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[ CAS No. 188869-05-8 ] {[proInfo.proName]}

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Chemical Structure| 188869-05-8
Chemical Structure| 188869-05-8
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Product Details of [ 188869-05-8 ]

CAS No. :188869-05-8 MDL No. :MFCD06738530
Formula : C10H16BrNO3 Boiling Point : -
Linear Structure Formula :- InChI Key :RGWGRRBHQUREDE-UHFFFAOYSA-N
M.W : 278.14 Pubchem ID :10683970
Synonyms :

Calculated chemistry of [ 188869-05-8 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 64.66
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) : -6.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.41
Log Po/w (XLOGP3) : 1.46
Log Po/w (WLOGP) : 1.58
Log Po/w (MLOGP) : 1.19
Log Po/w (SILICOS-IT) : 1.43
Consensus Log Po/w : 1.61

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.29
Solubility : 1.44 mg/ml ; 0.00517 mol/l
Class : Soluble
Log S (Ali) : -2.05
Solubility : 2.51 mg/ml ; 0.00901 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.01
Solubility : 2.7 mg/ml ; 0.00971 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.11

Safety of [ 188869-05-8 ]

Signal Word:Danger Class:8
Precautionary Statements:P264-P270-P271-P280-P303+P361+P353-P304+P340-P305+P351+P338-P310-P330-P331-P363-P403+P233-P501 UN#:3261
Hazard Statements:H302-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 188869-05-8 ]

* 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 [ 188869-05-8 ]
  • Downstream synthetic route of [ 188869-05-8 ]

