycles, 2001,54, 747.
With diisobutylaluminium hydride; In tetrahydrofuran; hexane; at -78℃; for 2h; To a solution of the compound prepared in Reference Example 23 (24.4g) in anhydrous tetrahydrofuran (250mL) was added dropwise diisobutylaluminum hydride (1.01M solution in hexane, 224mL) at -78C under an atmosphere of argon. The mixture was stirred for 2 hours. The reaction mixture was poured into ice-cooled 1N hydrochloric acid and then extracted with dichloromethane. The organic layer was dried and concentrated to give the title compound (19.5g) having the following physical data. TLC: Rf 0.25 (hexane : ethyl acetate = 1 : 1); NMR (CDCl3):delta 5.49(t, J = 7.0Hz, 1H), 4.18(d, J = 7.0Hz, 2H), 3.37-3.49(m, 4H), 2.23-2.31(m, 2H), 2.15-2.22(m, 2H), 1.47(s, 9H).

Reference： [1]Patent: US2016/185785,2016,A1 .Location in patent: Paragraph 2280; 2281
[2]Patent: WO2007/3964,2007,A1 .Location in patent: Page/Page column 48
[3]Patent: WO2005/33108,2005,A1 .Location in patent: Page/Page column 48
[4]Patent: EP1619193,2006,A1 .Location in patent: Page/Page column 67
[5]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5652 - 5656
[6]Organic Letters,2011,vol. 13,p. 1698 - 1701
[7]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5502 - 5506
[8]Journal of Organic Chemistry,2016,vol. 81,p. 1057 - 1074
[9]Angewandte Chemie - International Edition,2017,vol. 56,p. 9868 - 9871
    Angew. Chem.,2017,vol. 129,p. 10000 - 10003,4
  • 2
  • [ 1235842-48-4 ]
  • [ 198892-80-7 ]
  • [ 1235842-50-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl 4-(2-ethoxy-2-oxo-ethyl)-4-fluoro-piperidine-1-carboxylate With diisobutylaluminium hydride In dichloromethane at -78 - 20℃; Inert atmosphere; Stage #2: With water at 0℃; 20.C To tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1 -carboxylate (3.8g) inDCM (20ml) at -780C under nitrogen was added by syringe diisobutylaluminum hydride (2.2M in Toluene, 24ml). The mixture was stirred at -780C for 2 hours, then warmed up to room temperature. The mixture was then poured to ice (100g), acidified to pH 3, and extrated with ethyl acetate (200ml + 100ml x 3). Combined ethyl acetate layer was then dried over sodium sulphate, solvent removed to give tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1 -carboxylate which is contaminated with HF eliminated allylic alcohol in -3:1 ratio in favour of desired product (3g). As purification proved to be difficult, this was used for next step as a mixture.
Stage #1: tert-butyl 4-(2-ethoxy-2-oxo-ethyl)-4-fluoro-piperidine-1-carboxylate With diisobutylaluminium hydride In dichloromethane; toluene at -78℃; for 2h; Inert atmosphere; Stage #2: With water In dichloromethane; toluene 20.C C: tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylateTo tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (3.8 g) in DCM (20 ml) at -78° C. under nitrogen was added by syringe diisobutylaluminum hydride (2.2M in Toluene, 24 ml). The mixture was stirred at -78° C. for 2 hours, then warmed up to room temperature. The mixture was then poured to ice (100 g), acidified to pH 3, and extracted with ethyl acetate (200 ml+100 ml×3). Combined ethyl acetate layer was then dried over sodium sulphate, solvent removed to give tert-butyl 4-fluoro-4-(2-hydroxyethyl)piperidine-1-carboxylate which is contaminated with HF eliminated allylic alcohol in 3:1 ratio in favour of desired product (3 g). As purification proved to be difficult, this was used for next step as a mixture.
Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2010/81859, 2010, A1 Location in patent: Page/Page column 57-58
[2]Current Patent Assignee: MERCK & CO INC - US2010/184761, 2010, A1 Location in patent: Page/Page column 31
  • 3
  • [ 169206-65-9 ]
  • [ 198892-80-7 ]
YieldReaction ConditionsOperation in experiment
1.1 g With lithium aluminium tetrahydride In tetrahydrofuran at -65℃; Cooling with ice; Inert atmosphere;
