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[ CAS No. 1016258-66-4 ] {[proInfo.proName]}

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Chemical Structure| 1016258-66-4
Chemical Structure| 1016258-66-4
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Product Details of [ 1016258-66-4 ]

CAS No. :1016258-66-4 MDL No. :MFCD15144556
Formula : C14H22N2O4 Boiling Point : -
Linear Structure Formula :- InChI Key :IEKGLZRZMZMUCH-UHFFFAOYSA-N
M.W : 282.34 Pubchem ID :57750376
Synonyms :

Calculated chemistry of [ 1016258-66-4 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.79
Num. rotatable bonds : 6
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 76.59
TPSA : 79.63 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) : -6.89 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.06
Log Po/w (XLOGP3) : 1.6
Log Po/w (WLOGP) : 1.71
Log Po/w (MLOGP) : 0.94
Log Po/w (SILICOS-IT) : 1.48
Consensus Log Po/w : 1.76

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.2
Solubility : 1.77 mg/ml ; 0.00627 mol/l
Class : Soluble
Log S (Ali) : -2.88
Solubility : 0.369 mg/ml ; 0.00131 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.06
Solubility : 2.48 mg/ml ; 0.00877 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.66

Safety of [ 1016258-66-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1016258-66-4 ]

* 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 [ 1016258-66-4 ]
  • Downstream synthetic route of [ 1016258-66-4 ]