[ 188869-05-8 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 79099-07-3 ]
  • [ 188869-05-8 ]
YieldReaction ConditionsOperation in experiment
78%
Stage #1: With chloro-trimethyl-silane; triethylamine In N,N-dimethyl-formamide at 75℃;
Stage #2: With N-Bromosuccinimide In tetrahydrofuran at 0 - 20℃;
At room temperature,TEA (7.7 mL, 55 mmol) wasTMSCl (3.5 mL, 27.6 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol) in DMF (30 mL).The mixture was stirred at 75 °C overnight.The reaction solution was cooled to room temperature.Cold saturated aqueous sodium bicarbonate solution (200 mL) and cold n-hexane (200 mL) were added sequentially.The organic phase was washed with saturated brine, dried over Na2SO4 and concentrated to give a crude product which was used directly in the next step.The residue was dissolved in THF (15 mL) and stirred at 0 °C for 15 min.A solution of NBS (4.47 g, 25 mmol) in THF (80 mL) was slowly added dropwise.After the dropwise addition, the reaction was stirred at room temperature overnight.Water (200 mL) and n-hexane (200 mL) were added to the reaction. The organic phase was washed with saturated brine and dried over Na 2 SO 4 . The resulting crude product was concentrated on a silica gel column (60 g of silica gel, PE/EA=20/1 to 8 /1 gradient) purification,A white solid of tert-butyl 3-bromo-4-oxopiperidine-1 -carboxylate (5.56 g, 78percent) was obtained.
41% With bromine In dichloromethane at 0 - 20℃; for 0.5 h; To a solution of 141 N-(tert-Butoxycarbonyl)-4-piperidone (8g, 48.2mmol) in 60 CH2Cl2 (80mL) was added dropwise a solution of 142 bromine (7.06g, 44.17mmol) in CH2Cl2 (80mL) over a period of 1h. After addition, the reaction mixture was stirred for 0.5h at room temperature. The reaction mixture was quenched by the addition of 10percent 143 aqueous sodium bisulfite. The layers were separated, and the organic layer was washed with water and brine, dried over anhydrous Na2SO4, and filtered, and then the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate/petroleum (16mL, v/v, 1:1) to afford 18 9 as colorless solid (4.5g, 41percent). 1H NMR (300MHz, CDCl3): δ 4.35 (br, 1H), 4.03 (br, 2H), 3.50 (br, 2H), 3.03 (br, 1H), 2.43 (m, 1H), 1.52 (s, 9H).
5.56 g
Stage #1: With chloro-trimethyl-silane; triethylamine In N,N-dimethyl-formamide at 75℃;
Stage #2: With N-Bromosuccinimide In tetrahydrofuran at 0 - 20℃;
[0425] To a solution of tert-butyl4-oxopiperidine-1-carboxylate (5 g, 25 mmol) in 30 mL ofDMF at RT was added TEA (7.7 mL, 55 mmol) followed by TMSCl (3.5 mL, 27.6 mmol), thenthe mixture was stirred at 75 DC overnight. The reaction was cooled toRT, cold sat. aq. NaHC03(200 mL) was added followed by cold hexane (200 mL). The organic layer was washed withbrine, dried over Na2S04, concentrated to get the crude product directly used in the next step.The residue was dissolved in 15 mL of THF and stirred at 0 DC for 15 min. A solution of NBS(4.47 g, 25 mmol) in 80 mL of THF was added slowly. After addition, the reaction was stirred atRT overnight. Water (200 mL) was added to the reaction followed by 200 mL of hexane. Theorganic layer was washed with brine, dried over Na2S04 and concentrated to get crude productwhich was chromatographed on 60 g of silica gel using PE/EA (2011 to 811) as eluant to afford5.56 g (78percent) of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate as a white solid. 1H NMR(400 MHz, DMSO-d6) 8 4.85-4.70 (m, 1H), 4.20-4.00 (m, 1H), 3.90-3.55 (m, 3H), 2.80-2.68 (m,1H), 2.54-2.44 (m, 1H), 1.43 (s, 9H). MS (ESI) m/e [M-t-But 221.9, 224.0.
Reference: [1] ChemMedChem, 2012, vol. 7, # 12, p. 2087 - 2092
[2] Patent: TWI602818, 2017, B, . Location in patent: Paragraph 0424; 0425
[3] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 23-24, p. 5987 - 5999
[4] Patent: US6599895, 2003, B1,
[5] Patent: EP1801108, 2007, A1, . Location in patent: Page/Page column 56
[6] Patent: WO2007/95124, 2007, A2, . Location in patent: Page/Page column 63-64
[7] Patent: WO2012/29070, 2012, A1, . Location in patent: Page/Page column 13-14
[8] Patent: WO2014/173289, 2014, A1, . Location in patent: Paragraph 0422; 0424; 0425
[9] Patent: WO2016/30443, 2016, A1,
[10] Patent: WO2015/193506, 2015, A1, . Location in patent: Page/Page column 63-64
[11] Patent: EP3248968, 2017, A1,
[12] Patent: WO2008/20222, 2008, A1,
  • 2
  • [ 24424-99-5 ]
  • [ 188869-05-8 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.166667 h;
Stage #2: at 20℃;
