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Chemical Structure| 118156-93-7
Chemical Structure| 118156-93-7
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Product Details of [ 118156-93-7 ]

CAS No. :118156-93-7 MDL No. :MFCD02179020
Formula : C11H19NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :CTVHINDANRPFIL-UHFFFAOYSA-N
M.W : 213.27 Pubchem ID :9964448
Synonyms :

Calculated chemistry of [ 118156-93-7 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.82
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 61.6
TPSA : 46.61 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.84 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.44
Log Po/w (XLOGP3) : 1.07
Log Po/w (WLOGP) : 1.45
Log Po/w (MLOGP) : 1.05
Log Po/w (SILICOS-IT) : 1.24
Consensus Log Po/w : 1.45

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.57
Solubility : 5.71 mg/ml ; 0.0268 mol/l
Class : Very soluble
Log S (Ali) : -1.64
Solubility : 4.88 mg/ml ; 0.0229 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.23
Solubility : 12.6 mg/ml ; 0.059 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.58

Safety of [ 118156-93-7 ]

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

Application In Synthesis of [ 118156-93-7 ]

* 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.

  • Upstream synthesis route of [ 118156-93-7 ]
  • Downstream synthetic route of [ 118156-93-7 ]

[ 118156-93-7 ] Synthesis Path-Upstream   1~13

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Reference: [1] Patent: US6562811, 2003, B1,
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YieldReaction ConditionsOperation in experiment
92%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78 - 68℃; for 0.5 h;
Stage #2: With triethylamine In dichloromethane at 20℃; for 16 h;
DMSO (0.18 mL, 2.6 mmol) in CH2Cl2 (5 niL) was added dropwise to a solution of oxalyl chloride (2M in CH2Cl2, 0.65 mL, 1.3 mmol) in CH2Cl2 (4 mL) at -78 °C. The resulting mixture was stirred at -68 0C for 15 minutes. 3-Hydroxymethyl-piperidine-l-carboxylic acid tert-butyl ester (Dean A. Wacker et al. Bioorganic Medicinal Chemistry Letters 2002, 12, 1785-1789) (0.22 g, 1.0 mmol) in CH&2Cl2 (4 mL) was added dropwise and after 15 min stirring at -78 0C, Et3N (6 mL) was added. The resulting solution was stirred at ambient temperature for 16 h. Water was added and the mixture was extracted with diethyl ether, the organic layer was dried (Na2SO4) and concentrated to give the product as an yellow oil (0.20 g, 92percent yield). This crude product was used in the next step without further purification.MS (ESI) m/z 214 (M +1).
89%
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78 - -20℃; for 0.583333 h;
Stage #2: With triethylamine In dichloromethane at -20 - 20℃; for 1 h;
Dimethylsulphoxide (1.35 ml, 18.8 mmol) was added dropwise to a solution of oxalyl chloride (1.65 ml, 18.8 mmol) in dichloromethane (20 ml) at -78° C.
When the addition was complete, the reaction was stirred for a further 15 minutes at -78° C. 1-(tert-Butoxycarbonyl)-3-(hydroxymethyl)piperidine (2.7 g, 12.6 mmol) was added and the reaction warmed to -20° C. and stirred at this temperature for 20 minutes.
Triethylamine (5.25 ml, 37.6 mmol) was added and the reaction allowed to warm to room temperature and stirred for 1 hour.
The mixture was diluted with dichloromethane and washed with water (*2).
