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[ CAS No. 139962-95-1 ] {[proInfo.proName]}

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Chemical Structure| 139962-95-1
Chemical Structure| 139962-95-1
Structure of 139962-95-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 139962-95-1 ]

CAS No. :139962-95-1 MDL No. :MFCD01319043
Formula : C8H9BO4 Boiling Point : -
Linear Structure Formula :- InChI Key :ZSSNGMFKYFBOAG-UHFFFAOYSA-N
M.W : 179.97 Pubchem ID :2734365
Synonyms :

Calculated chemistry of [ 139962-95-1 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 48.15
TPSA : 66.76 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 : No
Log Kp (skin permeation) : -7.21 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 0.26
Log Po/w (WLOGP) : -0.81
Log Po/w (MLOGP) : -0.61
Log Po/w (SILICOS-IT) : -0.58
Consensus Log Po/w : -0.35

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.26
Solubility : 9.82 mg/ml ; 0.0546 mol/l
Class : Very soluble
Log S (Ali) : -1.22
Solubility : 10.8 mg/ml ; 0.0598 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.36
Solubility : 7.8 mg/ml ; 0.0434 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.61

Safety of [ 139962-95-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 139962-95-1 ]

* 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.

  • Downstream synthetic route of [ 139962-95-1 ]

[ 139962-95-1 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 15848-25-6 ]
  • [ 139962-95-1 ]
  • 2-benzoyl-4-methoxybenzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% With potassium carbonate; sodium iodide In N,N-dimethyl acetamide at 95℃; for 17h;
  • 2
  • [ 97511-04-1 ]
  • [ 139962-95-1 ]
  • [ 354529-43-4 ]
  • 3
  • [ 98015-07-7 ]
  • [ 139962-95-1 ]
YieldReaction ConditionsOperation in experiment
92.7% Stage #1: 2-Bromo-5-methoxybenzaldehyde ethylene glycol acetal With n-butyllithium In diethyl ether; hexane at -75℃; for 1h; Stage #2: With Triisopropyl borate In diethyl ether; hexane at 20℃; for 2.5h; Stage #3: With hydrogenchloride In diethyl ether; hexane for 1.5h; Heating; Further stages.;
81% Stage #1: 2-Bromo-5-methoxybenzaldehyde ethylene glycol acetal With n-butyllithium In diethyl ether; hexane at -78℃; for 0.75h; Stage #2: With boric acid tributyl ester at -78 - 20℃; Stage #3: With water; hydrogen cation at 25℃; for 2h;
Stage #1: 2-Bromo-5-methoxybenzaldehyde ethylene glycol acetal With n-butyllithium; Trimethyl borate In tetrahydrofuran at -100℃; Stage #2: With hydrogenchloride In tetrahydrofuran at 0℃;
Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran 2: hydrogenchloride; water

  • 4
  • [ 102020-26-8 ]
  • [ 139962-95-1 ]
  • 2-(1-undecylcarbonyl)-5-methoxybenzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; copper(I) thiophene-2-carboxylate; trifuran-2-yl-phosphane In tetrahydrofuran at 50℃; for 18h;
  • 5
  • [ 51516-96-2 ]
  • [ 139962-95-1 ]
  • 6-methoxy-2-(3-nitrophenyl)-1,2-dihydro-2,3,1-benzodiazaborin-1-ol [ No CAS ]
  • 6
  • [ 76-09-5 ]
  • [ 139962-95-1 ]
  • 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With magnesium sulfate In dichloromethane at 20℃; for 12h;
In benzene for 12h; Heating;
With magnesium sulfate In dichloromethane at 20℃; for 12h;
  • 7
  • [ 139962-95-1 ]
  • [ 681215-15-6 ]
  • [ 681215-17-8 ]
YieldReaction ConditionsOperation in experiment
65% With cesium fluoride In N,N-dimethyl-formamide for 24h;
  • 8
  • [ 139962-95-1 ]
  • [ 586-96-9 ]
  • 5-methoxy-2-phenylamino-benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: Nitrosobenzene With copper(l) chloride In N,N-dimethyl-formamide at 55℃; for 0.666667h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In N,N-dimethyl-formamide at 55℃; for 16h;
  • 9
  • [ 129265-60-7 ]
  • [ 139962-95-1 ]
  • [ 830328-51-3 ]
YieldReaction ConditionsOperation in experiment
71% With potassium carbonate In methanol; water; toluene at 85℃; for 20h;
  • 11
  • [ 927190-35-0 ]
  • [ 139962-95-1 ]
  • (+/-)-2-bis(tert-butoxycarbonyl)amino-1-(4-methyloxy-2-formylphenyl)-3-phenyl-propane-1-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With Cu(I) thiophenecarboxylate In tetrahydrofuran at 50℃; for 16h;
  • 12
  • [ 139962-95-1 ]
  • [ 958002-18-1 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; toluene at 85℃; for 4h; Intermediate 16 1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-, 1,1-dimethylethyl ester. tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85 C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf(Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried andconcentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6 50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30?100?30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50 4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70?95?70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO -d6) (400 MHz) ? 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2?), 7.06 (d, 1H, aryl H3?), 7.08 (s, 1H, aryl H6?), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
  • 13
  • [ 879498-90-5 ]
  • [ 139962-95-1 ]
  • [ 958002-18-1 ]
YieldReaction ConditionsOperation in experiment
74% With sodium carbonate; lithium chloride In ethanol; water; toluene at 85℃; for 4h; 1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-, 1,1-dimethylethyl ester. tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2.), 7.06 (d, 1H, aryl H3.), 7.08 (s, 1H, aryl H6.), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% With sodium carbonate; lithium chloride In ethanol; water; toluene at 85℃; for 4.25h; 1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-, 1,1-dimethylethyl ester. tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO -d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; toluene at 85℃; for 4h; 17 Intermediate 17; lH-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-, 1,1-dimethylethyl ester.; tert-Butyl 2-bromo-3-cyclohexyl-lH-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1 : 1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85°C for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product) = 0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC : 99.7% (RT = 6.30 min), Column : Cl 8 BDS (4.6 X 50 mm), SC-307, Mobile Phase : Gradient of 0.1% TFA in water : ACN (30 -» 100 -» 30), Flow rate 0.8 mL / min. LCMS : 98.0% (RT = 5.28 min), Column : Geneis, C18 (50X4.6 mm), Mobile Phase : Gradient of 0.1% Formic acid in water : ACN (70 -> 95 -» 70), Flow rate : 0.8 mL / min; M - I = 432.2; 1H NMR (DMSO -d6) (400 MHz) δ 1.40 - 1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84 - 1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, IH, CH of cyc.Hexyl - benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J = 4 Hz, IH, aryl H2O, 7.06 (d, IH, aryl H3'), 7.08 (s, IH, aryl H6O, 7.23 (d, IH, Indole-Hj), 7.53 (d, J = 8 Hz, IH, In(IoIe-H4), 7.70 - 7.75 (m, 2H, NH + Indole-H?), 8.06 (s, IH, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; toluene at 85℃; for 4h; 3; 17 tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water:ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% With sodium carbonate; lithium chloride In ethanol; toluene at 85℃; for 4h; 1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-, 1,1-dimethylethyl ester. tort-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% With sodium carbonate; lithium chloride In ethanol; water; toluene at 85℃; for 4.25h; 9 1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-, 1,1-dimethylethyl ester.; tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO -d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; toluene at 85℃; for 4h; Intermediate 9 1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-1,1-dimethylethyl ester. tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2,), 7.06 (d, 1H, aryl H3,), 7.08 (s, 1H, aryl H6,), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; water; toluene at 85℃; for 4h; tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; water; toluene at 85℃; for 4h; tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2), 7.06 (d, 1H, aryl H3), 7.08 (s, 1H, aryl H6), 7.23 9d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; water; toluene at 85℃; for 4h; tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; toluene at 85℃; for 4h; 17 Intermediate 17 1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-,1,1-dimethylethyl ester. tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
74% Stage #1: 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethyl ester With sodium carbonate; lithium chloride In ethanol; toluene for 0.25h; Stage #2: 2-formyl-4-methoxyphenylboronic acid In ethanol; toluene at 85℃; for 4h; 17 tert-Butyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) was dissolved in a 1:1 mixture of toluene and ethanol (720 mL) and degasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodium carbonate (720 mL, 1.0 M solution degasified separately,) and Pd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h, 2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and the reaction mixture was heated to 85° C. for 4 h. The reaction was then monitored by TLC, (Hexane-Ethyl acetate 80:20, Rf (Product)=0.55). On completion, the reaction mixture was cooled to rt and water (1.0 L) was added followed by ethyl acetate (1.0 L). The organic layer was washed with brine, and dried and concentrated under vacuum to afford the title compound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min), Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFA in water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28 min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M-1=432.2; 1H NMR (DMSO-d6) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H, t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84 (s, 3H, OCH3), 6.55 (d, J=4 Hz, 1H, aryl H2'), 7.06 (d, 1H, aryl H3'), 7.08 (s, 1H, aryl H6'), 7.23 (d, 1H, Indole-H5), 7.53 (d, J=8 Hz, 1H, Indole-H4), 7.70-7.75 (m, 2H, NH+Indole-H7), 8.06 (s, 1H, CHO).
