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Product Details of [ 1126-09-6 ]

CAS No. :1126-09-6 MDL No. :MFCD00006003
Formula : C8H15NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :RUJPPJYDHHAEEK-UHFFFAOYSA-N
M.W : 157.21 Pubchem ID :70770
Synonyms :
Chemical Name :Ethyl piperidine-4-carboxylate

Calculated chemistry of [ 1126-09-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.88
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.46
TPSA : 38.33 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.15
Log Po/w (XLOGP3) : 0.51
Log Po/w (WLOGP) : 0.17
Log Po/w (MLOGP) : 0.69
Log Po/w (SILICOS-IT) : 1.22
Consensus Log Po/w : 0.95

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.94
Solubility : 18.1 mg/ml ; 0.115 mol/l
Class : Very soluble
Log S (Ali) : -0.89
Solubility : 20.5 mg/ml ; 0.13 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.56
Solubility : 4.36 mg/ml ; 0.0277 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.42

Safety of [ 1126-09-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P210-P264-P280-P370+P378-P337+P313-P305+P351+P338-P302+P352-P332+P313-P362-P403+P235 UN#:N/A
Hazard Statements:H227-H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1126-09-6 ]

* 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.

  • Upstream synthesis route of [ 1126-09-6 ]
  • Downstream synthetic route of [ 1126-09-6 ]

[ 1126-09-6 ] Synthesis Path-Upstream   1~59

  • 1
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YieldReaction ConditionsOperation in experiment
100%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 20℃;
Stage #2: With sodium hydroxide; water In tetrahydrofuran at 20℃; for 0.5 h;
To A suspension of LIAIH4 (10. 10 G, 0. 266 MOL) IN THF (150 ML) AT 0 C, A SOLUTION OF ETHYL PIPERIDINE-4-CARBOXYLATE (18. 13 G, 0. 120 MOL) IN THF (300 ML) WAS ADDED slowly. This was stirred at room temperature overnight. It was cooled with an ice bath and A mixture of water (14 ML) and THF (28 ML) was added slowly. Afterwards, A mixture of 15percent aqueous NAOH (14 mL) and water (37 ML) was added followed by stirring at room temperature for 30 min. The precipitate obtained was filtered and the filtrate was concentrated, to afford 17. 88 g of the desired compound (yield : quantitative).
100%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With ethanol; water In tetrahydrofuran at 0℃;
2d) 4-Piperidinemethanol To a suspension of lithium aluminium hydride (8.3 mmol; 310 mg) in anhydrous THF (5 ml) at 00C was added dropwise a solution of ethyl isonipecotate (6.4 mmol; 1.0 g) in anhydrous THF (5 ml). The reaction mixture was stirred at room temperature for 35 minutes. After cooling to 00C, aqueous ethanol (95percent) was added cautiously and the hydroxides thus formed were removed by filtration. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1.34 g (100percent) of pure product as an oil.1H NMR (DMSO-d6, δ ppm): 1.09-1.18 (m, 2H); 1.50 (m, 1 H); 1.66- 1.69 (m, 2H); 2.53-2.61 (m, 3H); 3.05-3.08 (m, 2H); 3.25 (d, 2H); 4.60 (s, 1 H).
92% With lithium aluminium tetrahydride In diethyl ether for 7 h; Reflux To a solution of ethyl isonipecotate (2 mL, 13.0 mmol, 1.0 eq.) in Et2O (150 mL) was added portion-wise LiAlH4 (1.48 g, 39 mmol, 3.0 eq.) at 0°C and the reaction mixture was refluxed for 7h. The mixture was then cooled to 0°C and the reaction was then slowly quenched with 1.5 mL of water, 1.5 mL of 15percent NaOH solution followed by 4.5 mL of water to afford a granular inorganic precipitate. The white solid was filtered and washed several times with EtOAc. Evaporation of the filtrate under reduced pressure provided compound 21 as a colorless oil (92percent yield); 1H NMR (CDCl3, 400 MHz) δ 3.45 (d, 3J = 5.9 Hz, 2H), 3.08 (m, 2H), 2.59 (dt, 2J = 12.0 Hz, 3J = 3.0 Hz, 2H), 1.96 (br s, 1H), 1.71 (m, 2H), 1.60-1.55 (m, 1H), 1.17-1.07 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 66.9 (CH2), 45.9 (2*CH2), 38.8 (CH), 29.7 (2*CH2); IR (neat, cm-1) ν 3369, 2923, 2855, 1636, 1531, 1425, 1266, 1036. Spectral and analytical data matched with literature.[3]
61%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With sodium hydroxide; water In tetrahydrofuran at 0℃;
To a mixture of LiAIH4 (8.82 g, 0.23 mol) and THF (125 mL), cooled at 0 °C, a solution of ethyl isonipecotate (18 mL, 0.117 mol) in THF (325 mL) was added dropwise under Ar-atmosphere, the mixture was stirred at room temperature overnight. A mixture of H2O (12.03 mL) and THF (25 mL), followed by a mixture of 15 percent NaOH (10.03 mL) and H2O (32.4 mL) were slowly added at 0 °C. The resulting mixture was washed with THF, filtered and concentrated to dryness. The residue was partitioned between H2O and CHCI3, the phases were separated, the aqueous phase was extracted with CHCI3 and the combined organic phases were <n="70"/>dried over Na2SO4 and concentrated to afford 8.2 g of the desired product (61 percent yield).

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[3] RSC Advances, 2016, vol. 6, # 22, p. 17929 - 17940
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[11] Patent: US4925850, 1990, A,
[12] Patent: US4931449, 1990, A,
[13] Patent: US4977159, 1990, A,
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Reference: [1] Collection of Czechoslovak Chemical Communications, 1959, vol. 24, p. 212,216
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6938 - 6942,5
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 757 - 761
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Reference: [1] Patent: WO2003/105845, 2003, A1, . Location in patent: Page 104-106
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Reference: [1] Patent: US2016/128945, 2016, A1,
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  • [ 1126-09-6 ]
YieldReaction ConditionsOperation in experiment
94% at 0℃; for 48 h; Reflux Isonipecotic acid (1.29g, 10.0 mmol) was dissolved in absolute ethanol (50 ml). The solution was cooled to 0οC and thionyl chloride (2.91 ml, 40.0 mmol) added dropwise. The solution was then stirred and refluxed for 48 h. The solvent was removed in vacuo yielding yellow oil, which was dissolved in EtOAc and washed with 10percent NaOH. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to afford a clear oil (1.48 g, 94percent). 1H NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.07 (dt, J = 12.6, 3.6 Hz, 2H, 2 × CHpip), 2.61 (td, J = 12.3, 2.7 Hz, 2H, 2 × CHpip), 2.38 (tt, J = 11.3, 3.9 Hz, 1H, CH), 1.94 - 1.78 (m, 2H, 2 × CHpip), 1.59 (adtd, J = 13.4, 11.4, 4.0 Hz, 2H, 2 × CHpip), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3). Mass Spectrum (ESI): m/z 158.2 [M+H]+.
