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[ CAS No. 374930-88-8 ] {[proInfo.proName]}

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Chemical Structure| 374930-88-8
Chemical Structure| 374930-88-8
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Product Details of [ 374930-88-8 ]

CAS No. :374930-88-8 MDL No. :MFCD07375175
Formula : C13H19BrN4O2 Boiling Point : -
Linear Structure Formula :- InChI Key :UKCBGXCNXOKVTF-UHFFFAOYSA-N
M.W : 343.22 Pubchem ID :21914476
Synonyms :

Calculated chemistry of [ 374930-88-8 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.62
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 86.93
TPSA : 58.56 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) : -6.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.2
Log Po/w (XLOGP3) : 2.01
Log Po/w (WLOGP) : 1.53
Log Po/w (MLOGP) : 1.51
Log Po/w (SILICOS-IT) : 1.26
Consensus Log Po/w : 1.9

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.19
Solubility : 0.22 mg/ml ; 0.000642 mol/l
Class : Soluble
Log S (Ali) : -2.87
Solubility : 0.466 mg/ml ; 0.00136 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.15
Solubility : 0.242 mg/ml ; 0.000706 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.68

Safety of [ 374930-88-8 ]

Signal Word:Warning Class:
Precautionary Statements:P280-P305+P351+P338 UN#:
Hazard Statements:H317-H319 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 374930-88-8 ]

* 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 [ 374930-88-8 ]
  • Downstream synthetic route of [ 374930-88-8 ]

