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[ CAS No. 138642-62-3 ] {[proInfo.proName]}

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Chemical Structure| 138642-62-3
Chemical Structure| 138642-62-3
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Product Details of [ 138642-62-3 ]

CAS No. :138642-62-3 MDL No. :MFCD01632208
Formula : C7H6BNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :NPLZNDDFVCGRAG-UHFFFAOYSA-N
M.W : 146.94 Pubchem ID :2734610
Synonyms :
Chemical Name :(2-Cyanophenyl)boronic acid

Calculated chemistry of [ 138642-62-3 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 40.98
TPSA : 64.25 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 : Yes
Log Kp (skin permeation) : -6.81 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.54
Log Po/w (WLOGP) : -0.76
Log Po/w (MLOGP) : -0.36
Log Po/w (SILICOS-IT) : -0.78
Consensus Log Po/w : -0.27

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.43
Solubility : 5.47 mg/ml ; 0.0373 mol/l
Class : Very soluble
Log S (Ali) : -1.46
Solubility : 5.09 mg/ml ; 0.0346 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.35
Solubility : 6.52 mg/ml ; 0.0444 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.68

Safety of [ 138642-62-3 ]

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 [ 138642-62-3 ]

* 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 [ 138642-62-3 ]
  • Downstream synthetic route of [ 138642-62-3 ]