92% With sulfuryl dichloride In N,N-dimethyl-formamide at 80℃; for 6 h; Inert atmosphere To a solution of isonipecotic acid 1 (500 g, 3.87 mol) inmethanol (1.5 L), thionyl chloride (371 g, 5.03 mol) wasadded dropwise in nitrogen atmosphere at 0 °C. After addition,reaction was heated to reflux temperature under nitrogenatmosphere for 6 h. Excess methanol was distilled out to give yellow paste which was dissolved in ethyl acetate (1 L)and neutralized with saturated sodium bicarbonate solution.Organic layer was dried by using sodium sulphate and concentratedto afford 2 (560 g, 92percent) as colorless liquid. IR(neat) cm-1: 3296, 2949, 2856, 2812, 2739, 1734; 1H NMR(CDCl3, 400 MHz) : 1.02-1.05 (3H, t, J=7.2 Hz, CH3),1.33-1.43 (2H, m, CH2), 1.63-1.67 (2H, dd, CH2), 2.14-2.21(1H, m, CH), 2.37-2.44 (2H, m, CH2), 2.83-2.87 (2H, m,CH2), 3.88-3.93 (2H, q, J=7 Hz, CH2). 13C NMR (CDCl3,100 MHz) : 14.1, 29.0, 41.4, 45.6, 60.2, 175.0.
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[2] Letters in Organic Chemistry, 2015, vol. 12, # 4, p. 277 - 279
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 5, p. 505
[4] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 18, p. 2693 - 2698
[5] European Journal of Medicinal Chemistry, 2000, vol. 35, # 7-8, p. 699 - 706
[6] RSC Advances, 2016, vol. 6, # 26, p. 21577 - 21589
  • 9
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YieldReaction ConditionsOperation in experiment
71%
Stage #1: With 2,6-di-tert-butyl-4-methylpyridine; trifluoromethylsulfonic anhydride In dichloromethane at -78 - 0℃; for 2 h; Inert atmosphere
Stage #2: With ethylmagnesium bromide In diethyl ether; dichloromethane at -78℃; for 2 h; Inert atmosphere
General procedure: Tf2O (1.2 equiv) was added dropwise to a cooled (−78 °C) solution of amide 5 (1.0 equiv) and DTBMP (1.2 equiv) in CH2Cl2 (5 mL). The reaction was allowed warming to 0 °C over 2 h. A solution of Grignard reagent (1.0 equiv) in Et2O was added dropwise to the resultant mixture at −78 °C, and the mixture was stirred at the same temperature for 2 h. The reaction mixture was then quenched with an aqueous solution of 15percent HCl (5 mL). The organic layer was separated and the aqueous phase was extracted with diethyl ether (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired ketone 1. To isolate the corresponding amine, the aqueous solution layer was basified with an aqueous solution of 15percent NaOH (6 mL), and extracted with dichloromethane (3×10 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired amine 6.
Reference: [1] Tetrahedron, 2015, vol. 71, # 24, p. 4248 - 4254
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Reference: [1] Organic Letters, 2008, vol. 10, # 22, p. 5155 - 5158
  • 12
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[2] Journal of the Chemical Society, 1937, p. 1523,1525
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  • 14
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  • [ 50-00-0 ]
  • [ 24252-37-7 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With hydrogen; acetic acid In water at 20℃; for 3.5 h; Cooling with ice
Stage #2: With sodium hydroxide In waterCooling
Example 22
1-Methylpiperidine-4-carboxylic acid ethyl ester (21):
Ethyl isonipecotate (20) (5.00 g, 31.8 mmol) was dissolved in an ice-cold mixture of glacial acetic acid (3.80 g, 63.6 mmol) and water (11 mL).
Then, a 37percent aqueous formaldehyde solution (2.85 mL, 38.2 mmol) was added and the reaction mixture was hydrogenated over Pd/C (10percent, 338 mg) at 58 psi H2 for 3.5 h at room temperature.
The solid was removed by filtration through Celite, which was washed thoroughly with water (50 mL) and the filtrate was adjusted to pH 11 with 1 M NaOH under cooling.
The resulting solution was extracted with Et2O (5*100 mL), the combined organic fractions were dried (MgSO4), and the solvent was removed under reduced pressure to provide 21 (5.44 g, quant.) as a colorless liquid that was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): δ=1.25 (t, J=7.1 Hz, 3H, OCH2C3), 1.69-2.06 (m, 6H, 2-Hax, 3-H2, 5-H2, 6-Hax), 2.18-2.32 (m, 1H, 4-H), 2.27 (s, 3H, NMe), 2.75-2.87 (m, 2H, 2-Heq, 6-Heq), 4.13 (q, J=7.1 Hz, 2H, OC2CH3) ppm. -13C NMR (75.5 MHz, CDCl3): δ=14.1 (OCH2H3), 28.2 (C-3, C-5), 40.5 (C-4), 46.3 (NMe), 54.9 (C-2, C-6), 60.2 (OH2CH3), 175.0 (C=O) ppm. -MS (70 eV, EI): m/z (percent)=171 (31) [M]+, 142 (59) [M-CH2CH3]+, 126 (40) [M-OCH2CH3]+, 98 (56) [M-CO2Et]+. -C9H17NO2 (171.24).
100%
Stage #1: With hydrogen; acetic acid In water at 20℃; for 3.5 h;
Stage #2: With sodium hydroxide In water
Ethyl isonipecotate (20) (5.00 g, 31.8 nnno 1) was dissolved in an ice-cold mixture of glacial acetic acid (3.80 g, 63.6 mmol) and water (11 mL). Then, a 37percent aqueous formaldehyde solution (2.85 niL, 38.2 mmol) was added and the reaction mixture was hydrogenated over Pd/C (10percent, 338 mg) at 58 psi H2 for 3.5 h at room temperature. The solid was removed by filtration through Celite, which was washed thoroughly with water (50 mL) and the filtrate was adjusted to pH 11 with 1 M NaOH under cooling. The resulting solution was extracted with Et2O (5 x 100 mL), the combined organic fractions were dried (MgSψ4), and the solvent was removed under reduced pressure to provide 21 (5.44 g, quant.) as a colorless liquid that was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): δ = 1.25 (t, J= 7.1 Hz, 3 H, OCH2CH3), 1.69-2.06 (m, 6 H, 2-Hax, 3-H2, 5-H2, 6-Hax), 2.18-2.32 (m, 1 H, 4-H), 2.27 (s, 3 H, NMe), 2.75-2.87 (m, 2 H, 2-Heq, 6-Heq), 4.13 (q, J= 7.1 Hz, 2 H, OCH2CH3) ppm. - 13C NMR (75.5 MHz, CDCl3): δ = 14.1 (OCH2CH3), 28.2 (C-3, C-5), 40.5 (C-4), 46.3 (NMe), 54.9 (C-2, C-6), 60.2 (OCH2CH3), 175.0 (C=O) ppm. - MS (7O eV, EI): m/z (percent) = 171 (31) [M]+, 142 (59) [M-CH2CH3]+, 126 (40) [M-OCH2CH3]+, 98 (56) [M-CO2Et]+. - C9HnNO2 (171.24).