[ 1016258-66-4 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 1016258-66-4 ]
  • [ 124-41-4 ]
  • [ 362703-34-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5910 - 5915
  • 2
  • [ 541-41-3 ]
  • [ 91419-52-2 ]
  • [ 1016258-66-4 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78℃; for 1 h;
Lithium hexamethyldisilazide (1 M 20 mL 20 mmol) was added dropwise to a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (2.1 g 10 mmol) in anhydrous THF (30 mL) at -78 . The resulting mixture was stirred at this temperature for 1 h then ethyl carbonochloridate (2.2 g 20 mmol) was added at -78 and stirred at this temperature for 1 h. The reaction was quenched with sodium bicarbonate aqueous solution (1 M 30 mL) and extracted with ethyl acetate (100 mL × 3) the combined organic layers were washed with brine (20 mL) dried over anhydrous sodium sulfate filtered and concentrated. The crude product was purified by silica column chromatography (eluting with 10-25 ethyl acetate in petroleum ether) to give product as colorless oil (2.8 g 99) . LCMS (ESI) m/z 183.1 [M-99]+.
99%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere
Stage #2: at -78℃; for 1 h; Inert atmosphere
Step 1 1-(tert-Butyl) 4-ethyl 4-cyanopiperidine-1,4-dicarboxylate (0282) Lithium hexamethyldisilazide (1 M, 20 mL, 20 mmol) was added dropwise to a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (2.1 g, 10 mmol) in anhydrous THF (30 mL) at −78° C. The resulting mixture was stirred at this temperature for 1 h, then ethyl carbonochloridate (2.2 g, 20 mmol) was added at −78° C. and stirred at this temperature for 1 h. The reaction was quenched with sodium bicarbonate aqueous solution (1 M, 30 mL) and extracted with ethyl acetate (100 mL×3), the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica column chromatography (eluting with 10-25percent ethyl acetate in petroleum ether) to give product as colorless oil (2.8 g, 99percent). LCMS (ESI) m/z: 183.1 [M-99]+.
90%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -68 - -63℃; for 1 h;
Stage #2: at -68 - 20℃; for 2 h;
Tert-butyl 4-cyanopiperidine-1-carboxylate (163 g, 775 mmol) was dissolved in THF (700 mL) and cooled to -67oC in a dry ice-ethanol bath. Lithium bis(trimethylsilyl)amide (1M in THF) (837 mL, 837 mmol) was slowly added during 40 minutes while keeping the reaction temperature below -63oC during the addition. A pale brown homogeneous solution was obtained. Stirring continued for 20 minutes at -68oC and ethyl carbonochloridate (91 g, 837 mmol) was added slowly during 1h while keeping the temperature below -59oC. The mixture was allowed to reach room temperature during 1h. The reaction mixture was diluted in MTBE (1000 mL), AcOH (50 mL) was added and the mixture was washed with water (400 mL). PH aqueous layer was ~7. The yellow organic phase was washed once again with water (500 mL) and evaporated to dryness affording 230.5 g (816 mmol) of the title product as a yellow non viscous oil. 1H NMR showed an assay of 85percent w/w, effective yield 90percent. 1H NMR (500 MHz, DMSO) δ 1.25 (3H, t, J = 7.1 Hz), 1.41 (9H, s), 1.78 – 1.86 (2H, m), 2.04 – 2.10 (2H, m), 2.86 – 3.04 (2H, brs), 3.92 – 4.03 (2H, m), 4.24 (2H, q, J = 7.1 Hz).
51.6%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃;
2 IB. 1-tert-Butyl 4-ethyl 4-cvanopiperidine-l,4-dicarboxylate; A solution of LDA (107 ml, 214.01 mmol) was added to a stirred solution of tert-butyl 4- cyanopiperidine-1-carboxylate (30 g, 142.67 mmol) in THF (250ml) at -780C, under nitrogen. The resulting solution was stirred at -78 0C for 30 minutes. Ethyl chloroformate (16.37 ml, 171.21 mmol) was added. The resulting solution was stirred and allowed to warm to room temperature. The reaction mixture was quenched with saturated NaHCCβ <n="129"/>(250 ml), extracted with DCM, and the organic layer was washed with saturated brine (100 ml) then dried over MgSO4, filtered and evaporated to afford the crude material as a orange oil. This material was purified by flash silica chromatography, elution gradient 10percent EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-tert-butyl 4- ethyl 4-cyanopiperidine-l,4-dicarboxylate (20.80 g, 51.6 percent) as a yellow oil. IH NMR (400.13 MHz, CDCl3) δ 1.33 (3H, t), 1.46 (9H, s), 1.96 - 2.00 (2H, m), 2.04 - 2.08 (2H, m), 3.12 (2H, s), 4.09 - 4.14 (2H, m), 4.29 (2H, q).
51.6%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃;
Stage #3: With water; sodium hydrogencarbonate In water
Intermediate 7: 1-tert-butyl 4-ethyl 4-cyanopiperidine-l.,4-dicarboxylateA solution of LDA (107 ml, 214.01 mmol) was added to a stirred solution of tert-butyl 4- cyanopiperidine-1-carboxylate (30 g, 143 mmol) in THF (250ml) at -780C, under nitrogen. The resulting solution was stirred at -78 0C for 30 minutes. Ethyl chloroformate (16.37 ml, <n="90"/>171.2 mmol) was added. The resulting solution was stirred and allowed to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3 (250 ml), extracted with DCM, and the organic layer was washed with saturated brine (100 ml) then dried over MgSO4, filtered and evaporated to afford the crude material as a orange oil. This material was purified by flash silica chromatography, elution gradient 10percent EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 1-tert-butyl 4-ethyl 4- cyanopiperidine-l,4-dicarboxylate (20.8 g, 51.6 percent) as a yellow oil. IH NMR (400.13 MHz, CDCl3) δ 1.33 (3H, t), 1.46 (9H, s), 1.96 - 2.00 (2H, m), 2.04 - 2.08 (2H, m), 3.12 (2H, s), 4.09 - 4.14 (2H, m), 4.29 (2H, q).
48%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.75 h;
Stage #2: at -78 - 20℃; for 6 h;
A solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.75 g, 3.57 mmol) in THF (25.0 mL) was cooled to -78° C. followed by dropwise addition of LDA (1.8 M in THF, 6.0 mL, 5.35 mmol) and stirred at the same temperature (-78° C.) for 45 min followed by addition of ethyl chloroformate (0.46 g, 4.28 mmol). The temperature of the reaction was slowly raised to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3.x.100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 7percent EtOAc:hexane to obtain the product as an orange viscous liquid (0.4 g, 48percent yield). MS: 283.14 [M+H]+.