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In 1,2-dimethoxyethane; water at 70℃; for 1h;

Reference: [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/270406, 2007, A1 Location in patent: Page/Page column 5; 28-29
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/270405, 2007, A1 Location in patent: Page/Page column 47
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2009/67108, 2009, A1 Location in patent: Page/Page column 58-59
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/130057, 2009, A1 Location in patent: Page/Page column 5; 32
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2010/216774, 2010, A1 Location in patent: Page/Page column 54-55
[6]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/188458, 2008, A1 Location in patent: Page/Page column 30-31
[7]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/171015, 2008, A1 Location in patent: Page/Page column 21
[8]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226593, 2008, A1 Location in patent: Page/Page column 21
[9]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226591, 2008, A1 Location in patent: Page/Page column 39-40
[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226590, 2008, A1 Location in patent: Page/Page column 36-37
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/227769, 2008, A1 Location in patent: Page/Page column 71
[12]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/130056, 2009, A1 Location in patent: Page/Page column 30
[13]Location in patent: scheme or table Vendeville, Sandrine; Lin, Tse-I.; Hu, Lili; Tahri, Abdellah; McGowan, David; Cummings, Maxwell D.; Amssoms, Katie; Canard, Maxime; Last, Stefaan; Van Den Steen, Iris; Devogelaere, Benoit; Rouan, Marie-Claude; Vijgen, Leen; Berke, Jan Martin; Dehertogh, Pascale; Fransen, Els; Cleiren, Erna; Van Der Helm, Liesbet; Fanning, Gregory; Van Emelen, Kristof; Nyanguile, Origène; Simmen, Kenny; Raboisson, Pierre [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4437 - 4443]
  • 14
  • [ 1026685-05-1 ]
  • [ 139962-95-1 ]
  • 2-(benzhydrylidene-amino)-5-methoxy-benzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% In N,N-dimethyl-formamide at 50℃; for 2h;
  • 15
  • [ 33301-43-8 ]
  • [ 139962-95-1 ]
  • [ 489429-47-2 ]
YieldReaction ConditionsOperation in experiment
81% With cesium fluoride In 1,2-dimethoxyethane at 120℃; for 1h; microwave irradiation;
  • 16
  • [ 90-11-9 ]
  • [ 139962-95-1 ]
  • [ 199117-07-2 ]
YieldReaction ConditionsOperation in experiment
91% With tetrabutylammonium acetate In ethanol at 120℃; for 0.333333h; microwave irradiation;
  • 17
  • [ 51958-51-1 ]
  • [ 139962-95-1 ]
  • C4H2C5H3OC10H5C2H4CH2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With tetrabutylammonium acetate In ethanol at 120℃; for 0.333333h; microwave irradiation;
  • 18
  • [ 573-17-1 ]
  • [ 139962-95-1 ]
  • [ 199117-10-7 ]
YieldReaction ConditionsOperation in experiment
93% With tetrabutylammonium acetate In ethanol at 120℃; for 0.333333h; microwave irradiation;
  • 19
  • C3H4C4H2C10H7Br [ No CAS ]
  • [ 139962-95-1 ]
  • CH2OC24H18O [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With cesium fluoride In 1,2-dimethoxyethane at 120℃; for 1h; microwave irradiation;
  • 20
  • [ 1714-29-0 ]
  • [ 139962-95-1 ]
  • [ 448287-51-2 ]
YieldReaction ConditionsOperation in experiment
78% With tetrabutylammonium acetate In ethanol at 120℃; for 0.333333h; microwave irradiation;
  • 21
  • [ 54-85-3 ]
  • [ 139962-95-1 ]
  • (E)-(2-((2-isonicotinoylhydrazineylidene)methyl)-4-methoxyphenyl)boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% In aq. acetate buffer at 100℃; for 0.0666667h; 5.2.1. (p-OMe)BSIH (E)-N′-(5-Methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide). A portion of 4-methoxy-2-formylphenylboronic acid (1 mmol, 0.180 g) was added to a nearlysaturated solution of isoniazid (1 mmol, 0.137 g) in 0.1M sodiumacetate buffer, pH 4.5. The reaction mixture was stirred over an oilbath at 100 °C for 4 min. The white insoluble product was collected viavacuum filtration, washed with diethyl ether, and dried in vacuo to givean off-white powder corresponding to (E)-(2-((2-isonicotinoylhydrazineylidene)methyl)-4-methoxyphenyl)boronic acid((p-OMe)BASIH) in 88% yield. Portions of (p-OMe)BASIH (0.5 mmol,0.150 g) and pinacol (0.5 mmol, 0.059 g) were then dissolved in DMFand added to a round bottom flask. The reaction stirred for 21 h at rtthen dried via rotary evaporation to give an off-white powder in 82%yield.
70% In methanol; acetate buffer at 100℃; for 0.0833333h;
  • 22
  • [ 67587-20-6 ]
  • [ 139962-95-1 ]
  • C19H26O4 [ No CAS ]
  • C19H26O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (S)-BINAP derivative In 1,4-dioxane at 50℃; for 12h; Title compound not separated from byproducts.;
  • 23
  • [ 139962-95-1 ]
  • [ 23326-27-4 ]
  • C13H14O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With (2S,4S)-2,4-bis(diphenylphosphino)pentane In 1,4-dioxane at 50℃; for 12h;
  • 24
  • [ 18937-79-6 ]
  • [ 139962-95-1 ]
  • C15H18O4 [ No CAS ]
  • C15H18O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (S)-BINAP derivative In 1,4-dioxane at 50℃; for 12h; Title compound not separated from byproducts.;
  • 25
  • [ 7507-86-0 ]
  • [ 139962-95-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: 89 percent / p-toluenesulfonic acid / toluene / 15 h / Heating 2.1: n-BuLi / diethyl ether; hexane / 0.75 h / -78 °C 2.2: B(OBu)3 / -78 - 20 °C 2.3: 81 percent / H2O; H+ / 2 h / 25 °C
Multi-step reaction with 2 steps 1.1: 100 percent / toluene-p-sulfonic acid / benzene / 20 h / Heating 2.1: n-BuLi / diethyl ether; hexane / 1 h / -75 °C 2.2: triisopropyl borate / diethyl ether; hexane / 2.5 h / 20 °C 2.3: 92.7 percent / aq. HCl / diethyl ether; hexane / 1.5 h / Heating
Multi-step reaction with 2 steps 1.1: tetra-N-butylammonium tribromide; orthoformic acid triethyl ester / 12 h / 65 °C 2.1: n-butyllithium / tetrahydrofuran / 0.5 h / -78 °C 2.2: -78 - 20 °C 2.3: 20 °C
Multi-step reaction with 3 steps 1: APTS / benzene 2: n-butyllithium / tetrahydrofuran 3: hydrogenchloride; water
Stage #1: 2-bromo-5-methoxy-benzaldehyde With toluene-4-sulfonic acid; ethylene glycol In toluene Reflux; Stage #2: With n-butyllithium; Triisopropyl borate In diethyl ether at -78℃; Stage #3: With hydrogenchloride In water
Multi-step reaction with 2 steps 1.1: potassium acetate / 1,4-dioxane / 8 h / 90 °C / Inert atmosphere 2.1: sodium periodate / tetrahydrofuran; water / 0.33 h / 20 °C 2.2: 2 h
Multi-step reaction with 2 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 8 h / 80 °C / Inert atmosphere 2.1: sodium periodate / tetrahydrofuran; water / 0.33 h / 20 °C 2.2: 2 h / 20 °C
Multi-step reaction with 2 steps 1.1: montmorillonite K-10 / dichloromethane / 0.5 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; cyclohexane / 1 h / -78 °C 2.2: 1 h / -78 °C 2.3: -78 - 5 °C

  • 26
  • [ 866624-50-2 ]
  • [ 139962-95-1 ]
  • 3-(2'-formyl-4'-methoxy-biphenyl-2-ylmethyl)-1H-indole-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With potassium phosphate In 1,4-dioxane at 100℃; 1.B Part B. 3-(2'-formyl-4'-methoxy-biphenyl-2-ylmethyl)-1H-indole-6-carbonitrile A mixture of the compound of Part A (0.24 g, 0.77 mmol) and 2-formyl-4-methoxyphenylboronic acid (0.17 g, 0.93 mmol) in 10 mL dioxane was treated with K3PO4 (0.41 g, 1.9 mmol). The resulting mixture was degassed followed by addition of tetrakis(triphenylphosphine)palladium (36 mg, 0.03 mmol). The reaction was then heated in 100° C. oil bath overnight. Work-up and flash chromatography provided the desired product (0.2 g, 71%). 1H-NMR (500 MHz, CDCl3) δ 3.87 (s, 3H); 3.86-3.91 (m, 2H); 6.75 (s, 1H); 7.10 (m, 1H); 7.20 (m, 4H); 7.31 (m, 2H); 7.39 (m, 2H); 7.63, (s, 1H); 8.14 (bs, 1H); 9.44 (s, 1H). LC/MS m/z 365.3/367.2 (M+H)+.
