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[ CAS No. 877399-50-3 ] {[proInfo.proName]}

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Chemical Structure| 877399-50-3
Chemical Structure| 877399-50-3
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Product Details of [ 877399-50-3 ]

CAS No. :877399-50-3 MDL No. :MFCD09831980
Formula : C13H20BrN3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :IYNZAVDBHAQODX-UHFFFAOYSA-N
M.W : 330.22 Pubchem ID :45480278
Synonyms :

Calculated chemistry of [ 877399-50-3 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.69
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 80.86
TPSA : 47.36 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.17
Log Po/w (XLOGP3) : 2.27
Log Po/w (WLOGP) : 2.84
Log Po/w (MLOGP) : 2.1
Log Po/w (SILICOS-IT) : 1.37
Consensus Log Po/w : 2.35

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.25
Solubility : 0.186 mg/ml ; 0.000565 mol/l
Class : Soluble
Log S (Ali) : -2.9
Solubility : 0.414 mg/ml ; 0.00126 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.63
Solubility : 0.776 mg/ml ; 0.00235 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.57

Safety of [ 877399-50-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 877399-50-3 ]

* 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 [ 877399-50-3 ]
  • Downstream synthetic route of [ 877399-50-3 ]

[ 877399-50-3 ] Synthesis Path-Upstream   1~8

  • 1
  • [ 2075-45-8 ]
  • [ 141699-59-4 ]
  • [ 877399-50-3 ]
YieldReaction ConditionsOperation in experiment
77% at 80℃; for 12 h; Large scale 2.08 kg of cesium carbonate,0.78 kg of 4-bromopyrazole was dissolved in 4 liters of N-methylpyrrolidone,Heated to 80 degrees,A 5 liter solution of N-methylpyrrolidone was added to 1.8 kg of compound (CZT-7)Reaction for 12 hours.Cooled to room temperature,Add 50 litersMethyl tert-butyl etherwith50 liters of water,Stir for 1 hour.After dispensing,The organic phase was washed with 20 liters of * 4 water and dried 50percentLiter of hexane and stirred at room temperature for 2 hours. Filtered and dried to give 1.35 kg of compound (CZT-8) in a yield of 77percent
58%
Stage #1: With sodium hydride In dichloromethane at 0℃; for 1 h;
Stage #2: at 110℃;
B. To a cold solution (0 °C) of 4-bromo-lH-pyrazole (14.9 g, 0.10 mol) in 80 mL of dichloromethane was added sodium hydride (8.13 g, 0.20 mol) portion wise. The mixture was stirred at 0 °C for 1 hour, followed by the addition of a solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (34.0 g, 0.12 mol) in 30 mL of N,N-dimethylformamide. The resulting mixture was heated at 110 °C overnight. Purification by column chromatography afforded tert-butyl 4-(4-bromo-lH- pyrazol-l-yl)piperidine-l-carboxylate as a yellow oil in 58percent yield (19.5 g). 1H NMR (400 MHz, CDC13) δ 7.48 (s, 1H), 7.44 (s 1H), 4.35-4.20 (m, 3H), 2.95-2.85 (m, 2H), 2.15-2.05 (m, 2H), 1.92-1.81 (m, 2H), 1.48 (s, 9H).
45%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 100℃;
To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0° C., was slowly added NaH (60percent in mineral oil) (3.13 g, 78.133 mmol).
The solution was stirred for 1 hour at 0° C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g, 71.03 mmol) was added slowly and the reaction was heated to 100° C. overnight or until consumption of the pyrazole by NMR.
The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc.
The combined extracts were washed with saturated aqueous NaCl (4*20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil.
The oil was purified using silica gel chromatography eluding with 10percent EtOAc/hexanes to 25percent EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45percent yield) with a Rf=0.4 (25percent EtOAc/hexanes, using iodine as the stain).
1H NMR (CDCl3, 400 MHz) δ 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.47 (s, 9H).
45%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h;
Stage #2: at 100℃;
To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0°C, was slowly added NaH (60percent in mineral oil) (3.13 g, 78.133 mmol). The solution was stirred for 1 hour at 0°C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g , 71.03 mmol) was added slowly and the reaction was heated to 100°C overnight or until consumption of the pyrazole by NMR. The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCI (4 x 20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil. The oil was purified using silica gel chromatography eluting with 10percent EtOAc/hexanes to 25percent EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45percent yield) with a R^= 0.4 (25percent EtOAc/hexanes, using iodine as the stain). 1H NMR (CDCI3, 400 MHz) 8 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88(m, 2H), 1.47(s, 9H).