61%
Stage #1: With formic acid In water for 24 h; Reflux
Stage #2: With sodium hydrogencarbonate In dichloromethane for 1 h;
Reference Example 1; 1-Methyl-piperidine-4-carboxylic acid hydrochloride; a) Preparation of 1-methyl-piperidine-4-carboxylic acid ethyl ester; Ethyl isonipecotate (3.0 g, 19.1 mmol) was added to a mixture of 90percent formic acid (10 mL) and 30percent aqueous formaldehyde (10 mL, 100 mmol) then the mixture was heated at reflux for 24 h. After cooling, the mixture was concentrated in vacuo to give an oil which was dissolved in dichloromethane. Solid sodium bicarbonate (1 g) was added and the mixture stirred for 1 h then filtered. The filtrate was concentrated in vacuo to afford 1-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 61percent) as a liquid, which was used as such for the next step.
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YieldReaction ConditionsOperation in experiment
86% With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 18 h; 2f) Ethyl 4-benzylisonipecotateA mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous Λ/,Λ/-dimethylformamide (100 ml) was stirred at 700C for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3 * 200 ml). The combined organic phases were washed with saturated NaCI solution (3 x 100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86percent) of pure product as a yellow oil.1H NMR (CDCI3, δ ppm): 1.28-1.32 (t, 3H); 1.81 (m, 4H); 2.07-2.12 (m, 2H); 2.34 (m, 1 H); 2.91 (m, 2H); 3.55 (m, 2H); 4.15-4.21 (m, 2H); 7.31 -7.38 (m, 5H).
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  • 31
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YieldReaction ConditionsOperation in experiment
91%
Stage #1: With potassium carbonate In toluene for 0.25 h;
Stage #2: at 100℃; for 4 h;
Ethyl isonipecotate (1, 50 g, 0.31 mol) was dissolved in toluene (150 mL) in a round bottom flask, charged with potassium carbonate (60 g, 0.43 mol) and stirred for 15 min. Benzyl chloride (42 g, 0.31 mol) was charged and the reaction mass was refluxed for 4 h at 100 °C. Upon completion of the reaction as marked by TLC (hexane:ethyl acetate; 2:1), the reaction mass was cooled to room temperature and quenched with water (100 mL), stirred and the organic phase was separated. The aqueous phase was again extracted with toluene (100 mL). Combined organic phase was washed twice with saturated brine solution (50 mL). Remove toluene in vacuo to obtain N-benzyl ethyl isonipecotate (2, 6.97 g, 91 percent) as a yellow liquid.
75% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20 - 120℃; for 1.5 h; (a)
Synthesis of ethyl 1-benzyl-4-piperidinecarboxylate
Benzyl chloride (13.2 ml, 115 mmol) and potassium carbonate (19.8 g, 143 mmol) were added to a solution of ethyl 4-piperidinecarboxylate (15.0 g, 95.4 mmol) in N,N-dimethylformamide (50 ml) at room temperature and stirred at 120°C for 1.5 hours.
Then, the reaction suspension was filtered and the solvent of the filtrate was distilled off under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 4/1) to obtain ethyl 1-benzyl-4-piperidinecarboxylate (17.7 g, 75percent).
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YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane at 0 - 20℃; To a solution of ethyl isonipecotate (5.00 g, 0.032 mol) and triethylamine (4.9 [ML,] 0.035 mmol) in dichloromethane (25 mL) at [0°C] was slowly added a solution of di-tert-butyldicarbonate (7.2 g, 0.033 mol) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature overnight, then washed with potassium hydrogen sulfate three times and with brine once. The organic extract was-dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give the desired product (8.23 g, 100percent) as colorless [OIL. 1H] NMR [(C6D6,] 500 MHz) [5] 3.88 (q, J = 7.5 Hz, 2H), 2.52 (m, 1H), 1.60-1. 48 [(M,] 8H), 1.42 (s, 9H), 0.92 (t, 3H). Mass spec.: 280.44 (M+Na) [+.]
100% With triethylamine In dichloromethane at 20℃; Step 1: JV-Boc ethylisopinecotateBoc20 (15.8 g, 71.4 mmol) and triethylamine (10 mL, 77.8 mmol) were successively added to a solution of ethylisopinecotate (10.2 g, 64.9 mmol) in dichloromethane (50 mL) at room temperature. The reaction mixture was stirred overnight. The reaction mixture was diluted by addition of a saturated solution of ammonium chloride (50 ml_). The aqueous layer was separated and extracted with dichloromethane (2 x 50 ml_). The combined organic phases were dried over sodium sulphate, filtered and concentrated to dryness. The title product was obtained as a yellow oil (16.7 g, 100percent).*H NMR (CDCI3, 400 MHz) : δ (ppm) : 4.18 (q, J = 6.8 Hz, 2H), 4.08-4.04 (m, 2H), 2.88 (m, 2H), 2.49-2.45 (m, 1H), 1.93-1.88 (m, 2H), 1.71-1.63 (m, 2H), 1.50 (s, 9H), 1.30 (t, J = 6.8 Hz, 3H).
99.8% With sodium carbonate In tetrahydrofuran; water for 2 h; Heating / reflux A mixture of ethyl isonipecotate (5.00 g, 31.8 MMOL), di-tert-butyl dicarbonate (7.64 g, 34.99 MMOL), and sodium carbonate (6.74 g, 63.6 mmol) in water/tetrahydrofuran (50 mL: 20MOL) was heated at reflux for 2 hours. The mixture was allowed to cool to room temperature, and was extracted with ethyl acetate (2 X 200 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated under reduced pressure. A thick yellow oil was afforded, 8.17 g (99.8percent). MS (APCI) (M+L)/Z 258, (M-BOC + l)/z, 157.9.