With diisobutylaluminium hydride In tetrahydrofuran at -78 - 0℃; for 20h; B Step B Butyl 4-(2-hydroxyethylidene)piperidine-l-carboxylate To a solution of /er/-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-l- carboxylate (7.54 g, 29.5 mmol) in tetrahydrofuran (60 mL) at -78 °C was added a solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 60.0 mL, 60.0 mmol) dropwise and the reaction mixture was allowed to stir for 1 h at -78 °C. The reaction mixture was allowed to warm to 0 °C and stir for 1 h. A solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 40.0 mL, 40.0 mmol) was added dropwise and the reaction mixture was allowed to stand at 0 °C for 18 h. An aqueous solution of Rochelle’s salt (0.5 M) was added slowly and the resulting mixture was diluted with water and extracted with ethyl acetate (2 x). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried (magnesium sulfate) and filtered and the filtrate was concentrated under reduced pressure to afford the title compound in sufficient purity for use in the next step. MS: m/z = 195.2 [M+Na-tBu]
With diisobutylaluminium hydride In tetrahydrofuran; toluene at -70℃; Inert atmosphere;
With diisobutylaluminium hydride In tetrahydrofuran at -78 - 0℃; for 20h; Step B: tert-Butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate To a solution of tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1- carboxylate (7.54 g, 29.5 mmol) in tetrahydrofuran (60 mL) at -78°C was added a solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 60.0 mL, 60.0 mmol) dropwise and the reaction mixture was allowed to stir for 1 h at -78°C. The reaction mixture was allowed to warm to 0°C and stir for 1 h. A solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 40.0 mL, 40.0 mmol) was added dropwise and the reaction mixture was allowed to stand at 0°C for 18 h. An aqueous solution of Rochelle’s salt (0.5 M) was added slowly and the resulting mixture was diluted with water and extracted with ethyl acetate (2 ×). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried (magnesium sulfate) and filtered and the filtrate was concentrated under reduced pressure to afford the title compound in sufficient purity for use in the next step. MS: m/z = 195.2 [M+Na-tBu].
With diisobutylaluminium hydride In tetrahydrofuran at -78 - 0℃; for 20h; B Step B: tert-Butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate (I2b) To a solution of tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1- carboxylate (I2a, 7.54 g, 29.5 mmol) in tetrahydrofuran (60 mL) at -78 °C was added a solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 60.0 mL, 60.0 mmol) dropwise and the reaction mixture was allowed to stir for 1 h at -78 °C. The reaction mixture was allowed to warm to 0 oC and stir for 1 h. A solution of diisobutylammonium hydride in tetrahydrofuran (1 M, 40.0 mL, 40.0 mmol) was added dropwise and the reaction mixture was allowed to stand at 0 oC for 18 h. An aqueous solution of Rochelle’s salt (0.5 M) was added slowly and the resulting mixture was diluted with water and extracted with ethyl acetate (2 ×). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried (magnesium sulfate) and filtered and the filtrate was concentrated under reduced pressure to afford compound I2b in sufficient purity for use in the next step. MS: m/z = 195.2 [M+Na-tBu].

Reference： [1]Pohjakallio, Antti; Pihko, Petri M.; Laitinen, Ulla M. [Chemistry - A European Journal, 2010, vol. 16, # 37, p. 11325 - 11339]
[2]Current Patent Assignee: MERCK & CO INC - WO2019/212927, 2019, A1 Location in patent: Page/Page column 66-67
[3]Hirano, Koji; Miura, Masahiro; Xu, Shibo [Organic Letters, 2020, vol. 22, # 22, p. 9059 - 9064]
[4]Current Patent Assignee: MERCK & CO INC; DOMAIN THERAPEUTICS SA; BIONOMICS LIMITED - WO2020/223136, 2020, A1 Location in patent: Page/Page column 56
[5]Current Patent Assignee: MERCK & CO INC; CROWLEY BRENDAN M; BELL IAN M - WO2021/91751, 2021, A1 Location in patent: Page/Page column 45

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