To a solution of 1295 mg (5 mmol) 3-bromo-4-piperidone hydrobromide and 61 mg (0.5 mmol) 4-dimethyl aminopyridine in tetrahydrofurane (50 ml) was added at room temperature under nitrogen and stirring 646 mg (5 mmol) N,N-diisopropyl ethyl amine. The reaction was stirred at room temperature for 10 minutes. 1200 mg (5.5 mmol) di-tert.-butyl-dicarbonate was added and the reaction was stirred at room temperature over night. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed once with cold 1N aqueous HCl solution andonce with brine, dried over sodium sulphate, filtered and the solvent was evaporate under reduced pressure to yield 1240 mg (89percent) 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil which solidified to give a white solid. 1H NMR (CDCl3, 250 MHz): δ (ppm)=4.35 (br m, 1H), 3.98 (br m, 2H), 3.62 (br m, 2H), 3.04 (br m, 1H), 2.44 (m, 2H), 1.51 (s, 9H).
Reference: [1] Patent: US2008/280948, 2008, A1, . Location in patent: Page/Page column 18
  • 3
  • [ 211108-48-4 ]
  • [ 188869-05-8 ]
Reference: [1] Chemistry - A European Journal, 2006, vol. 12, # 32, p. 8336 - 8344
[2] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 189
[3] Patent: WO2008/20222, 2008, A1, . Location in patent: Page/Page column 110
  • 4
  • [ 24424-99-5 ]
  • [ 79099-07-3 ]
  • [ 188869-05-8 ]
YieldReaction ConditionsOperation in experiment
36%
Stage #1: With bromine In dichloromethane at 0℃; for 6 h;
Stage #2: at 0℃; for 2 h;
To the stuffing solution of tert-butyl 4-oxopiperidine-1-carboxylate (lOg, 50 mmol) in DCM 100 mL, Br2 was slowly added (8.0 g, 50 mmol) at 0 °C and the solution was stuffed at 0 °C for 6 h or until the reaction complete by TLC analysis. Na2SO3 (aq.) was then added, the mixture was extracted with DCM, organic phase was washed with aq. NaHCO3 and then separated. Boc2O (10.9g, 50 mmol) and TEA (7 ml) was then added, the resulting solution was stirred at 0 °C for a further 2h., Solvents were then evaporated and the residue used directly to the next step without further purification (5.0 g, yield: 36.0percent).
Reference: [1] Patent: WO2015/200677, 2015, A2, . Location in patent: Paragraph 00643; 00644
  • 5
  • [ 79099-07-3 ]
  • [ 188869-05-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 9, p. 1409 - 1416
  • 6
  • [ 79099-07-3 ]
  • [ 188869-05-8 ]
Reference: [1] Patent: US6051712, 2000, A,
  • 7
  • [ 24424-99-5 ]
  • [ 188869-05-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 9, p. 1409 - 1416
  • 8
  • [ 41979-39-9 ]
  • [ 188869-05-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 9, p. 1409 - 1416
  • 9
  • [ 188869-05-8 ]
  • [ 365996-06-1 ]
Reference: [1] Patent: WO2012/29070, 2012, A1,
[2] Patent: WO2015/200677, 2015, A2,
[3] Patent: WO2015/193506, 2015, A1,
  • 10
  • [ 17356-08-0 ]
  • [ 188869-05-8 ]
  • [ 365996-05-0 ]
YieldReaction ConditionsOperation in experiment
47% at 120℃; for 3 h; To the stuffing solution of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (5.0 g,18 mmol) in DMF (50 mL) was added thiourea (1.37 g, 18 mmol), resulting solution wasthen heated at 120 °C for 3h. The solvents were evaporated and the residue purified bycolumn separation to afford desired product as pale yellow oil (2.2 g, yield:47percent). LCMS:256.1 (M+1).
Reference: [1] Patent: WO2015/200677, 2015, A2, . Location in patent: Paragraph 00645; 00646
[2] Patent: WO2012/29070, 2012, A1, . Location in patent: Page/Page column 14
[3] Patent: WO2015/193506, 2015, A1, . Location in patent: Page/Page column 64
[4] Patent: WO2006/108709, 2006, A1, . Location in patent: Page/Page column 69
  • 11
  • [ 24424-99-5 ]
  • [ 17356-08-0 ]
  • [ 188869-05-8 ]
  • [ 365996-05-0 ]
Reference: [1] Patent: WO2007/95124, 2007, A2, . Location in patent: Page/Page column 63-64
  • 12
  • [ 16982-21-1 ]
  • [ 188869-05-8 ]
  • [ 1053656-51-1 ]
YieldReaction ConditionsOperation in experiment
60% With sodium hydrogencarbonate In isopropyl alcohol for 12 h; Reflux Compound 18 9 (4.0g, 14.4mmol) was dissolved in IPA (25mL). 20 Ethyl thioxamate (1.60g, 12.0mmol) and 146 NaHCO3 (2.01g, 24.0mmol) were added. The mixture was refluxed for 12h, followed by concentration. The residue was taken in 63 water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous Na2SO4 and concentrated to the desired compound (2.2g, 60percent), which is pure enough for the next step. mp: 138–140°C; 1H NMR (300MHz, CDCl3): δ 4.71(s, 2H), 4.48(q, J=12Hz, 2H,), 3.72(m, 2H), 2.96(t, J=5.4Hz, 2H), 2.41(t, J=6.3Hz, 2H), 1,51(s, 9H), 1,44(t, J=1.2Hz, 3H,); MS (ESI) m/z: 335.1 [M+Na]+.
Reference: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 23-24, p. 5987 - 5999
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 2, p. 443 - 454
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