  • 27
  • [ 866624-72-8 ]
  • [ 139962-95-1 ]
  • 1-ethyl-3-(2'-formyl-4'-methoxy-biphenyl-3-ylmethyl)-1H-indole-6-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With sodium carbonate In ethanol; water; toluene at 95℃; Heating / reflux; 9.A Part A. 1-ethyl-3-(2'-formyl-4'-methoxy-biphenyl-3-ylmethyl)-1H-indole-6-carbonitrile 1-Ethyl-3-(3-Bromobenzyl)-1H-indole-6-carbonitrile (0.14 g, 0.43 mmol) was dissolved in a mixture of 5 mL toluene and 2 mL EtOH. To the solution was added 2-formyl-4-methoxyphenyl boronic acid (0.12 g, 0.64 mmol) and a 2M solution of sodium carbonate (0.43 ml, 0.86 mmol). The mixture was degassed and then tetrakis(triphenylphosphine)palladium (25 mg) was added. The reaction was heated at reflux in a 95° C. oil bath under N2 overnight. Reaction was cooled to rt, diluted with EtOAc and washed with brine. The organic layer was dried over anh. Na2SO4, filtered and evaporated. Chromatography on silica gel (hexane/ethyl acetate 4:1) provided the product (0.15 g, 90%). 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (t, J=7.25 Hz, 3H) 3.88 (s, 3H) 4.15 (q, J=7.25 Hz, 2H) 7.08 (s, 1H) 7.18 (m, 3H) 7.33 (m, 4H) 7.47 (d, J=2.64 Hz, 1H) 7.53 (d, J=8.35 Hz, 1H) 7.64 (s, 1H) 9.89 (s, 1H).
  • 28
  • [ 866624-80-8 ]
  • [ 139962-95-1 ]
  • 6-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-2'-formyl-4'-methoxy-biphenyl-3-carboxylic acid (pyridin-2-ylmethyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With potassium phosphate In 1,4-dioxane at 95℃; 25.C Part B. 2'-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-biphenyl-2-carboxylic acid ethyl ester To a round-bottomed flask was added the compound of Part A (0.348 g, 0.9 mmol), ethyl 2-bromobenzoate (0.227 g, 0.99 mmol), K3PO4 (0.477 g, 2.25 mmol) and 1,4-dioxane (15 mL). The mixture was degassed by bubbling argon for 10 min. Next tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.036 mmol) was added and the reaction was stirred at 95° C. for 24 h. After cooling the reaction to rt, it was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. Chromatography on silica gel gave 0.2 g (55%) of product as a white solid. 1H NMR (400 MHz, CDCl3) δ0.90 (t, J=7.0 Hz, 3H), 1.39 (t, J=7.2 Hz, 3H), 3.81-4.01 (m, 4H), 4.05 (q, J=7.2 Hz, 2H), 6.99 (s, 1H), 7.08-7.46 (m, 9H), 7.57 (s, 1H), 7.94-7.96 (m, 1H). HRMS calc'd for C27H25N2O2 (M+H)+: 409.1916. Found: 409.1931. Part C. 6-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-2'-formyl-4'-methoxy-biphenyl-3-carboxylic acid (pyridin-2-ylmethyl)-amide:; The compound of Part B (0.2 g, 0.42 mmol) and 2-formyl-4-methoxyphenylboronic acid (0.11 g, 0.64 mmol) were dissolved in dioxane (10 mL) and potassium phosphate (0.22 g, 1.06 mmol) was added. The mixture was degassed followed by addition of tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.016 mmol). The resulting mixture was heated in a 95° C. oil bath overnight under N2. Reaction was cooled to rt, diluted with EtOAc, and washed with water and brine. Organic layer was dried over anh. Na2SO4, filtered and evaporated. Flash chromatography on silica gel provided the product (0.18 g, 82%). LC/MS m/z 529.2 (M+H)+.
With sodium carbonate In ethanol; water; toluene at 95℃; Heating / reflux; 12.C; 201.A Part C. Example 12:; The compound of Part B was coupled to 2-formyl-4-methoxyphenylboronic acid using the procedure outlined under Example 9, Part A. The resulting aldehyde was oxidized to the corresponding acid by the procedure of Example 1, Part C. Finally the nitrile group was converted to the corresponding amidine by the procedure described under Example 1, Part D to give Example 12. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (t, J=7.39 Hz, 3H) 3.83 (s, 3H) 3.87 (d, J=6.05 Hz, 2H) 4.18 (q, J=7.39 Hz, 2H) 4.55 (d, J=6.05 Hz, 2H) 7.13 (s, 2H) 7.17 (d, J=8.07 Hz, 1H) 7.21 (s, 1H) 7.34 (m, 4H) 7.66 (s, 1H) 7.73 (m, J=10.08 Hz, 2H) 7.84 (m, 1H) 7.99 (s, 1H) 8.53 (d, J=5.38 Hz, 1H) 8.74 (s, 2H) 9.09 (t, J=5.71 Hz, 1H) 9.11 (s, 2H). HRMS calcd for C33H32N5O4: 562.2454. Found: 562.2445.; Example 201; 2'-[1-Ethyl-6-(N-hydroxycarbamimidoyl)-1H-indol-3-ylmethyl]-4-methoxy-5'-[(pyridin-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid Part A. 2'-[(6-cyano-1-ethyl-1H-indol-3-ylmethyl)]-4-methoxy-5'-[(pyridine-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid:; The compound of Example 12, Part B (0.23 g, 0.48 mmol) was coupled to 2-formyl-4-methoxyphenylboronic acid using the procedure outlined under Example 9, Part A. The resulting aldehyde (50 mg, 0.094 mmol) was then oxidized to the corresponding acid by the procedure of Example 1, Part C.
  • 29
  • tert-butyl (6AS,10AR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6AH)-carboxylate [ No CAS ]
  • barium hydroxide octahydrate [ No CAS ]
  • [ 139962-95-1 ]
  • [ 313667-20-8 ]
YieldReaction ConditionsOperation in experiment
0.280 g (41%) In 1,2-dimethoxyethane; water; ethyl acetate A Step A Step A To a solution of tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.600 g, 1.59 mmol) in DME (35 mL) was added 2-formyl-4-methoxybenzeneboronic acid (0.344 g, 1.91 mmol), tetrakis(triphenylphosphine)palladium(0) (0.110 g), barium hydroxide octahydrate (0.753 g, 2.39 mmol), and H2O (10 mL). The combined mixture was refluxed for 20 h. Once at room temperature, the mixture was taken up in H2O (300 mL) and extracted with EtOAc (3*100 mL). The combined extracts were dried over MgSO4 and stripped of solvent under reduced pressure. Purification by normal phase HPLC using 25% EtOAc in hexanes afforded 0.280 g (41%) of tert-butyl (6aS,10aR)-2-(2-formyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate.
0.280 g (41%) In 1,2-dimethoxyethane; water; ethyl acetate 305.A Step A Step A To a solution of tert-butyl(6aS,10aR)-2-bromo-4,5,7,8, 10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.600 g, 1.59 mmol) in DME (35 mL) was added 2-formyl-4-methoxybenzeneboronic acid (0.344 g, 1.91 mmol), tetrakis(triphenylphosphine)palladium(0) (0.110 g), barium hydroxide octahydrate (0.753 g, 2.39 mmol), and H2O (10 mL). The combined mixture was refluxed for 20 h. Once at room temperature, the mixture was taken up in H2O (300 mL) and extracted with EtOAc (3*100 mL). The combined extracts were dried over MgSO4 and stripped of solvent under reduced pressure. Purification by normal phase HPLC using 25% EtOAc in hexanes afforded 0.280 g (41%) of tert-butyl (6aS,10aR)-2-(2-formyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate.
  • 30
  • [ 313688-72-1 ]
  • [ 139962-95-1 ]
  • [ 313671-76-0 ]
YieldReaction ConditionsOperation in experiment
41% With sodium carbonate A Step A Step A Tert-butyl (8aS,12aR)-2-(2-formyl-4-methoxyphenyl)-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.094 g, 41%) was prepared by the general method of Example 89, step C from tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol), 2-formyl-4-methoxyphenylboronic acid (0.18 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 463 (base, M+H).
