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[ CAS No. 1000068-25-6 ] {[proInfo.proName]}

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Chemical Structure| 1000068-25-6
Chemical Structure| 1000068-25-6
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Product Details of [ 1000068-25-6 ]

CAS No. :1000068-25-6 MDL No. :MFCD11109421
Formula : C13H15BFNO4 Boiling Point : -
Linear Structure Formula :- InChI Key :GIHZCAVQMVZATP-UHFFFAOYSA-N
M.W : 279.07 Pubchem ID :44118245
Synonyms :

Calculated chemistry of [ 1000068-25-6 ]

Physicochemical Properties

Num. heavy atoms : 20
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.31
Num. rotatable bonds : 4
Num. H-bond acceptors : 5.0
Num. H-bond donors : 2.0
Molar Refractivity : 73.92
TPSA : 71.69 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) : -6.36 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 2.31
Log Po/w (WLOGP) : 1.66
Log Po/w (MLOGP) : 1.35
Log Po/w (SILICOS-IT) : -0.06
Consensus Log Po/w : 1.05

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.09
Solubility : 0.224 mg/ml ; 0.000804 mol/l
Class : Soluble
Log S (Ali) : -3.45
Solubility : 0.0982 mg/ml ; 0.000352 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.53
Solubility : 0.831 mg/ml ; 0.00298 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.95

Safety of [ 1000068-25-6 ]

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 [ 1000068-25-6 ]

* 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 [ 1000068-25-6 ]
  • Downstream synthetic route of [ 1000068-25-6 ]

[ 1000068-25-6 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 129822-45-3 ]
  • [ 1000068-25-6 ]
YieldReaction ConditionsOperation in experiment
64% With n-butyllithium; Triisopropyl borate; diisopropylamine; lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.666667 h; Step 13 - Synthesis of (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0 °C was added n-BuLi (500 mL, 1.25 mol) dropwise. The mixture was stirred at 0 °C for 40 mm. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at -78 °C for another 40 mm. The reaction wasmonitored by HPLC. When the reaction was completed, the reaction was quenched with NH4C1(sat. 500 mL). Then the mixture was adjusted to pH = 6 with 1 N HC1. Extracted with EtOAc(2000 mL) and the combined organic layers were washed with brine (500 mL), dried overNa2504, filtered and concentrated. The obtained solid was recrystallized with EtOAc and PE togive (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (93 g, yield: 64percent, whichmight be unstable at high temp. work up, store in fridge). ‘H-NMR (CDC13, 400 MHz) 7.77 (d,J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS(M+H): 280.
64% With n-butyllithium; Triisopropyl borate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 1.33333 h; To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0 °C was added n-BuLi (500 mL, 1.25 mol, 2.5 M in hexane) dropwise. The mixture was stirred at 0°C for 40 mm. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-1H-indole-1- carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed bytriisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at -78 °C for another 40 mm. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with NH4C1 (sat. 500 mL). Then the mixture was adjusted to pH = 6 with 1 N HC1. Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The obtained solid was recrystallized withEtOAc and PE to give (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (93 g, yield:64percent, store in fridge). ‘H-NMR (CDC13, 400 MHz) 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44(s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H): 280.Step 14 - Synthesis of6-chloro-2-iodopyridin-3-ol
64% With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane at -78℃; for 0.666667 h; To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0 °Cwas added n-BuLi (500 mL, 1.25 mol, 2.5 Min hexane) dropwise. The mixture was stirred at 0°C for 40 min. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by5 triisopropyl borate (231 mL, 1. 00 mol). The mixture was stirred at -78 °C for another 40 min.The reaction was monitored by HPLC. When the reaction was completed, the reaction wasquenched with NH4Cl (sat. 500 mL). Then the mixture was adjusted to pH= 6 with 1 N HCl.Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500mL), dried over Na2S04, filtered and concentrated. The obtained solid was recrystallized with10 EtOAc and PE to give (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (93 g, yield:64percent, store in fridge). 1H-NMR (CDCh, 400 MHz) 8 7.77 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.44(s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+Ht: 280.
64%
Stage #1: With n-butyllithium; Triisopropyl borate; diisopropylamine In tetrahydrofuran at -78℃; for 0.666667 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; water
To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0°C was added n-BuLi (500 mL, 1.25 mol) dropwise. The mixture was stirred at 0°C for 40 minutes. Then the mixture was cooled to -78 °C. Tert-butyl4-fluoro-1H-indole-1-carboxylate (118 g, 0.50 mol) inTHF (300 mL) was added dropwise, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at -78 °C for another 40 mm. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with NH4C1 (sat. 500 mL). Then the mixture was adjusted to pH = 6 with 1 N HC1, extracted with EtOAc (2000 mE) and the combined organic layers were washed with brine (500 mL), dried over Na2504, filtered and concentrated. Theobtained solid was recrystallized with EtOAc and PE to give (1-(tert-butoxycarbonyl)-4-fluoro-1H- indol-2-yl)boronic acid (93 g, yield: 64percent). ‘H-NMR (CDC13, 400 MHz) 7.77 (d, J 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H): 280.
64% With n-butyllithium; Triisopropyl borate; diisopropylamine In tetrahydrofuran at -78 - 0℃; for 0.666667 h; To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0°C was added n-BuLi (500 mL, 1.25 mol) dropwise. The mixture was stirred at 0°C for 40 minutes. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (118 g,0.50 mol) in THF (300 mL) was added dropwise, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at -78 °C for another 40 mm. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with NH4C1 (sat. 500 mL). Then the mixture was adjusted to pH = 6 with 1 N HC1, extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2504, filtered andconcentrated. The obtained solid was recrystallized with EtOAc and PE to give (1-(tert- butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (93 g, yield: 64percent). ‘H-NMR (CDC13, 400 MHz) 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H): 280.