98% at 20℃; for 1 h; [0160] To a solution of ethyl isonipecotate (0.750 g, 4.77 mmol) in THF (24 mL) was added water (1 mL) followed by di-tert-butyl dicarbonate (1.09 g, 5.00 mmol) and the resultant mixture was stirred at room temperature for one hour. The mixture was diluted with ethyl acetate (50 mL) and the organic phase was washed with brine (3.x.20 mL), dried (MgSO4), and concentrated to provide 1.20 g (98percent) of 1-(tert-butoxycarbonyl)-4-(carboethoxy)-piperidine as a colorless oil. [0161] To a cold (-78° C.), stirred solution of the oil from above (1.20 g, 4.67 mmol) in dry THF (46 mL) was added diisobutylaluminum hydride (1.0 M in THF, 15 mL, 15 mmol). After 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 20 minutes. Saturated aqueous NH4Cl (5 mL) was added and the resultant white slurry was stirred at room temperature for 45 minutes. Solid MgSO4 (5 g) was added and the mixture was filtered through Florisil..(C). The column was washed with ethyl acetate (200 mL). The combined eluant was concentrated under reduced pressure to provide 1.01 g (97percent) of 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)-piperidine as a white solid. [0162] To a solution of the above alcohol (0.437 g, 2.03 mmol) in CH2Cl2 (10 mL), at room temperature, was added sequentially 3 molecular sieves (1.07 g), N-methylmorpholine N-oxide (0.365 g, 3.11 mmol), and tetrapropylammonium perruthenate (70 mg, 0.20 mmol). After 1 hour, the mixture was filtered through a short column of silica gel and the cake was washed with ethyl acetate. The solvent was removed from the filtrate under reduced pressure. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-ethyl acetate) provided 90 mg (20percent) of 1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde as a colorless oil. 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.51-1.62 (m, 2H), 1.85-1.93 (m, 2H), 2.37-2.46 (m, 1H), 2.88-2.97 (m, 2H), 3.94-4.00 (m, 2H), 9.66 (s, 1H). [0163] Using General Procedure B: Reaction of 1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde (0.090 g, 0.42 mmol) and (1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.110 g, 0.40 mmol) with NaBH(OAc)3 (0.223 g, 1.05 mmol) in CH2Cl2 (5 mL) for 20 h followed by purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-CH3OH-NH4OH) provided 0.120 g (63percent) of an off-white solid. [0164] Using General Procedure D: Conversion of the off-white solid (120 mg) to the hydrobromide salt with simultaneous removal of the BOC-protecting group, followed by re-precipitation of the intermediate solid from methanol/ether, gave COMPOUND 6 (98 mg) as a white solid. 1H NMR (D2O) δ 1.13-1.28 (m, 2H), 1.80-2.36 (m, 8H), 2.81-3.00 (m, 5H), 3.35-3.43 (m, 2H), 4.38 (d, 1H, J=16.5 Hz), 4.46 (d, 1H, J=16.5 Hz), 4.52 (dd, 1H, J=10.5, 6.0 Hz), 7.59-7.65 (m, 2H), 7.78-7.85 (m, 2H), 7.89 (dd, 1H, J=7.8, 6.0 Hz), 8.37 (d, 1H, J=8.1 Hz), 8.67 (d, 11H, J=5.7 Hz); 13C NMR (D2O) δ 17.72, 18.24, 24.98 (2 carbons), 25.71, 29.64, 41.94, 42.05, 45.79, 54.96, 57.53, 112.25, 124.08, 125.04, 128.97, 137.47, 139.09, 146.24, 148.75 (2 carbons); ES-MS m/z 376 (M+H). Anal. Calcd. for C23H29N5.3.1 HBr.1.8H2O: C, 41.93; H, 5.46; N, 10.63; Br, 37.60. Found: C, 42.07; H, 5.55; N, 10.28; Br, 37.43.
98% at 0 - 20℃; for 12.25 h; To a solution of ethyl isonipecotate (50 g, 0.318 mol) in CH2Cl2 (150 mL) at 0° C. was added a solution of di-t-butyl dicarbonate (73 g, 0.334 mol) in CH2Cl2 (150 mL) over 15 min. The ice bath was removed and the reaction mixture was stirred at rt for 12 h. The solvent was evaporated to yield a liquid. Subsequent purification by sgc (4:1 hexanes-Et2O) gave 80 g (98percent) of Compound 18.
98% at 0 - 20℃; for 48 h; A solution of di-tert-butyl dicarbonate (41.7 g, 0.19 mol) in ethyl acetate (75 ml) was added dropwise to a solution of ethyl 4-piperidinylcarboxylate (30 g, 0.19 mol) in ethyl acetate (150 ml) while maintaining the temperature in the range 0-5 °C. The reaction was stirred at ambient temperature for 48 hours, poured onto water (300 ml) and the organic layer was separated and washed with i) water (200 ml), ii) 0. 1N aqueous hydrochloric acid (200 ml), iii) saturated sodium hydrogen carbonate (200ML) and iv) brine (200ML). Evaporation and drying in vacuo yielded ethyl (L-TEJT-BUTYLOXYCARBONYLPIPERIDIN-4-YL) carboxylate (48 g, 98 percent yield) as a white solid: 1H NMR (CDCl3) : 4.15 (q, 2H), 3.91-4. 10 (s, 2H), 2.70-2. 95 (t, 2H), 2.35-2. 50 (m, 1H), 1.80- 2.00 (d, 2H), 1.55-1. 70 (M, 2H), 1.45 (s, 9H), 1.25 (t, 3H)
98% at 5 - 20℃; for 48 h; While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0. 19mol) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0. 19mol) in ethyl acetate (150ml) cooled at 5°C. After stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ML). The organic layer was separated, washed successively with water (200ML), O. 1N aqueous hydrochloric acid (200ML), saturated sodium hydrogen carbonate (200ML) and brine (200ml), dried (MGS04) and evaporated to give ethyl 4-(1-(TERT-BUTOXYVARBONYL) piperidine) carboxylate (48g, 98percent). H NMR Spectrum: (CDCl3) 1.25 (t, 3H); 1.45 (s, 9H); 1.55-1. 70 (m, 2H); 1.8-2. 0 (d, 2H); 2.35- 2.5 (m, 1H); 2.7-2. 95 (t, 2H); 3.9-4. 1 (br s, 2H); 4.15 (q, 2H)
98% at 5 - 20℃; for 48 h; While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0. 19MOL) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0. 19MOL) in ethyl acetate (150ML) cooled at 5°C. After stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ML). The organic layer was separated, washed successively with water (200ML), 0. IN aqueous hydrochloric acid (200ML), saturated sodium hydrogen carbonate (200ML) and brine (200ML), dried (MGS04) and evaporated to give ethyl 4-(1-(TERT-BUTOXYZARBONYL) piperidine) carboxylate (48g, 98percent). LH NMR SPECTRUM : (CDC13) 1.25 (t, 3H); 1.45 (s, 9H); 1.55-1. 70 (m, 2H); 1. 8-2.0 (d, 2H) ; 2.35- 2.5 (m, 1H); 2.7-2. 95 (t, 2H) ; 3.9-4. 1 (br s, 2H); 4.15 (q, 2H)
98% at 0 - 20℃; for 48 h; A solution of di-tert-butyl dicarbonate (41.7g, 0.19mol) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0.19mol) in ethyl acetate (150ml) cooled at 5°C, while maintaining the temperature in the range 0-5°C.
After stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ml).
The organic layer was separated, washed successively with water (200ml), 0.1 M aqueous hydrochloric acid (200ml), saturated sodium hydrogen carbonate (200ml) and brine (200ml), dried (MgSO4), and the volatiles were removed by evaporation to give ethyl 4-(1-tert-butyloxycarbonylpiperidine)carboxylate (48g, 98percent).
1H NMR Spectrum: (CDCl3) 1.25(t, 3H); 1.45(s, 9H); 1.55-1.70(m, 2H); 1.8-2.0(d, 2H); 2.35-2.5(m, 1H); 2.7-2.95(t, 2H); 3.9-4.1 (br s, 2H); 4.15 (q, 2H)
98% at 5 - 25℃; for 48 h; While maintaining the temperature in the range 0-5°C, a solution of di-tert-butyl dicarbonate (41.7g, 0.19mol) in ethyl acetate (75ml) was added in portions to a solution of ethyl 4-piperidinecarboxylate (30g, 0.19mol) in ethyl acetate (150ml) cooled at 5°C.
After stirring for 48 hours at ambient temperature, the mixture was poured onto water (300ml).
The organic layer was separated, washed successively with water (200ml), 0.1N aqueous hydrochloric acid (200ml), saturated sodium hydrogen carbonate (200ml) and brine (200ml), dried (MgSO4) and evaporated to give ethyl 4-(1-(tert-butoxycarbonyl)piperidine)carboxylate (48g, 98percent).
1H NMR Spectrum: (CDCl3) 1.25(t, 3H); 1.45(s, 9H); 1.55-1.70(m, 2H); 1.8-2.0(d, 2H); 2.35-2.5(m, 1H); 2.7-2.95(t, 2H); 3.9-4.1(br s, 2H); 4.15 (q, 2H)
98% at 0 - 20℃; General procedure: A solution of commercially available substituted piperidinederivative (12.7 mmol) in anhydrous DCM (100 mL) wascooled to 0 °C. Tert-butyldicarbonate (2.6 g, 12.1 mmol) inDCM (20 mL) was added drop-wise into solution. After beingstirred for 10 min, the reaction mixture was allowed to adjustto room temperature and stirred overnight. After dilutionwith water, the crude product was extracted with DCM (100mL×2). The combined organic extracts were washed withhydrochloric acid (0.5 mol/L, 50 mL), and brine (100 mL),dried over Na2SO4, filtered, and concentrated to yield compounds2a and 15a. The crude product was used without furtherpurification.
98% With potassium carbonate In 1,4-dioxane; water Example 1; Piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1); Di-te/t-butyl dicarbonate (5.25 g, 23.8 mmol) was added to a solution of ethyl 4- pipehdinecarboxylate (2.5 g, 15.9 mmol) and potassium carbonate (4.4 g, 31.8 mmol) in dioxane/water (2:1 , 90 ml_) and stirred over night. The dioxane was evaporated and the aqueous phase was extracted with ethyl acetate (4 x 40 ml_). The combined organic layers were washed with brine, dried over sodium sulphate, filtrated and evaporated to give piperidine-1 ,4-dicarboxylic acid 1 -fe/t-butyl ester 4-ethyl ester (4.76 g) as the crude product. Flash chromatography with ethylacetate-heptane as eluent gave piperidine-1 ,4-dicarboxylic acid 1 -fe/t-butyl ester 4-ethyl ester (3.99 g 98percent)
97% at 0 - 20℃; for 18 h; Preparation 49: 1-tert-butyl 4-ethyl 14-piperidinedicarboxVLate To a solution of ethyl 4-piperidinecarboxylate (15.4 ML, 0.1 mol) in dichloromethane (100 ML) stirred under nitrogen and cooled to 0 C was added di-tert-butyl dicarbonate (21.5 g, 0.1 mol). The reaction mixture was stirred at room temperature for 18 h before washing with water and then saturated brine. The organic extracts were dried (NA2SO4) and concentrated in vacuo to give the title compound as an oil (25 g, 97percent).
97% at 20℃; for 2 h; Step 1:
Piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester
To a solution of of ethyl isonipecotate (4.72g, 0.03 mmol) in 30mL of THF was added slowly di-tert-butyl dicarbonate (7.2g, 0.03 mmol) at room temperature.
The resulting mixture was stirred for two hours and diluted with EtOAc.
The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel eluding with ethyl acetate:hexanes (1:9) to provide 7.52g (97percent) of the desired product as a colorless oil.
Electrospray Mass Spec: 258.3 (M+H)+
96.3% at 0 - 25℃; for 2 h; This reaction was conducted in a jacketed, 49 L reactor equipped with a retreat curve agitator, nitrogen purge system, and condenser system. The reactor was charged with di-t-butyl dicarbonate (1) in tetrahydrofuran ("THF") (75percent, 4.674 Kg, 16.06 mol) and tetrahydrofuran (5.50 Kg, 76.3 moles). After cooling the mixture to 0° C., ethyl isonipecotate (2) (2.500 Kg, 15.90 mol) was charged to the reactor while maintaining the contents at a temperature of from 0 to 15° C. After all the ethyl isonipecotate was added, the contents were warmed to 25° C., and then stirred for 2 hours at that temperature. The mixture was then cooled to 0° C. The THF was then removed by vacuum distillation until the batch temperature reached 80° C. Afterward, the contents were cooled to 25° C. This yielded 3.99 Kg of product in the form of an amber oil. The concentration of the Boc-20 protected ethyl isonipecotate (3) was 96.3percent (by weight). [TABLE-US-00001] TABLE 1 Reaction Summary for Part A volume MW equiv. wt (kg) moles density (g/mL) (L) materials compound (1) (75percent) 218.25 1.01 4.674 16.06 0.913 5.12 tetrahydrofuran 72.11 4.8 5.50 76.3 0.889 6.19 compound (2) 157.21 1.00 2.500 15.90 1.020 2.45 product compound (3) 257.33 (1.00) (4.092) (15.90) The numbers in parenthesis in the above table are theoretical..