  • 31
  • [ 313669-58-8 ]
  • [ 139962-95-1 ]
  • [ 313672-05-8 ]
YieldReaction ConditionsOperation in experiment
38% With sodium carbonate A Step A Step A Tert-butyl (7aS,11aR)-2-(2-formyl-4-methoxyphenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.084 g, 38%) was prepared by the general method of Example 89, step C from tert-butyl (7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.20 g, 0.50 mmol), 2-formyl-4-methoxyphenylboronic acid (0.18 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 449 (base, M+H).
  • 32
  • [ 886041-35-6 ]
  • [ 139962-95-1 ]
  • [ 886041-36-7 ]
YieldReaction ConditionsOperation in experiment
72% With sodium carbonate In 1,4-dioxane for 1h; Heating / reflux; 1.2 To a solution of methyl 2-bromo-3-cyclohexyl-l-(l,3-dioxolan-2-ylmethyl)-lH-indole-6-carboxylate (from Step 1) in dioxane (0.1 M) were added Na2CO3 (6 eq., 2 M aqueous solution), 4-methoxy-2- formylphenylboronic acid (2 eq.) and bis(triphenylphosphine)palladium(II) dichloride (0.2 eq.). The mixture was degassed before being heated at reflux for 30 min. RP-HPLC analysis of the reaction mixture showed starting material persisted. The reaction mixture was allowed to cool and an additional 1 eq of 4-methoxy-2-formylphenylboronic acid and 0.1 eq of bis(triphenylphosphine)palladium(II) dichloride introduced. Heating at reflux was then resumed for a further 30 min. The reaction was EPO allowed to cool to RT and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc and the combined organics washed with aqueous HCl (1 N), water and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10 - 20 % gradient EtOAc/PE) to afford the title compound as a yellow foam (72 %). 1H NMR (400 MHz, DMSO-fi?6, 300 K) δ 1.10-1.24 (m, 3H), 1.60-1.80 (m, 7H), 2.30-2.39 (m, IH), 3.41- 3.48 (m, IH), 3.56-3.65 (m, 3H), 3.89 (s, 3H), 3.94 (s, 3H), 3.98 (dd, J 15.3, 4.4, IH), 4.25 (dd, J 15.3, 2.6, IH), 4.92-4.93 (m, IH), 7.40-7.46 (m, 2H), 7.49 (d, J2.2, IH), 7.70 (d, J8.8, IH), 7.85 (d, J8.8, IH), 8.21 (s, IH), 9.61 (s, IH); MS (ES+) m/z 478 (M+H)+
72% With sodium carbonate In 1,4-dioxane; water for 1h; Heating / reflux; 4.2 Step 2: methyl 3-cγclohexyl-l -( 1.3-dioxolan-2-ylmethyl)-2-(2-formyl-4-methoxyphenyl)-l H-indole-6- carboxylate; To a solution of methyl 2-bromo-3-cyclohexyl-l-(l,3-dioxolan-2-ylmethyl)-lH-indole-6-carboxylate in dioxane (0.1 M) was added Na2CO3 (6 eq, 2 M aqueous solution), 4-methoxy-2-formylphenylboronic acid (2 eq) and bis(triphenylphosphine) palladium(II) dichloride (0.2 eq). The mixture was degassed before being heated at reflux for 30 min. RP-HPLC analysis of the reaction mixture showed starting material persisted. The reaction mixture was allowed to cool and an additional 1 eq of 4-methoxy-2- formylphenylboronic acid and 0.1 eq of bis(triphenylphosphine)palladium(II) dichloride introduced. Heating at reflux was then resumed for a further 30 min. The reaction was allowed to cool to RT and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc and the combined organics washed with aqueous HCl (IN), water and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10 - 20 % gradient EtOAc/PE) to afford the title compound as a yellow foam (72 %); MS (ES+) m/z 478 (M+H)+
  • 33
  • [ 139962-95-1 ]
  • [ 762263-92-3 ]
YieldReaction ConditionsOperation in experiment
With sodium tetrahydroborate In methanol at 20℃; for 2h; 24.1 Example 24: Synthesis of 109Step 1:50 mg (0.278 mmol) 4-methoxy-2-formylphenylboronic acid (1) is desolved in methanol. 32 mg (0.834 mmol; 3 eq.) sodium borhydride are carefully added. After 2 hours of stirring at room temperature the solvent is removed in the evaporator. After adding 50 ml of saturated sodium EPO cloride solution and 50 ml ethylacetate the aquous phase is extracted three times with ethylacetate. The commbined organic phases are dried over magnesium sulphate and the solvent is removed in vacuum. The raw product is used without purification in the next reaction step.
  • 34
  • [ 494799-19-8 ]
  • [ 139962-95-1 ]
  • [ 902147-82-4 ]
YieldReaction ConditionsOperation in experiment
63% With sodium carbonate; lithium chloride In ethanol; water; toluene at 100℃; for 3h; To a slurried solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (4.3 g, 13 mmol), 4-methoxy-2-formylphenylboronic acid (3.0 g, 17 mmol) and LiCl (2.2 g, 51 mmol) in EtOH/toluene (1:1, 100 mL) was added Pd(PPh3)4 (1.4 g, 1.3 mmol) and then 1M Na2CO3 (aq.) (32 mL, 32 mmol). The reaction solution was flushed with nitrogen and heated at 100° C. for 3 h and cooled to rt. The reaction was concentrated to remove EtOH, diluted with H2O (200 mL) and extracted with EtOAc (2×150 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with CH2Cl2 and the solids were collected by filtrated and washed with Et2O and CH2Cl2 to yield methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.0 g, 8.0 mmol, 63%) as a yellow solid which was used without further purification. LCMS: m/e 374 (M+H)+, ret time 3.09 min, column B, 3 minute gradient.
63% With sodium carbonate; lithium chloride In ethanol; water; toluene at 100℃; for 3h; To a slurried solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (4.3 g, 13 mmol), 4-methoxy-2-formylphenylboronic acid (3.0 g, 17 mmol) and LiCl (2.2 g, 51 mmol) in EtOH/toluene (1:1, 100 mL) was added Pd(PPh3)4 (1.4 g, 1.3 mmol) and then 1M Na2CO3 (aq.) (32 mL, 32 mmol). The reaction solution was flushed with nitrogen and heated at 100° C. for 3 h and cooled to rt. The reaction was concentrated to remove EtOH, diluted with H2O (200 mL) and extracted with EtOAc (2×150 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with CH2Cl2 and the solids were collected by filtrated and washed with Et2O and CH2Cl2 to yield methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.0 g, 8.0 mmol, 63%) as a yellow solid which was used without further purification. LCMS: m/e 374 (M+H)+, ret time 3.09 min, column B, 3 minute gradient.
63% With sodium carbonate; lithium chloride In ethanol; water; toluene at 100℃; for 3h; The general methods below were used with the following experimental procedures until indicated otherwise: LCMS data: Stop time: Gradient time+1 minute; Starting conc: 0% B unless otherwise noted; Eluent A: 5% CH3CN/95% H2O with 10 mM NH4OAc (for columns A and D); 10% MeOH/90% H2O with 0.1% TFA (for columns B and C); Eluent B: 95% CH3CN/5% H2O with 10 mM NH4OAc (for columns A and D); 90% MeOH/10% H2O with 0.1% TFA (for columns B and C); Column A: Phenomenex 10 4.6×50 mm C18; Column B: Phenomenex C18 10 3.0×50 mm; Column C: Phenomenex 4.6×50 mm C18 10μ; Column D: Phenomenex Lina C18 5μ 3.0×50 mm; Column E: Phenomenex 5μ 4.6×5.0 mm C18. To a slurried solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (4.3 g, 13 mmol), 4-methoxy-2-formylphenylboronic acid (3.0 g, 17 mmol) and LiCl (2.2 g, 51 mmol) in EtOH/toluene (1:1, 100 mL) was added Pd(PPh3)4 (1.4 g, 1.3 mmol) and then 1M Na2CO3 (aq.) (32 mL, 32 mmol). The reaction solution was flushed with nitrogen and heated at 100° C. for 3 h and cooled to rt. The reaction was concentrated to remove EtOH, diluted with H2O (200 mL) and extracted with EtOAc (2×150 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered and concentrated to dryness. The residue was triturated with CH2Cl2 and the solids were collected by filtrated and washed with Et2O and CH2Cl2 to yield methyl 11-cyclohexyl-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxylate (3.0 g, 8.0 mmol, 63%) as a yellow solid which was used without further purification. LCMS: m/e 374 (M+H)+, ret time 3.09 min, column B, 3 minute gradient.