Reference: [1] Patent: WO2015/78374, 2015, A1, . Location in patent: Page/Page column 708
[2] Patent: US2016/340309, 2016, A1, . Location in patent: Paragraph 0281; 0282; 0283
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 119 - 124
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5910 - 5915
[5] Patent: WO2008/75110, 2008, A1, . Location in patent: Page/Page column 126-127
[6] Patent: WO2009/47563, 2009, A1, . Location in patent: Page/Page column 87-88
[7] Patent: US2012/88750, 2012, A1, . Location in patent: Page/Page column 32
[8] Patent: US2015/31674, 2015, A1, . Location in patent: Paragraph 0368; 0582
  • 3
  • [ 4395-98-6 ]
  • [ 1016258-66-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5910 - 5915
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 119 - 124
[3] Patent: US2015/31674, 2015, A1,
  • 4
  • [ 24424-99-5 ]
  • [ 1016258-66-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 119 - 124
[2] Patent: US2015/31674, 2015, A1,
  • 5
  • [ 1016258-66-4 ]
  • [ 1016258-69-7 ]
YieldReaction ConditionsOperation in experiment
83% at 25℃; for 24 h; 21C. 1-tert-Butyl 4-ethyl 4-(aminomethyl)piperidine-l,4-dicarboχylate; Platinum(IV) oxide (0.724 g, 3.19 mmol) and 1-tert-butyl 4-ethyl 4-cyanopiperidine-l,4- dicarboxylate (9g, 31.88 mmol) in acetic acid (100ml) were stirred under an atmosphere of hydrogen at 5 bar and 25 0C for 1 day. The crude product was filtered through celite and the filtrate purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-tert-butyl 4-ethyl 4-(aminomethyl)piperidine-l,4- dicarboxylate (7.59 g, 83 percent) as a colourless oil.IH NMR (400.13 MHz, CDC13) δ 1.27 - 1.28 (3H, m), 1.30 - 1.37 (2H, m), 1.41 (2H, s), 1.45 (9H, s), 2.10 (2H, d), 2.78 (2H, s), 2.91 - 2.97 (2H, m), 3.89 (2H, s), 4.21 (2H, q).
83% at 25℃; for 24 h; Intermediate 8: 1-tert-butyl 4-ethyl 4-(aminomethyl)piperidine-l.,4-dicarboxylatePlatinum(IV) oxide (0.724 g, 3.19 mmol) and 1-tert-butyl 4-ethyl 4-cyanopiperidine-l,4- dicarboxylate (Intermediate 7) (9g, 31.9 mmol) in acetic acid (100ml) were stirred under an atmosphere of hydrogen at 5 bar and 25 0C for 1 day. The crude product was filtered through celite and the filtrate purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3ZMeOH and pure fractions were evaporated to dryness to afford 1-tert-butyl 4-ethyl 4- (aminomethyl)piperidine-l,4-dicarboxylate (7.59 g, 83 percent) as a colourless oil.IH NMR (400.13 MHz, CDC13) δ 1.27 - 1.28 (3H, m), 1.30 - 1.37 (2H, m), 1.41 (2H, s), 1.45 (9H, s), 2.10 (2H, d), 2.78 (2H, s), 2.91 - 2.97 (2H, m), 3.89 (2H, s), 4.21 (2H, q).
Reference: [1] Patent: WO2008/75110, 2008, A1, . Location in patent: Page/Page column 127
[2] Patent: WO2009/47563, 2009, A1, . Location in patent: Page/Page column 88
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5910 - 5915
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