94% for 0.5 h; Piperidine-4-carboxylic acid ethyl ester (3.14 g, 20 mmol) was dissolved in acetonitrile (25 mL). Di-t-butyldicarbonate (5.23 g, 24 mmol) was added and the reaction was stirred for 30 minutes. Polyamine scavenger resin was added and reaction mix was allowed to stand for 18 hours. The resin was filtered away and the volatiles were evaporated. The residue was chromatographed on silica gel with 0-25percent ethyl acetate in hexane. The title compound (4.88 g, 94percent) was isolated as a colorless oil. 1H NMR (300MHz, DMSO-d6): D (ppm) 4.06 (q, J = 7.0Hz, 2H), 3.85-3.80 (m, 2H), 2.86-2.78 (m, 2H), 2.54-2.46 (m, 2H), 1.80-1.76 (m, 2H), 1.39 (s, 9H)5 1.18 (t, J = 7.0Hz, 3H).
93% With triethylamine In dichloromethane at 0 - 25℃; for 16 h; Step 1:
1-tert-Butyl 4-ethyl piperidine-1,4-dicarboxylate
Di-tert-butyldicarbonate (95.39 mmol, 1.5 eq.) was added to a stirred solution of ethyl piperidine-4-carboxylate (63.7 mmol, 1.0 eq.) and Et3N (127.40 mmol, 2.0 eq.) in MC (200 ml) at 0° C.
The mixture was then stirred at 25° C. for 16 h.
It was diluted with MC (100 ml) and washed with water (100 ml) and brine (100 ml).
The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the desired product which was employed in the next step without further purification. Yield: 93percent
91% at 20℃; for 1 h; A solution of ethyl [ISONIPECOTATE] (20.0 g, 127 mmol) and [DI-TERKBUTYL] dicarbonate (29.1 g, 134 mmol) in dry dichloromethane was stirred at room temperature for 1 hour and the solvent removed under reduced pressure to yield the BOC derivative as a colourless oil (31 g, 91percent). [ON] (360MHz, [CDCL3)] 1.26 (3H, t, J=7. [1HZ),] 1.46 (9H, s), 1.61-1. 66 (2H, m), 1.85 (2H, m), 2.43 [(1H,] [M),] 2.83 (2H, m), 3.95-4. 05 (2H, m), 4.14 (2H, dd, J=7.1 and 14.2Hz).
89% With triethylamine In 1,4-dioxane; water at 0℃; for 2 h; To a solution of ethyl isonipecotate (20 g, 127 mmol) in dioxane:water (1:1, 120 mlL) was added triethylamine (12.87 g, 127 mmol) at 0° C. followed by di-tert-butylcarbonate (35.2 g, 161 mmol) and the resulting mixture maintained at this temperature for 2 h. The product was then extracted with ethyl acetate (3.x.100 mL) and the combined organic extracts washed with HCl (1 N, 100 mL), brine (100 miL), dried over sodium sulfate, filtered and evaporated. Purification by Kugelrohr distillation afforded the title compound (29.0 g, 89percent) as a colourless liquid, bp 140° C. at 0.13 mbar. MS: m/e=275.2 (M+NH4).
89% With triethylamine In 1,4-dioxane; water at 0℃; for 2 h; a) To a solution of ethyl isonipecotate (20 g, 127 mmol) in dioxane:water (1:1, 120 mL) was added triethylamine (12.87 g, 127 mmol) at 0° C. followed by di-tert-butyl dicarbonate (35.2 g, 161 mmol) and the resulting mixture maintained at this temperature for 2 h. The product was then extracted with ethyl acetate (3.x.100 mL) and the combined organic extracts washed with HCl (1 N, 100 mL), brine (100 mL), dried over sodium sulfate, filtered and evaporated. Purification by Kugelrohr distillation afforded the title compound (29.0 g, 89percent) as a colourless liquid, bp 140° C. at 0.13 mbar. MS: m/e=275.2 (M+NH4).
88% at 0 - 25℃; for 24 h; At about 0° C., di-tert-butyl dicarbonate (4.56 g, 20.92 mmol, 1.10 equiv) was added in several batches to a solution of ethyl piperidine-4-carboxylate (3.14 g, 19.97 mmol, 1.00 equiv) and ethyl acetate (40 mL).
The resulting solution was stirred at 0-25° C. for about 24 hours, and then concentrated in vacuo.
The resulting residue was purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether 4:1) to give the title product as a colorless oil (4.5 g, yield 88percent).
84% With triethylamine In tetrahydrofuran at 0 - 20℃; for 16 h; 1. Synthesis of intermediate B-1: A-1 B-1 To a solution of A-1 (100 g, 0.64 mol) and Et3N (64.37 g, 0.64 mol) in THF (1000 mL) was added Boc20 (138.82 g, 0.64 mol) at 0°C, the mixture was stirred at room temperature for 16 hrs. Then the reaction mixture was poured into H20 (1000 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuum to give intermediate B-1 (138.10 g, yield: 84percent).
84% With triethylamine In tetrahydrofuran at 0 - 20℃; for 16 h; To a solution of A-1 (100 g, 0.64 mol) and Et3N (64.37 g, 0.64 mol) in THF (1000 mL) was added Boc2O (138.82 g, 0.64 mol) at 0° C., the mixture was stirred at room temperature for 16 hrs. Then the reaction mixture was poured into H2O (1000 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuum to give intermediate B-1 (138.10 g, yield: 84percent).
84% With triethylamine In tetrahydrofuran at 0 - 20℃; for 16 h; To a solution of A-1 (100 g, 0.64 mol) and Et3N (64.37 g, 0.64 mol) in THF (1000 mL) was added Boc2O (138.82 g, 0.64 mol) at 0° C., the mixture was stirred at room temperature for 16 hrs. Then the reaction mixture was poured into H2O (1000 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuum to give intermediate B-1 (138.10 g, yield: 84percent).