  • 35
  • [ 914497-91-9 ]
  • [ 139962-95-1 ]
  • [ 914497-93-1 ]
YieldReaction ConditionsOperation in experiment
57% With sodium carbonate In 1,4-dioxane; water for 0.333333h; Heating / reflux; 4.1 tert-Butyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-] pyrrole-2-carboxylate (1 eq., prepared as described in Example 1, Step 3) and 2-formyl-4-methoxyphenylboronic acid (1.5 eq.) were dissolved in dioxane (0.1 M) and treated with 2 M Na2CO3 solution (2 eq.). The solution was degassed by bubbling argon through it and Pd(PPh3)2Cl2 (0.1 eq.) was added. The reaction mixture was heated to reflux for 20 min. After cooling down to RT, the mixture was diluted with EtOAc and washed with 1 N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo and the residue purified by chromatography (PE:EtOAc, 9:1) to afford the pure title compound (57%) as a solid. 1H-NMR (400 MHz, DMSO-J6, 300 K, δ) 9.64 (s, IH), 7.89 (s, IH), 7.43 (s, IH), 7.41-7.38 (m, 2H), 4.92 (d, J 18.0, IH), 4.73 (d, J 18.0, IH), 3.90 (s, 3H), 3.50 (s, 3H), 2.14-2.09 (m, IH), 1.73-1.19 (m, 10H), 1.54 (s, 9H). MS (ES+) m/z: 534 [M+Na]+.
  • 36
  • [ 902148-40-7 ]
  • [ 139962-95-1 ]
  • [ 902148-53-2 ]
YieldReaction ConditionsOperation in experiment
88% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; lithium chloride In ethanol; toluene
With sodium carbonate; lithium chloride In ethanol; water; toluene at 85℃; for 18h; To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (4.3 g, 10 mmol), 4-methoxy-2-formylphenylboronic acid (2.5 g, 14 mmol) and LiCl (1.05 g, 25 mmol) in EtOH/toluene (1:1, 80 mL) was added Pd(PPh3)4 (1.12 g, 1.0 mmol) and then 1M Na2CO3 (aq.) (30 mL, 30 mmol). The reaction solution was flushed with nitrogen and heated at 85° C. for 18 h and cooled to rt. The reaction was diluted with EtOAc (200 mL), washed with 0.5N aqueous HCl (100 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated to yield 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamide which was used without further purification. LCMS: m/e 482 (M-H)-, ret time 1.63 min, column A, 2 minute gradient.
  • 37
  • [ 902148-40-7 ]
  • [ 139962-95-1 ]
  • [ 928844-26-2 ]
YieldReaction ConditionsOperation in experiment
99% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; potassium carbonate In toluene for 0.5h; Reflux; Inert atmosphere;
87% With potassium carbonate In toluene for 0.5h; Heating / reflux; Intermediate 4 1H-Indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-. A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2?,6?-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24g, 0.02 mol) in toluene (30 mL) was stirred under reflux under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22 C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
87% With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; for 20h; To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-(52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient. 6H-Isoindolo[2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-. To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(65.9 g) as a yellow solid. HPLC purity, 98%.
87% With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; An alternative procedure for the preparation of 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- is provided below:To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.
87% Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.166667 - 0.333333h; Stage #2: In ethanol; water; toluene at 70℃; for 20h; Intermediate 4 An alternative procedure for the preparation of 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- is provided below: To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70 C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) ? 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) ? 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient;6H-Isoindolo[2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-. To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70 C. for 20 h. After cooling to 35 C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2 1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50 C. to 0 C.) to give 3-cyclohexyl-N(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(65.9 g) as a yellow solid. HPLC purity, 98%.
87% With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; 4 An alternative procedure for the preparation of lH-indole-6-carboxamide, 3- cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- is provided below:To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1 : 1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70 0C (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with IN aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et20 (600 mL) for Ih and collected by filtration to yield lH-indole-6-carboxamide, 3- cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8g, 109 mmol, 87%) as a yellow powder which was used without further purification. IHNMR (300 MHz, d6-DMSO) δ 11.66 (s, IH), 8.17 (s, IH), 7.75 (d, J = 8.4 Hz, IH), 7.74 (d, J = 8.4 Hz, IH), 7.59 (dd, J = 1.4, 8.4 Hz, IH), 7.23 - 7.16 (m, 2H), 7.08 (dd, J = 2.6, 8.4 Hz, IH), 6.54 (d, J = 8.8 Hz, IH), 3.86 (s, 3H), 3.22 - 3.08 (m, IH), 2.91 (s, 6H), 2.00 - 1.74 (m, 7H), 1.60 - 1.38 (m, 3H). 13CNMR (75 MHz, CDC13) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M- H)", ret time 2.56 min, column A, 4 minute gradient.
87% Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.166667h; Heating / reflux; Stage #2: In ethanol; water; toluene at 70℃; for 20h; 4; 5 To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1H NMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9 (2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.Intermediate 5 6H-Isoindolo[2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-. To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.
87% With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; Inert atmosphere; To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for lh and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.
87% With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; 4 An alternative procedure for the preparation of 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- is provided below:; To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.
87% Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.166667 - 0.416667h; Stage #2: In ethanol; water; toluene at 70℃; for 20h; An alternative procedure for the preparation of 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- is provided below:To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9 (2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.; Intermediate 5 6H-Isoindolo[2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-. To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.
87% Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.166667h; Stage #2: In ethanol; water; toluene at 70℃; To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with IN aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.
87% Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.166667h; Stage #2: In ethanol; water; toluene at 70℃; To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification.1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.
87% Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.166667h; Stage #2: In ethanol; water; toluene at 70℃; To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-(52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9 (2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.
87% With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; for 20h; 4; 5 An alternative procedure for the preparation of 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- is provided below:To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2(2), 34.7, 32.0(2), 25.9(2), 24.9. LCMS: m/e 482 Intermediate 5 6H-Isoindolo[2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-. To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(65.9 g) as a yellow solid. HPLC purity, 98%.(M-H)-, ret time 2.56 min, column A, 4 minute gradient.
87% Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate; lithium chloride In ethanol; water; toluene for 0.166667h; Heating / reflux; Stage #2: In ethanol; water; toluene at 70℃; 4 To a slurried solution of 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide (54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164 mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added a solution of Na2CO3 (40.1 g, 379 mmol) in water (380 mL). The reaction mixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) was added. The reaction solution was flushed with nitrogen and heated at 70° C. (internal monitoring) overnight and then cooled to rt. The reaction was diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1N aqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered and concentrated. The residual solids were stirred with Et2O (600 mL) for 1 h and collected by filtration to yield 1H-indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)- (52.8 g, 109 mmol, 87%) as a yellow powder which was used without further purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4, 8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74 (m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8, 147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3, 110.4, 109.8, 79.6, 45.9, 37.2 (2), 34.7, 32.0 (2), 25.9 (2), 24.9. LCMS: m/e 482 (M-H)-, ret time 2.56 min, column A, 4 minute gradient.
With potassium carbonate for 0.5h; Heating / reflux; 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide;. A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 1H-Indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-. A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 1H-Indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-. A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.0 15 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 4 Intermediate 4; lH-Indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2- formyl-4-methoxyphenyl)-.; A mixture of the 2-Bromo-3-cyclohexyl- ν- [(dimethylamino)sulfonyl]-lH-indole-6-carboxamide (4.28g, 0.01 mol), 4-methoxy- 2-formylphenyl boronic acid (2.7g, 0.015 mol), 2-dicyclohexylphosphino-2',6'- dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 4 A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide. A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 4 1H-Indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-.; A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium carbonate In toluene for 0.5h; Heating / reflux; Intermediate 4 1H-Indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-. A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With lithium chloride In ethanol; toluene for 0.25h; Stage #2: With sodium carbonate In ethanol; water; toluene for 0.166667h; Stage #3: In ethanol; water; toluene at 70℃; for 20h; To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.
With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; for 20.4167h; To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.
With potassium carbonate In toluene for 0.5h; Heating / reflux; A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 4 Intermediate 4 1H-Indole-6-carboxamide, 3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-. A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
With potassium carbonate In toluene for 0.5h; Heating / reflux; 4 A mixture of the 2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide (4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015 mol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (41 mg, 0.0001 mol), palladium acetate (11.2 mg), and finely ground potassium carbonate (4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and under nitrogen for 30 min, at which time LC/MS analysis showed the reaction to be complete. The reaction mixture was then diluted with ethyl acetate and water, and then acidified with an excess of dilute HCl. The ethyl acetate layer was then collected and washed with dilute HCl, water and brine. The organic solution was then dried (magnesium sulfate), filtered and concentrated to give a gum. The gum was diluted with hexanes (250 ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at 22° C. during which time the product was transformed into a bright yellow granular solid (4.8 g) which was used directly without further purification.
Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With lithium chloride In ethanol; toluene for 0.25h; Stage #2: With sodium carbonate In ethanol; water; toluene for 0.166667h; Stage #3: In ethanol; water; toluene at 70℃; for 20h; 5 To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.