[ 138642-62-3 ] Synthesis Path-Upstream   1~13

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Reference: [1] Organic Letters, 2013, vol. 15, # 11, p. 2742 - 2745
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YieldReaction ConditionsOperation in experiment
95%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium; lithium chloride In tetrahydrofuran; hexane at -50 - -10℃; for 3 h; Inert atmosphere
Stage #2: With hydrogenchloride In tetrahydrofuran; hexaneInert atmosphere
In a 300 ml flask purged with nitrogen, 7.88 g (55.8 mmol) of 2,2,6,6-tetramethylpiperidine, 2.77 g of lithium chloride (65.3 mmol: 2,2,6,6-tetramethylpiperidine To 1.17 equivalents) THF was added, 24.2 g (58.2 mmol) of a 15percent n-butyllithium hexane solution was dropped at -10 ° C. to obtain lithium 2,2,6,6-tetramethyl Piperidide solution was prepared. After cooling this solution to -50 ° C., 10.93 g (58.2 mmol) of triisopropoxyborane was added dropwise, followed by dropwise addition of 4.98 g (48.3 mmol) of benzonitrile, followed by aging at the same temperature for 3 hours did. Analysis of the reaction liquid by HPLC revealed that the areapercent of 2-cyanophenylboronic acid was 98.6percent, the areapercent was 1.38percent, 1-phenyl-1- (2,2,6,6-tetramethylpiperidine -1-yl) methyl imine as by-product was confirmed. This reaction solution was added to 38 ml of 3N HCl and hydrolyzed. 150 ml of ethyl acetate was added and stirred, The acid phase was separated. The organic phase was washed with 50 ml of 0.2 N HCl and the resultant organic phase solution was subjected to quantitative determination of 2-cyanophenylboronic acid using HPLC. As a result, 2-cyanophenylboronic acid was obtained in a yield of 95.0 percent Confirmed that it was obtained. Further, it contained 0.45percent of 1-phenyl- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine in areapercent.
Reference: [1] Patent: JP2015/160823, 2015, A, . Location in patent: Paragraph 0053
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YieldReaction ConditionsOperation in experiment
55%
Stage #1: With n-hexyllithium In tetrahydrofuran; hexane at -78 - 69℃; for 3 h; Industry scale; Cryogenic reactor
Stage #2: With sulfuric acid In water
Dissolve 2-bromobenzonitrile (melt in water bath at 65°C before use, 6.733 kg, 37.0 mol, leq) in THF (52.5 L) in a cryogenic reactor and cool to-78 °C. Add triisopropylborate (13.96 kg, 74 mol, 2 eq). Allow the mixture to cool to-78°C again. Add hexyllithium (2. 5M in hexane, 15.38 kg, 55.5 mol, 1.5 eq) over a period of 2 h (max internal temp = 69°C). After the addition, stir for 1 h at-75°C. Add the mixture (-74°C) to water (48 L, 5 °C) over a period of 15 min with stirring to give a slightly yellow emulsion (-1 °C). Warm the mixture to 23°C and stir at this temperature for 90 min. Separate the layers. Extract the aqueous layer with isopropyl acetate (24 L). Combine the organic layers and re-extract with brine (22 L). Combine the aqueous layers and acidify to pH 1 with 1M sulfuric acid (31 L). Extract the product twice with isopropyl acetate (41 L and 39 L). Combine the organic layers and stir overnight with brine (21 L) at 2°C. Collect the organic solution (90 L) and distill under reduced pressure at 50-60°C to reduce the volume to 10 L. Strip the suspension with isopropyl acetate (11 L). Add methylcyclohexane (20 L) at 25°C. Cool the suspension to-7°C. Collect the precipitated product by filtration. Wash the filter cake with a mixture of isopropyl acetate (2 L) and methylcyclohexane (4 L). Dry the filter cake on the rotovap at reduced pressure at 50°C to obtain 2.997 kg of title compound as a white powder; 55percent yield (poor yield due to some material sticking to the reactor wall). 1H NMR (solvent-dx) : .sect. 7.53 (dt, 1H, J= 1.5 Hz, 7.5 Hz), 7.62 (dt, 1H, J= 1. 5 Hz, 7.5 Hz), 7.73 (m, 2H).
Reference: [1] Patent: WO2005/40110, 2005, A1, . Location in patent: Page/Page column 88
  • 4
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YieldReaction ConditionsOperation in experiment
66%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium; magnesium; magnesium chloride In tetrahydrofuran; hexane; 1,2-dichloro-ethane at -40 - 0℃; for 3 h; Inert atmosphere
Stage #2: at -20 - 20℃; for 4 h; Inert atmosphere
Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; 1,2-dichloro-ethaneInert atmosphere
In a 200 ml flask purged with nitrogen, 0.77 g (31.7 mmol) of scaled magnesium and 65 ml of THF were added. 3.17 g (32.0 mmol) of 1,2-dichloroethane was added dropwise and the reaction was stirred for about 3 hours until all the magnesium was consumed. 9.04 g (64.0 mmol) of 2,2,6,6-tetramethylpiperidine and THF (30 ml) were placed in another 300 ml flask purged with nitrogen. The solution was cooled to -40 ° C. and 27.3 g (63.9 mmol) of a 15percent n-butyllithium hexane solution was added dropwise. After the addition, the reaction solution was warmed to 0 ° C. and stirred at the same temperature for 30 minutes. The MgCl 2 solution was added dropwise to the lithium-2,2,6,6-tetramethylpiperidide solution at 0 ° C. and the reaction mixture was stirred at 0 ° C. for 30 min, then warmed to room temperature and stirred for an additional hour. The solution was removed under reduced pressure, then 100 ml of THF was added while stirring until the salt was completely dissolved. 3.0 g (29.1 mmol) of benzonitrile was added dropwise at -20 ° C. to the prepared lithium magnesium di-2,2,6,6-tetramethyl piperidide-THF solution, aged at -20 ° C. for 3 hours , 4.54 g (43.7 mmol) of trimethoxyborane was added dropwise at the same temperature. After the dropwise addition, aging was carried out at -20 ° C. for 1 hour and then aged at room temperature for 3 hours. This reaction solution was added to 50 ml of 3 N HCl and hydrolyzed. The organic phase solution obtained by extraction three times with 50 ml of ethyl acetate was subjected to quantitative determination of 2-cyanophenylboronic acid by HPLC. As a result, it was confirmed that 2-cyanophenylboronic acid was obtained at 66.0percent confirmed. Also, it contained 0.27percent of 1-phenyl- (2,2,6,6-tetramethylpiperidin-1-yl) methyl imine.
Reference: [1] Patent: JP2015/160823, 2015, A, . Location in patent: Paragraph 0058; 0059
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YieldReaction ConditionsOperation in experiment
84.1%
Stage #1: With n-butyllithium; lithium chloride In tetrahydrofuran; hexane at -10℃; Inert atmosphere