The organic layer was dried (MgSO4) and concentrated in vacuo.
The residue was taken up in tetrahydrofuran and filtered through cotton wool.
The filtrate was evaporated in vacuo to give the title compound (2.32 g, 89percent).
δH (400 MHz, CDCl3): 9.70 (1H, s), 3.95-3.90 (1H, m), 3.66-3.63 (1H, m), 3.35-3.30 (1H, m), 3.12-3.06 (1H, m), 2.44-2.40 (1H, m), 1.97-1.93 (1H, m), 1.72-1.63 (3H, m), 1.46 (9H, s); m/z (ES+) 158 (M-tBu)+.
85.5% With Dess-Martin periodane In dichloromethane at 25℃; for 14 h; To a solution of compound 21-4-1B (1 g, 4.8 mmol) in DCM (20 mL), Dess-Martin oxidizer (6.1 g, 14.4 mmol) was added in portions, and the resulting solution was stirred at 25° C. for 14 h, followed by quenched with saturated sodium sulfite (Na2SO3) (aq., 20 mL), adjusted to pH 8 with NaHCO3 (aq.) and extracted with DCM (20 mL×3). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give compound 21-4-1 (850 mg, Yield 85.5percent) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 9.702 (s, 1H), 3.94-3.91 (d, 1H), 3.66-3.63 (d, 1H), 3.35-3.30 (m, 1H), 3.12-3.06 (m, 1H), 2.42 (s, 1H), 1.96-1.95 (d, 1H), 1.71-1.65 (m, 2H), 1.46-1.36 (m, 10H).
68.5% With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 20℃; for 2 h; Step 1.
1-BOC-3-formylpiperidine
1-BOC-3-hydroxymethylpiperidine (2.15 g, 10 mmol) and triethylamine (3.03 g, 30 mmol) were dissolved in 10 mL DMSO, 15 mL DMSO solution of SO3Py (4.77 g, 30 mmol) was added to the above mixture in dropwise and the result mixture was stirred at rt for 2 hrs.
The mixture was poured into 100 mL ice-water, extracted with EtOAc (100 mL*3), organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo.
The crude product was purified by chromatography on silica gel (PE/EtOAc 5:1) to give 1.46 g product as colorless oil (68.5percent).
1H NMR (300 MHz, CDCl3) δ: 9.70 (1H, s), 3.91-3.93 (1H, m), 3.62-3.67 (1H, m), 3.29-3.36 (1H, m), 3.05-3.13 (1H, m), 2.40-2.45 (1H, m), 1.95-1.97 (1H, m), 1.63-1.72 (1H, m), 1.49-1.59 (1H, m), 1.46 (9H, s).
80% With pyridinium chlorochromate In dichloromethane EXAMPLE 2
Synthesis of N-Boc-Piperidin-3-yl-formaldehyde (3)
To a stirred suspension of pyridinium chlorochromate (98percent, 34.0 g, 0.155 mol) and Celite (24 g) in 200 mL of dry CH2Cl2 was added N-Boc-3-piperidinemethanol (2) (22.15 g, 0.103 mol) in 30 mL of CH2Cl2 in one portion, and the mixture was stirred at room temperature overnight.
The mixture was filtered by passing through a funnel filled with 20 g of Celite.
After the solvent was removed, the remaining oily residue was purified by a flash column (silica gel; hexane:ethyl acetate, 4:1) to afford 3 as a colorless oil 17.5 g (80percent).
80% With pyridinium chlorochromate In dichloromethane EXAMPLE 2
Synthesis of N-Boc-piperidin-3-yl-formaldehyde (3)
To a stirred suspension of pyridinium chlorochromate (98percent, 34.0 g, 0.155 mol) and Celite (24 g) in 200 mL of dry CH2Cl2 was added N-Boc-3-piperidinemethanol (2) (22.15 g, 0.103 mol) in 30 mL of CH2Cl2 in one portion, and the mixture was stirred at room temperature overnight.
The mixture was filtered by passing through a funnel filled with 20 g of Celite.
After the solvent was removed, the remaining oily residue was purified by a flash column (silica gel; hexane:ethyl acetate, 4:1) to afford 3 as a colorless oil 17.5 g (80percent).