[ 374930-88-8 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 374930-88-8 ]
  • [ 73183-34-3 ]
  • [ 470478-90-1 ]
Reference: [1] Patent: WO2009/74812, 2009, A1, . Location in patent: Page/Page column 53-54
  • 2
  • [ 32779-36-5 ]
  • [ 57260-71-6 ]
  • [ 374930-88-8 ]
YieldReaction ConditionsOperation in experiment
88.7% With potassium carbonate In 1,4-dioxane at 110℃; for 12 h; To 1,4-dioxane (30 mL) were added tert-butyl piperazine-1-carboxylate (2.89 g, 15.51 mmol), 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol) and potassium carbonate (2.86 g, 20.68 mmol) sequentially. The mixture was heated to 110 °C, after stirring for 12 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (3.15 g, 88.7percent).MS (ESI, pos. ion)m/z: 343.1 [M+H] and‘HNMR(400IVIHz, CDC13): (ppm) 8.29 (s, 2H), 3.83-3.66 (m, 4H), 3.56-3.41 (m, 4H), 1.48 (s, 9H).
87.7% With potassium carbonate In acetonitrile at 80℃; To a solution of commercially available S-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CH3CN (100 mL) was added compound i-Boc-piperazine (9.25 g, 50 mmol) and K2003 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 00 overnight. Then, the reaction mixture was concentrated under vacuo andextracted with EA and washed with water, dried by Na2SO4 and concentrated under vacuo to give the KR-7 (15 g 87.7percent yield). ESI-MS (Mi-i): 343, 345calc. for C13H19BrN4O2: 342.1.
87.7% With potassium carbonate In acetonitrile at 80℃; Preparation of reagents Preparation of reagent KR-1 : 1 - e/t-Butoxycarbonyl-4-(5-bromopyrimidin-2- vQpiperazine To a solution of commercially available 5-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CH3CN (100 mL) was added compound 1 -Boc-piperazine (9.25 g, 50 mmol) and K2CO3 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 °C overnight. Then, the reaction mixture was concentrated under vacuo and extracted with EA and washed with water, dried by Na2SO4 and concentrated under vacuo to give the KR-1 (15 g 87.7percent yield). ESI-MS (M+1 ): 343, 345 calc. for Ci3H19BrN4O2: 342.1.
84.5% With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h; To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g,51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). Theformed precipitate was filtered and washed with diethyl ether (50 mL) to afford the titleproduct. Yield: 84.5percent (15 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.49(s, 2H),3.69 (t, J = 5.2 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 1.42 (5, 9H). LCMS: (Method A) 345.23 (M+2), Rt. 4.92 mm, 99.6percent (Max).
84.5% With triethylamine In N,N-dimethyl-formamide at 80℃; for 14 h; To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). The formed precipitate was filtered and washed with diethyl ether (50 mL) to afford the title product. Yield: 84.5percent (15 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 2H), 3.69 (t, J = 5.2 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 1.42 (s, 9H). LCMS: (Method A) 345.23 (M +2), Rt. 4.92 min, 99.6percent (Max).
80% With potassium carbonate In 1,4-dioxane for 1.5 h; Reflux To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h. The reaction was cooled to RT, quenched by water (500 mL) and extracted with diethyl ether (1000 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether:ethyl acetate=8:1-4:1) to give the title compound (70.5 g, 80percent) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342. found: 243 [M+H−100]+.
80% With potassium carbonate In 1,4-dioxane for 1.5 h; Reflux Step 4:
Synthesis of tert-butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate
To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h.
The mixture was diluted with water (500 mL) and extracted with diethyl ether (1000 mL*2).
The combined organic layers were dried over sodium sulfate, filtered and concentrated.
The residue was purified with silica gel chromatography (elute: hexane:ethyl acetate=8:1 to 4:1) to give tert-butyl 4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (70.5 g, 80percent) as a white solid. MS (ES+) C13H19BrN4O2 requires: 342, found: 243 [M+H-100]+.
78% With potassium carbonate In 1,4-dioxane at 20℃; for 4 h; Reflux To a solution of 5-bromo-2-chloro-pyrimidine (0.5 g, 2.58 mmol) in 1,4-dioxane (20 mL),tert-butyl piperazine-1-carboxylate (0.722 g, 3.88 mmol) and K2C03 (0.713 g, 5.17 mmol)were added at RT. The reaction mixture was refluxed for 4 h (TLC indicated complete consumption of starting material). The reaction mixture was brought toRT, diluted withwater (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts werewashed with water (2 x 40 mL), brine (1 x 40 mL), dried over Na2S04 and concentratedunder reduced pressure to give the residue. The residue was further purified by columnchromatography (100-200 silica gel, 15 g, 10percent EtOAc-Hexane) to afford tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-l-carboxylate (0.7 g, 78percent) as a white solid.1H NMR [400 MHz, CDCh]: J 8.29 (s, 2H), 3.75 (t, J = 4.8 Hz, 4H), 3.47 (t, J = 5.2 Hz,4H), 1.47 (s, 9H).LCMS: m/z: 287.44 [M-tBut.
76% With triethylamine In N,N-dimethyl-formamide at 90℃; for 8 h; To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent EtOAc in pet ether) to afford the title compound. Yield: 76percent (7 g, white). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3,37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 min, 99.05percent (Max).
76% With triethylamine In N,N-dimethyl-formamide at 90℃; for 8 h; To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent EtOAc in pet ether) to afford the title compound. Yield: 76percent (7 g, white). 1H NMR (400 MHz, DMSO-d6): 6 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3,37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 mm, 99.05percent (Max).

Reference: [1] Patent: WO2016/192657, 2016, A1, . Location in patent: Page/Page column 50
[2] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 54; 55
[3] Patent: WO2016/20307, 2016, A1, . Location in patent: Page/Page column 44
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
[5] Patent: WO2017/144633, 2017, A1, . Location in patent: Page/Page column 109
[6] Patent: WO2017/144639, 2017, A1, . Location in patent: Page/Page column 94
[7] Patent: US2015/111887, 2015, A1, . Location in patent: Paragraph 0282; 0283
[8] Patent: US2015/111857, 2015, A1, . Location in patent: Paragraph 0159; 0166; 0167
[9] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 114; 115
[10] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 129-130
[11] Patent: WO2017/144637, 2017, A1, . Location in patent: Page/Page column 65
[12] Patent: EP1956009, 2008, A1, . Location in patent: Page/Page column 98
[13] Patent: WO2010/94126, 2010, A1, . Location in patent: Page/Page column 75
[14] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 47-48
[15] Patent: US2011/301143, 2011, A1, . Location in patent: Page/Page column 47
[16] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 20
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  • [ 374930-88-8 ]
  • [ 73183-34-3 ]
  • [ 940284-98-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5361 - 5379
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