83.6% With sodium hydroxide In tetrahydrofuran at 20 - 45℃; for 15 h; 60 g (0.381 mol) of ethyl isonipecotate and 400 ml of THF are placed in a three-necked flask which is protected from moisture and which is under an inert atmosphere, and 18.3 g (0.458 mol) of sodium hydroxide pellets are added. A solution of 100 g (0.458 mol) of di-t-butyl dicarbonate in 170 ml of THF is added over 1 h with stirring to the suspension. The temperature reaches 45° C. The reaction mixture is left stirring for 14 h at 20-25° C. and is then poured onto 2 l of water and ice and extracted with 3 times 500 ml of ether. The organic phase is washed with 3 times 250 ml of a saturated NaCl solution, dried over Na2SO4 and concentrated. The residue is chromatographed by eluting with CH2Cl2 gradually enriched with acetone and then distilled under a vacuum of 0.09 mm Hg and at a vapour temperature of 95-102° C. 82 g are obtained (Yd=83.6percent). TLC (95/5 CH2Cl2/acetone): Rf=0.60. [0246] N.M.R.: CDCl3 1H ((ppm): 1.2-1.3 (t, 3H), 1.4 (s, 9H), 1.5-1.6 (m, 2H), 1.8-1.9 (m, 2H), 2.35-2.45 (m, 1H), 2.7-2.85 (m, 2H), 3.9-4.0 (m, 2H), 4.05-4.15 (q, 2H))
80% With triethylamine In tetrahydrofuran at 20℃; Cooling with ice Under ice-cooling, piperidine-4-carboxylic acid(20.0 g, 127 mmol), BoC2 (30 g, 140 mmol) was added toTHF (lOOmL) and triethylamine (19.2 g, 190 mmol) was slowly added dropwise.Add to the ice in the ice bath for 30 minutes, then heated to room temperature stirring overnight. The organic phase was washed with saturated brine, the organic phase was separated, dried and concentrated, and the crude product was purified by column chromatography (ΡΕ: ΕΑ = 10: 1). The organic phase was extracted with ethyl acetate and extracted with ethyl acetate.To give 1-tert-butyl-4-ethyl-piperidine-1,4-dicarboxylic acidEster (26 g, yield 80percent)

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YieldReaction ConditionsOperation in experiment
81% for 18 h; Reflux; Inert atmosphere Method ACompound 1: l-Pyrimidin-2-yl-piperidine-4-carboxylic acid ethyl esterA mixture of 2-chloropyrimidine (2.28g, 20mmol) and ethyl isonipecotate (4.72g, 30mmol) in toluene (10ml) was heated at reflux for 18 h. then cooled to RT. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organics were separated, dried, and the solvents removed in vacuo. The residue was purified by flash chromatography on silica (eluant: EtOAc/pet. ether 40/60 v/v) to yield the title compound as a colourless oil.Yield = 4.0Og, 81percent. (ESI+): [M+H]+ = 236.0
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YieldReaction ConditionsOperation in experiment
94% With sodium carbonate In dichloromethane at 0 - 20℃; for 60 h; A solution of benzyl chloroformate (95g, 0. 56mol) in dichloromethane (200ml) was added dropwise to an ice-bath-cooled, stirred mixture of ethyl isonipecotate (87G, 0. 55MOL), sodium carbonate (60g, 0. 57mol) and dichloromethane (200ml) over 70 minutes. The mixture was stirred at ambient temperature for 2.5 days and filtered though a pad of Celte. The filtrate was concentrated in vacuo. The residue was partitioned between 2M aqueous hydrochloric acid and diethyl ether. Organic layer was separated, dried (MGS04), filtered and concentrated. The residue was chromatographed on silica gel (ethyl ACETATE/ISO-HEXANE) to give the title product (152g, 94percent). lE NMR (360 MHz, CDCl3) : 5 7. 4 1-7. 27 (5H, M), 5.12 (2EI, s), 4.22-3. 99 (2H, M), 4. 14 (2H, Q, J7. 4HZ), 2.93 (2H, br T, J 11. 6HZ), 2.45 (2H, m), 1.97-1. 81 (2H, M), 1.74-1. 56 (2EI, m), 1. 25 (3H, T, J7. 4Hz).
92% With caesium carbonate In tetrahydrofuran; water at 20℃; for 18 h; EXAMPLE 38; 2-{1-[(dimethylamino)sulfonyl]-4-methylpiperidin-4-yl}-1H-benzimidazole-4-carboxamide; EXAMPLE 38A; 1-benzyl 4-ethyl piperidine-1,4-dicarboxylate A solution of ethyl piperidine-4-carboxylate (30 g) in 1:1 THF/water (300 mL) was treated with cesium carbonate (74.5 g) and benzyl chloroformate (32.2 mL) and stirred at room temperature for 18 hrs. The reaction mixture was partitioned between ethyl acetate and water and the organics concentrated. The residue was purified by flash chromatography (silica gel, ethylacetate/hexanes) to provide Example 38A (50.87 g, Yield: 92percent). MS (DCI/NH3) m/z 292 (M+H)+.
89% With pyridine In dichloromethane at 0 - 20℃; Example 1; Piperidine-1 ,4-dicarboxylic acid 1 -benzyl ester 4-ethyl ester (1); Ethyl 4-piperidinecarboxylate (99.48 g, 632,78 mmol) and pyridine (56.8 g, 696 mmol) were dissolved in dichloromethane (800 ml_) and cooled to 00C. Benzyl chloroformate (88.1 ml_, 601 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature overnight. The reaction was quenched with aqueous hydrochloric acid (1 M), extracted with dichloromethane, washed with brine, dried over sodium sulphate, filtered and concentrated to give piperidine-1 ,4-dicarboxylic acid 1- benzyl ester 4-ethyl ester (165 g, 89percent) as a yellow oil.
79.5% With triethylamine In tetrahydrofuran at 0 - 20℃; 4-Ethoxycarbonylpiperidine (1.572 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); triethylamine (2.79 ml, 20.0 mmol) and benzyl chlorocarbonate (1.71 ml, 12.0 mmol) were added dropwise while cooled with an ice water bath; and the reaction mixture was stirred at room temperature overnight.
The reaction mixture was partitioned between ethyl acetate and the saturated aqueous solution of sodium hydrogencarbonate.
The organic layer was washed with brine and dried over anhydrous sodium sulfate.
The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 3) to yield the title compound (2.315 g, 7.95 mmol, 79.5percent) as a colorless oil.
1H-NMR Spectrum (CDCl3) δ (ppm): 1.26 (3H, t, J=7.2 Hz), 1.60-1.70 (2H, m), 1.80-2.00 (2H, m), 2.46 (1H, m), 2.80-3.00 (2H, m), 4.00-4.20 (2H, m), 4.15 (2H, q, J=7.2 Hz), 5.13 (2H, s), 7.29-7.38 (5H, m).