Reference: [1] Patent: WO2006/62465, 2006, A1, . Location in patent: Page/Page column 40
[2] Patent: US2004/229864, 2004, A1, . Location in patent: Page/Page column 11
[3] Patent: US2017/313683, 2017, A1, . Location in patent: Paragraph 0560-0561
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1368 - 1373
[5] Patent: US2014/31354, 2014, A1, . Location in patent: Paragraph 0421; 0422
[6] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 12, p. 1525 - 1530
[7] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 13, p. 1785 - 1789
[8] Patent: US6645980, 2003, B1,
[9] Patent: US2002/16337, 2002, A1,
[10] Patent: US6635661, 2003, B2,
[11] Patent: WO2007/12900, 2007, A1, . Location in patent: Page/Page column 20-21
[12] Patent: US2003/220341, 2003, A1, . Location in patent: Page/Page column 11-12
[13] Patent: WO2014/139328, 2014, A1, . Location in patent: Page/Page column 352
[14] Patent: CN104119341, 2018, B, . Location in patent: Paragraph 0027-0029
[15] Patent: CN104119339, 2018, B, . Location in patent: Paragraph 0028-0030
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 15, p. 4013 - 4017
[2] Patent: US6562811, 2003, B1,
[3] Patent: EP854870, 2009, B1, . Location in patent: Page/Page column 29
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 12, p. 3737 - 3741
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Reference: [1] Patent: US2004/19058, 2004, A1,
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Reference: [1] Patent: US4987132, 1991, A,
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Reference: [1] Patent: US6331545, 2001, B1,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 15, p. 4013 - 4017
[2] Patent: US2017/313683, 2017, A1,
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 15, p. 4013 - 4017
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Reference: [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 13, p. 1785 - 1789
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Reference: [1] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 13, p. 1785 - 1789
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Reference: [1] Patent: WO2014/139328, 2014, A1,
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YieldReaction ConditionsOperation in experiment
86.1% With potassium carbonate In methanol at 20℃; for 3 h; Dimethyl 1-diazo-2-oxopropylphosphonate(96 mg, 1.0 mmol) in methanol (2 mL) was added dropwise to a stirred mixture oftert-butyl3-formylpiperidine-1-carboxylate (107 mg, 0.50 mmol) and potassiumcarbonate (138 mg, 2.0 mmol) in methanol (4 mL) at room temperature. The resulting mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated to a residue.The residue was dissolved in diethyl ether (10 mL) and washed with saturatedaqueous sodium bicarbonate solution (10 mL). The aqueous phase was extractedwith ether (10 mL x 2), and the combined organic solvent was dried over sodiumsulfate, filtered, and concentrate to a crude residue. The residue was purified by silica gelchromatography (12 g) eluting with ethyl acetate in petroleum ether from 0 to30percent over 20 minutes to afford tert-butyl 3-ethynylpiperidine-1-carboxylate (90mg, yield: 86.1percent) as a colorless oil. MS(M+Na)+ = 232.2
79% With potassium carbonate In methanol at 20℃; for 3 h; The product of Description 42 (2.3 g, 10.8 mmol), potassium carbonate (3.9 g, 28 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (5.2 g, 27 mmol) were combined in methanol (15 ml) and stirred at room temperature for 3 hours.
The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and brine.
The organic layer was dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash column chromatography on silica, eluding with 2-5percent ethyl acetate/i-hexane, to give the title compound (1.77 g, 79percent).
δH (400 MHz, CDCl3): 3.89-3.78 (1H, m), 3.68-3.63 (1H, m), 2.95-2.90 (2H, m), 2.39-2.34 (1H, m), 1.99 (1H, d, J 2.3 Hz), 1.93-1.88 (1H, m), 1.66-1.61 (1H, m), 1.55-1.49 (1H, m), 1.39 (9H, s), 1.39-1.33 (1H, m).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1993 - 1996
[2] Patent: US2004/229864, 2004, A1, . Location in patent: Page/Page column 11
[3] Patent: WO2014/139328, 2014, A1, . Location in patent: Page/Page column 352
[4] Patent: WO2018/109198, 2018, A1, . Location in patent: Page/Page column 35
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YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In methanol for 2.16667 h; Cooling with ice Step 2.
1-BOC-3-ethynylpiperidine
A solution of 1-BOC-3-formylpiperidine (1.46 g, 6.85 mmol) and (diazomethyl) phosphonic acid dimethyl ester (1.79 g, 11.94 mmol) in 50 mL methanol was stirred at ice-bath for 10 min, K2CO3 (1.96 g, 14.2 mmol) was added to the above mixture and stirred at ice-bath for 2 hrs, then stirred at rt overnight.
The mixture was evaporated in vacuo, to the residue was added EtOAc and water, the organic layer was separated and water layer was extracted with EtOAc (100 mL*3).
The combined organic layers were washed with water and brine successively, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo to give 1.44 g product as colorless oil (100.0percent).
1H NMR (300 MHz, CDCl3) δ: 3.90 (1H, brs), 3.70-3.75 (1H, m), 2.95-3.02 (2H, m), 2.40-2.47 (1H, m), 2.05 (1H, d, J=2.1 Hz), 1.94-1.99 (1H, m), 1.69-1.73 (1H, m), 1.50-1.63 (2H, m), 1.46 (9H, s).
Reference: [1] Patent: US2014/31354, 2014, A1, . Location in patent: Paragraph 0296; 0421; 0422
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