Reference: [1] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1227 - 1238
[2] Patent: WO2014/123794, 2014, A1, . Location in patent: Page/Page column 36
[3] Patent: WO2014/123793, 2014, A1, . Location in patent: Page/Page column 36; 37
[4] Patent: WO2014/121416, 2014, A1, . Location in patent: Page/Page column 36; 37
[5] Patent: WO2014/205592, 2014, A1, . Location in patent: Page/Page column 55
[6] Patent: WO2014/209729, 2014, A1, . Location in patent: Page/Page column 52
[7] Patent: WO2008/14186, 2008, A1, . Location in patent: Page/Page column 46
  • 2
  • [ 5419-55-6 ]
  • [ 129822-45-3 ]
  • [ 1000068-25-6 ]
YieldReaction ConditionsOperation in experiment
76.7%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 0℃; for 2.66667 h;
Stage #2: at -78℃; for 0.666667 h;
Step 11-Synthesis of (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid
To a solution of diisopropylamine (7.5 mL, 0.11 mol) in THF (35 mL) at 0° C. was added n-BuLi (21 mL, 0.055 mol) dropwise.
The mixture was stirred at 0° C. for 40 minutes.
Then the mixture was cooled to -78° C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (5 g, 0.02 mol) in THF (13 mL) was added dropwise slowly.
After addition, the mixture was stirred at -78° C. for 2 hours.
Then triisopropyl borate (3.29 g, 0.03 mol) was added.
The mixture was stirred at -78° C. for another 40 minutes.
The reaction was monitored using TLC.
When the reaction was completed, the mixture was adjusted to pH=6 with 1 N HCl.
After extracted with EtOAc (25 mL*3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo.
The obtained solid was recrystallized with EtOAc and petroleum ether to provide (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (4.5 g, yield: 76.7percent, which might be unstable at high temp. work up, store in fridge).
1H-NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
64% With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.666667 h; To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0 °C was added n-BuLi (500 mL, 1.25 mol) dropwise. The mixture was stirred at 0 °C for 40 min. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-lH-indole-l-carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at -78 °C for another 40 min. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with H4C1 (sat. 500 mL). Then the mixture was adjusted to pH = 6 with 1 N HC1. Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2S04, filtered and concentrated. The obtained solid was recrystallized with EtOAc and PE to give (l-(tert- butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (93 g, yield: 64percent, store in fridge). 1H- MR (CDCI3, 400 MHz) δ 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
64% With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.666667 h; To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0 °C was added n-BuLi (500 mL, 1.25 mol) dropwise. The mixture was stirred at 0 °C for 40 min. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-lH-indole-l-carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at -78 °C for another 40 min. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with H4C1 (sat. 500 mL). Then the mixture was adjusted to pH = 6 with 1 N HC1. Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2S04, filtered and concentrated. The obtained solid was recrystallized with EtOAc and PE to give (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (93 g, yield: 64percent, which might be unstable at high temp, work up, store in fridge). 1H- MR (CDC13, 400 MHz) δ 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Reference: [1] Patent: US2014/213571, 2014, A1, . Location in patent: Paragraph 0800
[2] Patent: WO2014/121418, 2014, A1, . Location in patent: Page/Page column 35
[3] Patent: WO2014/121417, 2014, A1, . Location in patent: Page/Page column 38
  • 3
  • [ 387-43-9 ]
  • [ 24424-99-5 ]
  • [ 1000068-25-6 ]
Reference: [1] Patent: WO2014/123794, 2014, A1,
[2] Patent: WO2014/123793, 2014, A1,
[3] Patent: US2014/213571, 2014, A1,
[4] Patent: WO2014/121417, 2014, A1,
[5] Patent: WO2014/121418, 2014, A1,
[6] Patent: WO2014/121416, 2014, A1,
  • 4
  • [ 387-43-9 ]
  • [ 1000068-25-6 ]
Reference: [1] Patent: WO2014/205592, 2014, A1,
[2] Patent: WO2014/209729, 2014, A1,
[3] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1227 - 1238
  • 5
  • [ 24424-99-5 ]
  • [ 1000068-25-6 ]
Reference: [1] Patent: WO2014/205592, 2014, A1,
[2] Patent: WO2014/209729, 2014, A1,
[3] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1227 - 1238
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