76.4%
Stage #1: With caesium carbonate In tetrahydrofuran at 0 - 5℃; for 0.166667 h;
Stage #2: at 20 - 27℃; for 18 h;
Ethyl piperidine-4-carboxylate (3.0 g, 19.1 mmol) was dissolved in THF (15 mL) and Cs2CO3 (7.4 g, 22.9 mmol) added at OC. The resulting reaction mixture was stirred at 0 - 5°C for 10 mins, then benzyl chloroformate (3.2 g, 19.1 mmol ) was added dropwise, and the reactionmixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between H20 (100 mL) and EtOAc (200 mL), the aqueous layer was extracted with EtOAc (2 x 200 mL), the organic layers were combined, dried (Na2SO4) and the solvent was removed in vacuc. The residue was purified by column chromatography (Normal silica, mesh size: 60-120, 0percent to 10percent EtOAc in Hexane) to give 1-benzyl 4-ethyl piperidine-1,4-dicarboxylate (4.2 g, 76.4percent) as ayellow solid.
66% With triethylamine In chloroform at 0 - 20℃; Method AA: 1-benzyl 4-ethyl piperidine-1,4-dicarboxylate
Benzyl chloroformate (4.99 ml, 34.98 mmol) was added dropwise to a solution of ethyl isonipecotate (5.0 g, 31.8 mmol) and triethylamine (5.76 ml, 41.34 mmol) in chloroform (70 ml) at 0° C.
After addition, the reaction mixture was stirred at 0° C. for 1 hour, then allowed to warm up to room temperature and stirred for 18 hours.
The reaction mixture was washed with 1 M HCl twice and brine.
The solution was dried over magnesium sulfate and concentrated in vacuo.
The residue was purified on silica gel by flash column chromatography to afford the desired compound as a colourless oil (6.10 g, 66percent yield).
1H NMR (CDCl3, 400 MHz) δ 1.26 (3H, t), 1.66 (2H, dq), 1.82-1.97 (2H, m), 2.46 (1H, tt), 2.93 (2H, t), 4.02-4.19 (4H, m), 5.13 (2H, s), 7.28-7.39 (5H, m).
66% With triethylamine In chloroform at 0 - 20℃; Benzyl chloroformate (11.9 g, 70.0 mmol) was added dropwise to a solution of ethyl isonipecotate (13) (10.0 g, 63.6 mmol) and Et3N (11.5 ml, 83.0 mmol) in CHCl3 (140 mL) at 0 °C.
After addition, the reaction mixture was stirred at 0 °C for 1 h, then allowed to warm up to room temperature and stirred overnight.
The reaction mixture was washed brine, with 2 M HCl, and again with brine.
The solution was dried over magnesium sulfate and concentrated in vacuo.
The residue (6.10 g, 66percent yield) was used without further purification. 1H NMR (CDCl3, 500 MHz): δ l.26 (3H, t, J = 7.1 Hz), 1.66 (2H, dq, J = 11.6, 3.4 Hz), 1.84-1.95 (2H, m), 2.46 (1H, tt, J = 11.0, 4.0 Hz), 2.93 (2H, t, J = 10.4 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.02-4.17 (2H, m), 5.13 (2H, s), 7.28-7.39 (5H, m).
30.1 g With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 2 h; [0398] Benzyl chloroformate (29.5 mL) was added to a solution of ethyl piperidine-4-carboxylate (25.0 g) and diisopropylethylamine (55.5 mL) in THF (150 mL) at 0°C, and the resultant was stirred for 2 hours at 0°C. After an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture at room temperature, extraction thereof was performed using ethyl acetate. The obtained organic layer was sequentially washed with an aqueous saturated sodium hydrogen carbonate solution, 1 M hydrochloric acid and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column chromatography (NH, hexane/ethyl acetate), thereby obtaining the title compound (30.1 g). 1H NMR (400 MHz, CDC13) δ 1.25 (3H, t, J = 7.0 Hz), 1.58-1.73 (2H, m), 1.88 (2H, brs), 2.38-2.52 (1H, m), 2.93 (2H, t, J = 11.6 Hz), 4.01-4.19 (4H, m), 5.13 (2H, s), 7.27-7.40 (5H, m).

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YieldReaction ConditionsOperation in experiment
60% at 150℃; for 72 h; To a 250 mL salable tube was added 3,5- DI. BROMO PYRIDINE (5.00 G, 21. 1 MMOL), ethyl iso- NEPICOTATE (16.0 G, 106 mmol) and cesium carbonate (7.22 g, 22.2 mmol). THE-. tube was vented with N2 and sealed. The mixture was heated to 150°C for 72 h then cooled to ambient temperature. The crude prod- uct was dissolved in toluene and filtered. The or- ganic layer was concentrated in vacuo and the resi- due was purified by flash chromatography on silica gel eluting with 1: 1 EtOAc/Hexane to provide the title compound (3.95g, 60percent) as a light yellow oil. 1H NMR (CDCl3, 400 MHz) 5 8.21 (d, J=2.73 Hz, 1H), 8.1 (d, J=1.95 Hz, 1H), 7.3 (t, J=2.34 Hz, 1H), 4.18 (q, J=7.03, 14. 43HZ, 2H), 3.66 (m, 2H), 2.89 (m, 2H), 2.48 (m, 1H), 2.04 (m, 2H), 1.87 (m, 2H), 1.28 (t, J=7.21 Hz, 3H).
12% at 150℃; for 1 h; Microwave irradiation A stirred mixture of 3,5-dibromopyridine (0.500 g, 2.11 mmol), ethyl piperidine-4- carboxylate (1.60 g, 10.2 mmol) and cesium carbonate (0.729 g, 2.24 mmol) was heated in a microwave reactor at 150 °C for 1 hour. The reaction was cooled and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl l-(5-bromopyridin-3-yl)piperidine-4-carboxylate as a yellow oil (0.078 g, 12percent)). Using the final three steps described in Example 106, this intermediate was used to prepare the title compound. H NMR (500 MHz, CDC13) δ 8.30 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.55-7.52 (m, 2H), 7.30 (s, 1H), 7.16 (t, J = 8.5 Hz, 2H), 5.43 (s, 1H), 3.85-3.82 (m, 2H), 3.06-2.85 (m, 8H), 2.40-2.23 (m, 2H), 1.99-1.54 (m, 13H) ppm. 13C NMR (125 MHz, CDCI3) δ 173.8, 163.8, 161.8, 146.9, 139.0, 137.6, 135.8, 134.5, 128.9, 121.1, 116.0, 115.8, 59.5, 53.1, 48.6, 47.6, 46.1, 43.7, 39.2, 36.1, 28.8, 28.5, 25.1, 24.3, 24.2 ppm. Purity: > 99percent LCMS (214 nm & 254 nm); retention time 1.19 min; (M+H+) 437.3.
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  • [ 1334536-88-7 ]
Reference: [1] Patent: US2011/230459, 2011, A1,
  • 59
  • [ 1126-09-6 ]
  • [ 1208087-83-5 ]
Reference: [1] Patent: WO2013/41457, 2013, A1,
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