Reference: [1] Patent: CN106317024, 2017, A, . Location in patent: Paragraph 0060; 0061
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4092 - 4108
[3] Patent: WO2015/81257, 2015, A2, . Location in patent: Page/Page column 81
[4] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[5] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 64-65
[6] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 74; 75
[7] Patent: WO2008/148867, 2008, A2, . Location in patent: Page/Page column 51-52
[8] Patent: WO2010/48131, 2010, A1, . Location in patent: Page/Page column 54
[9] Patent: WO2013/53983, 2013, A1, . Location in patent: Page/Page column 31
[10] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[11] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0136
[12] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[13] Patent: WO2009/150240, 2009, A1, . Location in patent: Page/Page column 119
  • 2
  • [ 109384-19-2 ]
  • [ 877399-50-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[2] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[3] Patent: US2015/11548, 2015, A1,
[4] Patent: WO2015/81257, 2015, A2,
[5] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[6] Patent: CN106317024, 2017, A,
[7] Patent: WO2013/53983, 2013, A1,
  • 3
  • [ 5382-16-1 ]
  • [ 877399-50-3 ]
Reference: [1] Patent: US2015/11548, 2015, A1,
[2] Patent: WO2013/53983, 2013, A1,
  • 4
  • [ 24424-99-5 ]
  • [ 877399-50-3 ]
Reference: [1] Patent: US2015/11548, 2015, A1,
[2] Patent: WO2013/53983, 2013, A1,
  • 5
  • [ 877399-50-3 ]
  • [ 73183-34-3 ]
  • [ 877399-74-1 ]
YieldReaction ConditionsOperation in experiment
81% With isopropylmagnesium chloride In tetrahydrofuran at -10 - 30℃; for 9 h; Inert atmosphere; Large scale 1.3 kg of compound (CZT-8) was dissolved in 6.5 liters of dry tetrahydrofuran,Nitrogen protection,Down to -10 degrees,A solution of 3.2 liters of 2N isopropylmagnesium chloride in tetrahydrofuran was slowly added,After the completion of heating to 20 degrees,Add 1.0 publicjinEven boronic acid6.5 liters of tetrahydrofuran solution,Control the temperature between 20 degrees to 30 degrees,After the completion of the reaction at room temperature for 9 hours.Add 9 liters of ethyl acetate and 10 liters of water,Stir for 2 hours,Dispensing,Dried and concentrated.Recrystallization gave 1.2 kg of a white solid(CZT-9). Yield 81percent
44% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 0.166667 h; Inert atmosphere C. A mixture of tert-butyl 4-(4-bromo- lH-pyrazol- 1 -yl)piperidine- 1-carboxylate (20.0 g, 0.61 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (30.8 g, 0.12 mmol) and potassium acetate (17.8 g, 0.18 mol) in 50 mL of dimethyl sulfoxide was purged with nitrogen gas for 10 min. After the addition of [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.55 g, 4.85 mmol), the mixture was purged with nitrogen gas for another 10 minutes, heated at 80 °C overnight under nitrogen atmosphere and filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and removal of the solvent, the residue was purified by column chromatograph eluted with hexane to afford an oil which was recrystallized from hexane to afford tert-butyl 4-(4-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate as a white solid in 44percent yield (10 g). 1H NMR (400 MHz, CDC13) δ 7.79 (s, 1H), 7.72 (s, 1H), 4.32-4.13 (m, 3H), 2.95-2.80 (m, 2H), 2.15-2.05 (m, 2H), 1.93-1.82 (m, 2H), 1.47 (s, 9H), 1.31 (s, 12H).
5.4 g With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 12 h; Inert atmosphere; Sealed tube d) tert-Butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine- 1 -carboxylateTo a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- (1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10 percent ethyl acetate in hexane) to give the product in 59 percent yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3[(M+H]+ (RT: 1.83 min).
5.4 g With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 110℃; for 12 h; Inert atmosphere To a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b).
The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10percent ethyl acetate in hexane) to give the product in 59percent yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3 [(M+H]' (RT: 1.83 min).

Reference: [1] Patent: CN106317024, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065'; 0066
[2] Patent: WO2015/81257, 2015, A2, . Location in patent: Page/Page column 81-82
[3] Patent: WO2010/48131, 2010, A1, . Location in patent: Page/Page column 54-55
[4] Patent: WO2013/53983, 2013, A1, . Location in patent: Page/Page column 31; 32
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[6] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0137
[7] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
  • 6
  • [ 877399-50-3 ]
  • [ 61676-62-8 ]
  • [ 877399-74-1 ]
YieldReaction ConditionsOperation in experiment
51% With n-butyllithium In tetrahydrofuran; hexane at -70 - 20℃; for 3 h; To a stirred solution of tert-butyl 4-(4-bromo-lH-pyrazol-1-yl)piperidine-1-carboxylate (25.0g, 0.076 mole) in THF ( 500 ml) at- 70°C was added BuLi 1.6 Min Hexane solution (10 56.75 ml, 0.091 mole) dropwise followed by addition of 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.52 ml , 0.091 mole) at same temperature. Reaction mixture wasstirred at -70°C for lh then warmed to room temperature and continued stirring for 2h atroom temperature. Reaction mixture was quenched with ammonium chloride solution (25 ml)water (500 ml), and ethyl acetate (750 ml) was added to reaction mixture, followed by15 extraction with ethylacetate (100 ml x 2). The combined organic layer was washed withbrine, concentrated under vacuum to get crude product which was crystallized from nHeptaneto give pure title compound.Yield: 51 percent (14.7g)HPLC Purity: 96.7percent20 MS (m/z): 378 (M + 1) 1HNMR (400 MHz, CDCh) 8: 7.81 (s, lH), 7.75 (s, lH), 4.27 (m, 3H), 2.9 (m, 2H), 2.14 (m,2H), 1.91 (m, 2H), 1.49 (s, 9H), 1.33 (s, 12 H).
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[2] Patent: WO2014/20467, 2014, A2, . Location in patent: Page/Page column 20
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  • [ 877399-50-3 ]
  • [ 1195-66-0 ]
  • [ 877399-74-1 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
  • 8
  • [ 877399-50-3 ]
  • [ 185990-03-8 ]
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Reference: [1] Chemical Science, 2015, vol. 6, # 5, p. 2943 - 2951
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