Stage #2: at -50℃; Inert atmosphere
Stage #3: With hydrogenchloride In tetrahydrofuran; hexan-1-olInert atmosphere
In a 300 ml flask purged with nitrogen, 7.88 g (55.8 mmol) of 2,2,6,6-tetramethylpiperidine, 2.77 g of lithium chloride (65.3 mmol: 2,2,6,6-tetramethylpiperidine To 1.17 equivalents) THF was added, 24.2 g (58.2 mmol) of a 15percent n-butyllithium hexane solution was dropped at -10 ° C. to obtain lithium 2,2,6,6-tetramethyl Piperidide solution was prepared. After cooling this solution to -50 ° C., 10.93 g (58.2 mmol) of triisopropoxyborane was added dropwise, followed by dropwise addition of 4.98 g (48.3 mmol) of benzonitrile, followed by aging at the same temperature for 3 hours did. Analysis of the reaction liquid by HPLC revealed that the areapercent of 2-cyanophenylboronic acid was 98.6percent, the areapercent was 1.38percent, 1-phenyl-1- (2,2,6,6-tetramethylpiperidine -1-yl) methyl imine as by-product was confirmed. This reaction solution was added to 38 ml of 3N HCl and hydrolyzed. 150 ml of ethyl acetate was added and stirred, The acid phase was separated. The organic phase was washed with 50 ml of 0.2 N HCl and the resultant organic phase solution was subjected to quantitative determination of 2-cyanophenylboronic acid using HPLC. As a result, 2-cyanophenylboronic acid was obtained in a yield of 95.0 percent Confirmed that it was obtained. Further, it contained 0.45percent of 1-phenyl- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine in areapercent.
Reference: [1] Patent: JP2015/160823, 2015, A, . Location in patent: Paragraph 0053; 0054
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Reference: [1] Organic Letters, 2016, vol. 18, # 15, p. 3630 - 3633
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Reference: [1] Patent: US2009/184289, 2009, A1, . Location in patent: Page/Page column 4-5
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Reference: [1] Patent: US2009/184289, 2009, A1, . Location in patent: Page/Page column 3
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Reference: [1] Organic Letters, 2012, vol. 14, # 18, p. 4814 - 4817,4
[2] Patent: US2014/357886, 2014, A1,
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Reference: [1] Patent: US2009/184289, 2009, A1, . Location in patent: Page/Page column 4
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Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11667 - 11673
  • 12
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  • [ 504-63-2 ]
  • [ 172732-52-4 ]
YieldReaction ConditionsOperation in experiment
82.4% at 20℃; for 1 h; 3.69 g (48.5 mmol) of 1,3-propanediol was added to the organic phase obtained in Example 1, and the mixture was stirred at room temperature for 1 hour. After separation of the separated aqueous phase, the solvent was distilled off with an evaporator. 2 ml of toluene and 120 ml of heptane were added to the remaining oily matter to precipitate crystals. The obtained crystals were washed with 30 ml of heptane and then dried, 7.44 g (yield: 82.4percent) of 1,3-propanediol ester (2- (1,3,2-dioxaborinan-2-yl) benzonitrile) of 2-cyanophenylboronic acid was obtained. The crystal contained 0.40percent of 1-phenyl-1- (2,2,6,6-tetramethylpiperidin-1-yl) methylimine
57.2% for 20 h; Step 1: Synthesis of 2-(1,3,2-dioxaborinan-2-yl)benzonitrile
49.0 g (334 mmol) 2-cyanobenzeneboronic acid and 25.9 g (340 mmol) 1,3-propanediol were dissolved in 1 L CH2Cl2 with stirring in a 2 L round bottom flask for 20 h. The solution was then poured over a filter with suction to remove gummy solids. The filtrate was then dried with anhydrous MgSO4 to remove residual water, filtered and evaporated of solvent to give light-colored oil. The oil was then dissolved in CH2Cl2 and purified on a silica gel plug using CH2Cl2 as eluent. The product fractions were evaporated down to give the product as clear oil (35.7 g, 57.2percent yield).
57.2% for 20 h; Step 1: synthesis of 2-(1,3,2-dioxaborainan-2-yl)benzonitrile 49.0 g (334 mmol) 2-cyano-benzeneboronic acid and 25.9 g (340 mmol) 1,3-propanediol and stirred while 2 ℓ 1 ℓ round bottom flask in CH2Cl2 20 hours dongan was dissolved. Then, the solution was poured into a suction filter to remove the solids on the gum. Then, the filtrate was dried over anhydrous MgSO4 and removal of the residue, filtered, to give a lighter colored oil by evaporation of the solvent. Thereafter, the oil was dissolved in CH2Cl2, was purified using CH2Cl2 as eluent on a silica gel plug. Distilling the product fractions to obtain the product (35.7 g, 57.2percent yield) as a clear oil
20% for 24 h; Reflux 2-cyano phenyl boronic acid and 1,3 propanediol was solubilized in anhydrous toluene. The reaction mixture was refluxed in a flask equipped with a Dean-Stark apparatus. After 24 h, the reaction was concentrated under reduced pressure to give colorless oil. The crude product was purified on silica gel (DCM) to give 2-[1-3]dioxaborinan-2-yl-benzonitrile; yield: 20percent; 1H NMR (300 MHz, CDCl3) δ ppm 2.08 (t, J = 5.4 Hz, 2H), 4.21 (q, J = 5.4 Hz, 4H), 5.31 (ls, 2H), 7.45 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.53 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H). The 2-[1-3]dioxaborinan-2-yl-benzonitrile was readily solubilized in toluene (0.2 M). To this solution, compound 3e (1eq), PdCl2(dppf) (2percent) and K3PO4 (2 eq) were added. The mixture was refluxed during 2 h, then was concentrated under reduced pressure. The obtained crude product was dissolved in ethyl acetate and washed by HCl 1N. The organic layer was concentrated under reduced pressure and purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (70/30) to give 9 as a yellow powder; purity 99percent; yield: 83percent; mp: 169-170 °C; 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (t, J = 6.9 Hz, 3H), 2.10 (s, 3H), 4.23 (q, J = 6.9 Hz, 2H), 7.61 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.69 (dd, J1 = 7.8 Hz, J2 = 0.9 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.82 (td, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.82 (dd, J1 = 7.8 Hz, J2 = 0.9 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 9.13 (s, 1H), 9.95 (sl, 1H); 13C NMR (75 MHz, CDCl3) δ ppm 15.0, 23.9, 60.8, 110.2, 110.9, 119.3, 119.5, 129.3, 130.1, 130.2, 132.7, 134.5, 134.8, 137.1, 139.6, 144.2, 148.4, 162.7, 169.6; LCMS (EI (+)) m/z = 389 [M + H] +. HRMS (EI) calcd for C21H18N4O2 [M + H]+ 375.14517. Found 375.14454.