Reference: [1]Gentles, Robert G.; Ding, Min; Bender, John A.; Bergstrom, Carl P.; Grant-Young, Katharine; Hewawasam, Piyasena; Hudyma, Thomas; Martin, Scott; Nickel, Andrew; Regueiro-Ren, Alicia; Tu, Yong; Yang, Zhong; Yeung, Kap-Sun; Zheng, Xiaofan; Chao, Sam; Sun, Jung-Hui; Beno, Brett R.; Camac, Daniel M.; Chang, Chong-Hwan; Gao, Mian; Morin, Paul E.; Sheriff, Steven; Tredup, Jeff; Wan, John; Witmer, Mark R.; Xie, Dianlin; Hanumegowda, Umesh; Knipe, Jay; Mosure, Kathy; Santone, Kenneth S.; Parker, Dawn D.; Zhuo, Xiaoliang; Lemm, Julie; Liu, Mengping; Pelosi, Lenore; Rigat, Karen; Voss, Stacey; Wang, Yi; Wang, Ying-Kai; Colonno, Richard J.; Gao, Min; Roberts, Susan B.; Gao, Qi; Ng, Alicia; Meanwell, Nicholas A; Kadow, John F. [Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 1855 - 1879]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/275930, 2007, A1 Location in patent: Page/Page column 17
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/270406, 2007, A1 Location in patent: Page/Page column 23
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/270405, 2007, A1 Location in patent: Page/Page column 41-42
[5]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/275930, 2007, A1 Location in patent: Page/Page column 17; 18
[6]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2009/67108, 2009, A1 Location in patent: Page/Page column 44-45
[7]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/130057, 2009, A1 Location in patent: Page/Page column 27
[8]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2010/216774, 2010, A1 Location in patent: Page/Page column 49
[9]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/188458, 2008, A1 Location in patent: Page/Page column 29
[10]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/171015, 2008, A1 Location in patent: Page/Page column 19
[11]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226593, 2008, A1 Location in patent: Page/Page column 15-16
[12]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226591, 2008, A1 Location in patent: Page/Page column 34
[13]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226590, 2008, A1 Location in patent: Page/Page column 31
[14]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/227769, 2008, A1 Location in patent: Page/Page column 66
[15]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/130056, 2009, A1 Location in patent: Page/Page column 25
[16]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/60565, 2007, A1 Location in patent: Page/Page column 73
[17]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/270405, 2007, A1 Location in patent: Page/Page column 41
[18]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/270406, 2007, A1 Location in patent: Page/Page column 22
[19]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2009/67108, 2009, A1 Location in patent: Page/Page column 43-44
[20]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/130057, 2009, A1 Location in patent: Page/Page column 26-27
[21]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/287694, 2007, A1 Location in patent: Page/Page column 16
[22]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/188458, 2008, A1 Location in patent: Page/Page column 28-29
[23]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/171015, 2008, A1 Location in patent: Page/Page column 19
[24]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226592, 2008, A1 Location in patent: Page/Page column 38-39
[25]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226593, 2008, A1 Location in patent: Page/Page column 15
[26]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226591, 2008, A1 Location in patent: Page/Page column 34
[27]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226591, 2008, A1 Location in patent: Page/Page column 34-35
[28]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226590, 2008, A1 Location in patent: Page/Page column 31
[29]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/226590, 2008, A1 Location in patent: Page/Page column 31
[30]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2008/227769, 2008, A1 Location in patent: Page/Page column 65-66
[31]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/130056, 2009, A1 Location in patent: Page/Page column 24-25
[32]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/130056, 2009, A1 Location in patent: Page/Page column 25
  • 38
  • methyl 2-bromo-1-(2-tert-butoxy-2-oxo-ethyl)-3-[(1R*,2S*)-2-fluoro-cyclohexyl]-1H-indole-6-carboxylate [ No CAS ]
  • [ 139962-95-1 ]
  • methyl 1-(2-tert-butoxy-2-oxo-ethyl)-3-[(1S,2R)-2-fluoro-cyclohexyl]-2-[2-formyl-4-methoxy-phenyl]-1H-indole-6-carboxylate [ No CAS ]
  • methyl 1-(2-tert-butoxy-2-oxo-ethyl)-3-[(1R,2S)-2-fluoro-cyclohexyl]-2-[2-formyl-4-methoxy-phenyl]-1H-indole-6-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In water; toluene at 100℃; for 4.5h; 4.1 Example 4: 6-[2-(dimethylamino)ethyl]-14-[(l1S',2λ)-2-fluorocyclohexyl]-3-methoxy-5,6,7,8- tctrahydroindolo[2,l -a] [2,5]bcnzodiazocinc-ll -carboxylic acid and 6-[2-(dimethylamino)ethyl]-14- [(l/?,25)-2-fluorocyclohcxyl]-3-mcthoxy-5,6,7,8-tctrahydroindolo[2,1-a][2,5]bcnzodiazocinc-ll- carboxylic acid Step 1: methyl l-(2-tert-butoxy-2-oxoethyl)-3-F(lR,2S) or (ISJR) -2-fluorocvclohexyll-2-(2-formyl-4- methoxyphenyl)-lH-indole-6-carboxylate Following the procedure described in Example 1, Step 7, treatment of (-)-methyl 2-bromo-l-(2-tert- butoxy-2-oxoethyl)-3-[(trans)-2-fluorocyclohexyl]-lH-indole-6-carboxylate prepared as described in Example 1, Step 6) with 2-formyl-4-methoxyphenylboronic acid (1.5 eq), aqueous Na2CO3 (2 N, 6 eq) and PdCl2(PPh3)2 (0.2 eq) gave a residue that was purified by flash chromatography (9: 1 to 8:2 PE:EtOAc) to give the title compound (68%) as a solid. This material was identified as a 1:1* mixture of isomers by 1H NMR. 1H NMR (300 MHz, DMSO-^6, 300 K) δ 1.15-1.51 (m, 3H), 1.25 (s, 9H), 1.55-1.96 (m, 4H), 2.00-2.15 (m, IH), 2.49-2.52 (m, obscured by residual signal from DMSO, IH), 3.89 (s, 3H), 3.93 (s, 3H), 4.59 and 4.63* (d, J, J* 17.7, IH), 4.88 and 4.89* (d, J, J* 17.7, IH), 4.74-5.09 (m, IH), 7.31-7.52 (m, 3H), 7.73 (d, J8.4, IH), 7.93 and 7.95* (d, J8.4, IH), 8.16 (s, IH), 9.53 and 9.61* (s, IH).
  • 39
  • [ 1005346-97-3 ]
  • [ 139962-95-1 ]
  • [ 1005346-85-9 ]
YieldReaction ConditionsOperation in experiment
58% With caesium carbonate In ethanol; toluene at 150℃; for 0.166667h; microwave irradiation;
  • 40
  • [ 21906-31-0 ]
  • [ 139962-95-1 ]
  • [ 1005346-87-1 ]
YieldReaction ConditionsOperation in experiment
51% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; toluene; at 150℃; for 0.166667h;Microwave irradiation; General procedure: To a thick-well borosilicate glass vial (10 mL) was added phenyl propanone starting materials (0.20 g, 0.94 mmol), 4-methoxy-2-formyl boronic acid (0.20 g, 1.12 mmol), Pd (PPh3)4 (0.043 g, 4mol %), Cs2CO3 ( 0.91 g, 2.82 mmol) and S-Phos (0.022 g, 6 mol%) sequentially in a toluene: ethanol (4 mL:2 mL) mixture. The reaction vial was then sealed and placed in a microwave reactor and irradiated with 60-80 W power at 150 C for 10 min. The reaction mixture was then cooled to room temperature and diluted with excess ethyl acetate. The resulting solution was filtered through celite and concentrated in vacuo. The crude solid was purified by column chromatography (10-15% ethyl acetate/hexane).
  • 41
  • [ 1292766-17-6 ]
  • [ 102020-26-8 ]
  • [ 139962-95-1 ]
  • B(OH)2(C4H3SCOO) [ No CAS ]
  • [ 52403-06-2 ]
  • 2-(1-undecylcarbonyl)-5-methoxybenzaldehyde [ No CAS ]
  • 42
  • [ 902148-40-7 ]
  • [ 139962-95-1 ]
  • [ 958002-14-7 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; for 20h; Inert atmosphere; 6H-Isoindolo[2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy, To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-brorno-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.The mother liquid from the trituration was concentrated in vacua The residue was refluxed with EtOH (50 mL) for 3 h. The solution was then cooled to 0° C. The precipitates were filtered and washed with cooled TBME (5° C.) (20 mL). The filter cake was house vacuum air dried to give a further quantity of the title compound as a white solid (16.0 g). HPLC purity, 99%. 1HNMR (CDCl3, 300 MHz) δ 8.75 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4 and 1.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.4 and 2.2 Hz, 1H), 6.50 (s, 1H), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m, 3H), 1.85-1.93 (m, 7H), 1.40-1.42 (m, 3H), 1.05 (t, J=7.1 Hz, 3H). m/z 512 (M+H)+.
With sodium carbonate; lithium chloride In ethanol; water; toluene at 70℃; for 20.42h; 5 6H-Isoindolo [2,1-a]indole-3-carboxamide, 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-.; To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%. The mother liquid from the trituration was concentrated in vacuo. The residue was refluxed with EtOH (50 mL) for 3 h. The solution was then cooled to 0° C. The precipitates were filtered and washed with cooled TBME (5° C.) (20 mL). The filter cake was house vacuum air dried to give a further quantity of the title compound as a white solid (16.0 g). HPLC purity, 99%. 1H NMR (CDCl3, 300 MHz) δ 8.75 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4 and 1.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.4 and 2.2 Hz, 1H), 6.50 (s, 1H), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m, 3H), 1.85-1.93 (m, 7 H), 1.40-1.42 (m, 3H), 1.05 (t, J=7.1 Hz, 3H). m/z 512 (M+H)+.
  • 43
  • [ 902148-40-7 ]
  • [ 139962-95-1 ]
  • [ 928844-26-2 ]
  • [ 958002-14-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; 2-formyl-4-methoxyphenylboronic acid With lithium chloride In ethanol; water; toluene for 0.25h; Stage #2: With sodium carbonate In ethanol; water; toluene for 0.166667h; Stage #3: In ethanol; water; toluene at 70℃; for 20h; To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with N2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in H2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70° C. for 20 h. After cooling to 35° C., a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide (65.9 g) as a yellow solid. HPLC purity, 98%.The mother liquid from the trituration was concentrated in vacuo. The residue was refluxed with EtOH (50 mL) for 3 h. The solution was then cooled to 0° C. The precipitates were filtered and washed with cooled TBME (5° C.) (20 mL). The filter cake was house vacuum air dried to give a further quantity of the title compound as a white solid (16.0 g). HPLC purity, 99%. 1H NMR (CDCl3, 300 MHz) δ 8.75 (s, 1H), 7.96 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4 and 1.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.4 and 2.2 Hz, 1H), 6.50 (s, 1H), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m, 3H), 1.85-1.93 (m, 7H), 1.40-1.42 (m, 3H), 1.05 (t, J=7.1 Hz, 3H). m/z 512 (M+H)+.
  • 44
  • [ 1049796-90-8 ]
  • [ 139962-95-1 ]
  • [ 1049796-92-0 ]
YieldReaction ConditionsOperation in experiment
58% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate In toluene for 2h; Heating / reflux; Potassium phosphate (830 mg, 3.9 mmol), 2-formyl-4-methoxyphenylboronic acid (470 mg, 2.6 mmol), palladium (II) acetate (44 mg, 65 μmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (70 mg, 170 μmol) were added to a solution of Intermediate 5 in toluene (13 mL). The heterogeneous mixture was brought to reflux under N2 for 2 h, then allowed to cool to r.t. and H2O (25 mL) was added. The biphasic mixture was poured into EtOAc (200 mL), and a black emulsion formed. The mixture was filtered through filter paper (EtOAc rinse), the organic phase was collected, and the aqueous phase re-extracted with EtOAc. The combined organic phases were washed with H2O (20 mL) and brine, dried over Na2SO4, filtered, and concentrated. Chromatography on silica gel (gradient elution: 10%→20% EtOAc in C6H14 over 800 mL, then→100% EtOAc over 200 mL) afforded 475 mg of the title compound (58% yield). LC/MS (ESI) retention time: 2.20 min, m/z 631 (MH+); 1H NMR (400 MHz, CDCl3) δ ppm -0.09 (s, 9 H) 0.68-0.84 (m, 2 H) 1.16 (s, 3 H) 1.50-1.64 (m, 2 H) 1.64-1.80 (m, 5 H) 2.40-2.50 (m, 1 H) 3.04 (s, 6 H) 3.41-3.49 (m, 2 H) 3.96 (s, 3 H) 5.37 (d, J=9.82 Hz, 1 H) 6.27 (d, J=9.82 Hz, 1 H) 7.27 (d, J=2.52 Hz, 1 H) 7.30-7.35 (m, 1 H) 7.59 (d, J=2.77 Hz, 1 H) 7.87 (d, J=8.56 Hz, 1 H) 8.15 (d, J=8.56 Hz, 1 H) 9.66 (s, 1 H) 14.69 (s, 1 H).
  • 45
  • [ 1049796-94-2 ]
  • [ 139962-95-1 ]
  • [ 1049796-96-4 ]
YieldReaction ConditionsOperation in experiment
78% With sodium carbonate; lithium chloride In ethanol; water; toluene for 5h; Heating / reflux; To a suspension of Intermediate 10 (1.95 g, 5.3 mmol) in EtOH (19.5 mL)/toluene (19.5 mL) was added lithium chloride (400 mg, 9.5 mmol), sodium carbonate (1 M aqueous solution, 9 mL, 9 mmol), 2-formyl-4-methoxyphenylboronic acid (1.3 g, 7.2 mmol), and tetrakis(triphenylphosphine)palladium (950 mg, 0.82 mmol). A reflux condenser was affixed and the light orange suspension was refluxed under N2 for 5 h before being cooled to r.t. The reaction was partitioned between 1 N HCl (100 mL) and 1:1 EtOAc/tBME (100 mL) and the organic phase was re-extracted with 1 N HCl (3×15 mL). The combined aqueous phases were basified to pH 10 with 1 N NaOH and the solution was extracted with CH2Cl2 (5×50 mL). The CH2Cl2 layer was concentrated and the residue re-dissolved in CH2Cl2 (50 mL). A light yellow ppt. formed which was filtered off, and the filtrate was introduced to a silica gel column. Gradient elution with 10%→50% EtOAc in hexanes over 700 mL afforded the title compound as a yellow solid (2.2 g, 1H NMR shows the solid is 20% w/w solvent, therefore 78% yield). LC/MS (ESI) retention time: 1.61 min, m/z 425 (MH+); 1H NMR (400 MHz, CDCl3) δ ppm 1.22-1.35 (m, 3 H) 1.69-1.88 (m, 7 H) 2.65-2.87 (m, 1 H) 3.91 (s, 3 H) 5.83 (s, 2 H) 6.79 (t, J=6.80 Hz, 1 H) 7.20 (dd, J=8.56, 2.77 Hz, 1 H) 7.32-7.40 (m, 3 H) 7.41-7.47 (m, 2 H) 7.47-7.60 (m, 3 H) 8.20 (d, J=7.05 Hz, 1 H) 10.01 (s, 1 H).
  • 46
  • [ 130611-34-6 ]
  • [ 139962-95-1 ]
  • [ 1062680-26-5 ]
YieldReaction ConditionsOperation in experiment
82% With caesium carbonate In 1,4-dioxane; isopropyl alcohol at 130℃; for 0.5h; microwave irradiation;
  • 47
  • [ 1042722-43-9 ]
  • [ 139962-95-1 ]
  • [ 1042722-44-0 ]
YieldReaction ConditionsOperation in experiment
89% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In ethanol; toluene at 150℃; for 0.166667h; Microwave irradiation;
87% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate In ethanol; toluene at 150℃; for 0.166667h; Microwave irradiation; Inert atmosphere;
  • 48
  • [ 902148-40-7 ]
  • [ 64-17-5 ]
  • [ 139962-95-1 ]
  • [ 958002-14-7 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide; ethanol; 2-formyl-4-methoxyphenylboronic acid With lithium chloride In toluene for 0.25h; Stage #2: With sodium carbonate In water; toluene at 70℃; for 20.1667h; 5 Intermediate 5; 6H-Isoindolo[2, l-aJindole-3-carboxamide, 11-cyclohexyl-N- [(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-.; To a 5 L four necked round bottom flask equipped with a temperature controller, a condenser, a N2 inlet and a mechanical stirrer, was charged toluene (900 mL), EtOH (900 mL), 2-bromo-3- cyclohexyl-N^NjN-dimethylsulfamoyiyiH-indole--carboxamide (90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273 mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbled with ν2 for 15 mins. A solution of Na2CO3 (66.8 g, 0.63 mol) in η2O (675 mL) was added and the reaction mixture was bubbled with N2 for another (10 mins). Pd(PPh3)4 (7.0 g, 6.3 mmol) was added and the reaction mixture was heated to 70 0C for 20 h. After cooling to 35 0C, a solution of 1 N HCl (1.5 L) was added slowly. The resulting mixture was transferred to a 6 L separatory funnel and extracted with EtOAc (2 X 1.5 L). The combined organic extracts were washed with brine (2 L), dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated with 20% EtOAc in hexane (450 mL, 50 0C to 0 0C) to give 3-cyclohexyl-N-(N,N-dimethylsulfamoyl)-2-(2-formyl-4- methoxyphenyl)-lH-indole-6-carboxamide(65.9 g) as a yellow solid. HPLC purity, 98%.The mother liquid from the trituration was concentrated in vacuo. The residue was refluxed with EtOH (50 mL) for 3 h. The solution was then cooled to 0 0C. The precipitates were filtered and washed with cooled TBME (5 0C) (20 mL). The filter cake was house vacuum air dried to give a further quantity of the title compound as a white solid (16.0 g). HPLC purity, 99%. 1H NMR (CDC13, 300 MHz) δ 8.75 (s, IH), 7.96 (s, IH), 7.73 (d, J= 8.4 Hz, IH), 7.67 (d, J= 8.4 Hz, IH), 7.45 (dd, J= 8.4 and 1.4 Hz, IH), 7.09 (d, J= 2.2 Hz, IH), 6.98 (dd, J= 8.4 and 2.2 Hz, IH), 6.50 (s, IH), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m, 3H), 1.85-1.93 (m, 7 H), 1.40-1.42 (m, 3H), 1.05 (t, J= 7.1 Hz, 3H). m/z 512 (M + H)+.