Reference: [1] Patent: JP2015/160823, 2015, A, . Location in patent: Paragraph 0056
[2] Patent: EP2243785, 2010, A1,
[3] Patent: US9281483, 2016, B2, . Location in patent: Page/Page column 93
[4] Patent: KR2016/30582, 2016, A, . Location in patent: Paragraph 0258; 0259; 0260; 0261; 0262
[5] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 3867 - 3876
[6] Patent: US2009/184289, 2009, A1, . Location in patent: Page/Page column 4
[7] Organic Letters, 2013, vol. 15, # 11, p. 2742 - 2745
[8] Patent: US2014/357886, 2014, A1, . Location in patent: Paragraph 0061; 0062
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YieldReaction ConditionsOperation in experiment
48.7% With hydrogen In methanol at 20℃; for 4 h; j00498j A solution of (2-cyanophenyl) boronic acid (300 mg, 2.0 mmol) in 20 mL of methanol was charged with Raney nickel (100 mg, 10 percent w/w). The reaction was stirred at room temperature for 4 h under hydrogen pressure 50 psi. Reaction mixture was filteredthrough pad of Celite and the solution was concentrated in vacuo resulting in 150 mg (48.7 percentyield) of title compound as a white solid. MS (ES+): m/z = 152.20, 153.40, 154.35, 155.65 [M+H] LCMS: tR= 0.76 mm.
Reference: [1] Patent: WO2015/81280, 2015, A1, . Location in patent: Paragraph 00497; 00498
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