  • 49
  • [ 2142-69-0 ]
  • [ 139962-95-1 ]
  • [ 1149344-87-5 ]
YieldReaction ConditionsOperation in experiment
94% With potassium fluoride; palladium diacetate; di‐tert‐butyl‐(1‐phenylindol‐2‐yl)phosphane In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
  • 50
  • [ 14369-81-4 ]
  • [ 139962-95-1 ]
  • C14H16O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With [(1,3-bis(diphenylphosphino)propane)Pd(H2O)2](BF4)2 In toluene at 50℃; for 0.666667h; diastereoselective reaction;
  • 51
  • [ 106-37-6 ]
  • [ 139962-95-1 ]
  • [ 1219700-08-9 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 1,2-dimethoxyethane; nitrogen; water; ethyl acetate 1 Step 1 Step 1 A solution of 1,4-dibromobenzene (5.11 g, 21.67 mmol), potassium carbonate (6.91 g, 50.0 mmol) and 2-formyl-4-methoxyphenylboronic acid (3 g, 16.67 mmol) in DME (75 mL) and water (15 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(Ph3P)4 (0.578 g, 0.500 mmol) was added and then the reaction was heated to 90° C. overnight. The reaction was cooled to r.t. and evaporated on rotovap. The residue was diluted with EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (5-15% EtOAc:Hex) to give 4'-bromo-4-methoxybiphenyl-2-carbaldehyde (2.72 g, 9.34 mmol, 56% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.91 (s, 3H) 7.18-7.26 (m, 3H) 7.34 (d, J=824 Hz, 1H) 7.52 (d, J=2.75 Hz, 1H) 7.54-7.70 (m, 2H) 9.94 (s, 1H).
  • 52
  • [ 60941-07-3 ]
  • [ 139962-95-1 ]
  • C14H17BO5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% With ammonium chloride; zinc In tetrahydrofuran at 25℃;
  • 54
  • [ 53939-30-3 ]
  • [ 139962-95-1 ]
  • C21H17NO4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In methanol; water; toluene at 100℃; for 12h; Inert atmosphere; diastereoselective reaction;
  • 55
  • [ 1266162-02-0 ]
  • [ 139962-95-1 ]
  • [ 1266162-03-1 ]
YieldReaction ConditionsOperation in experiment
62% With potassium phosphate In N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; 232.4 Step 4:[00312] A mixture of 6-chloro-4-(methylthio)-2,3'-bipyridine-5-carbonitrile (57.7 mg, 0.220 mmol), 2-formyl-4-methoxyphenyl boron ic acid (83.4 mg, 0.463 mmol), aqueous potassium phosphate (550 μL, 1.100 mmol) and palladium tetrakis(triphenylphosphine) (16.1 mg, 0.014 mmol) in N,N-dimethy.forrnamide (1 mL) was pumped under vacuum and backfilled with nitrogen twice. After 2 h at 90 °C, the mixture was cooled to room temperature, diluted with methanol (2 mL) and filtered to give 6-(2-formyl-4- methoxyphenyl)-4-(methylthio)-2,3'-bipyϖdine-5-carbonitrile as brown solid (56.9 mg, 62% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.99 (1 H, s), 9.20 (1 H, δ, J=1.92 Hz), 8.72 (1 H, dd, J=4.67, 1.65 Hz), 8.34 (1 H, dt, J=7.97, 1.92 Hz), 7.71 (1 H, δ, J=8.52 Hz), 7.57 (1 H, δ> J=2.75 Hz), 7.56 (1 H, s), 7.45 - 7.49 (1 H5 m), 7.44 (1 H, dd, J=8.1 1, 4.81 Hz), 3.95 (3 H, s), 2.74 (3 H, s); MS (ES+) m/z: 362 (M+H); LC retention time: 3.088 min (analytical HPLC Method A).
  • 56
  • [ 100-39-0 ]
  • [ 139962-95-1 ]
  • [ 1292302-64-7 ]
YieldReaction ConditionsOperation in experiment
73% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran at 95℃; for 12h; Inert atmosphere;
With potassium phosphate; bis(benzonitrile)palladium(II) dichloride In N,N-dimethyl acetamide; water at 80℃;
  • 57
  • [ 1285527-73-2 ]
  • [ 139962-95-1 ]
  • [ 1285527-77-6 ]
YieldReaction ConditionsOperation in experiment
76% Stage #1: C18H17NO2 With potassium hexamethylsilazane In tetrahydrofuran at -78℃; Stage #2: With chlorophosphoric acid diphenyl ester In tetrahydrofuran at -78℃; for 0.333333h; Stage #3: 2-formyl-4-methoxyphenylboronic acid Further stages;
  • 58
  • [ 1453-58-3 ]
  • [ 139962-95-1 ]
  • [ 1310531-86-2 ]
YieldReaction ConditionsOperation in experiment
3% With pyridine; copper diacetate In dichloromethane; N,N-dimethyl-formamide at 20℃; for 120h; Molecular sieve; 25 To a solution of 2-formyl-4-methoxyphenylboronic acid (2.5 g, 13.89 mmol) in CH2CI2 (30 mL) and DMF (15 mL) are added 3-methyl-lH-pyrazole (0.80 g, 9.72 mmol), Cu(OAc)2 (3.78 g, 20.84 mmol), pyridine (2.27 mL, 27.78 mmol) and molecular sieves (2.5 g) at room temperature. The mixture is stirred at the same temperature for 5 days with loose cap. The mixture is filtered through a short pad of diatomaceous earth and the solids are washed with CH2CI2. The combined filtrates are concentrated and the remaining residue is diluted with water and ethyl acetate. The layers are separated and the aqueous phase extracted with EtOAc (3x). The combined organics are dried (MgS04), filtered, and concentrated. The remaining residue is purified via flash chromatography (silica gel, 0- 15% EtO Ac/heptane) to afford 5-methoxy-2-(3-methyl-pyrazol- l-yl)- benzaldehyde (90 mg, 3%).
  • 59
  • [ 41731-23-1 ]
  • [ 139962-95-1 ]
  • [ 1310531-81-7 ]
YieldReaction ConditionsOperation in experiment
63% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 20 - 120℃;Microwave irradiation; To a solution of 2-formyl-4-methoxyphenylboronic acid (200 mg, 1.11 mmol) in DMF (10 mL) and H20 (2 mL) are added <strong>[41731-23-1]2-bromo-5-methylthiazole</strong> (217 mg, 1.22 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol) and K2C03 (230 mg, 1.67 mmol) at room temperature. The solution is heated to 120 C for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and filtered. The filtrate is washed with H20 (15 mL) and is extracted with EtOAc (3 x 15 mL). The combined organic layer is dried with MgS04 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash chromatography eluting with 50% EtOAc in heptane to afford 5-methoxy-2-(5- methyl-thiazol-2-yl)-benzaldehyde (160 mg, 63%) as a white foam.
  • 60
  • [ 21734-85-0 ]
  • [ 139962-95-1 ]
  • [ 1310531-87-3 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate;bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 100℃; for 20h;Sealed; Microwave irradiation; In a microwave vial are combined 2-formyl-4-methoxyphenylboronic acid (432 mg, 2.40 mmol), 5-chloro-3-methyl- l,2,4-thiadiazole (270 mg, 2.00mmol), potassium acetate (390 mg, 4.00 mmol), and bis(di-ieri-butyl(4-dimethylaminophenyl)phosphine)- dichloropalladium(II) (283 mg, 0.40 mmol) in 1,4-dioxane (6 mL) and water (0.50 mL). The reaction vial is sealed and stirred at 100 C for 20 hours. The reaction mixture is cooled to ambient temperature and poured into water and extracted with EtOAc (3x). The combined organics are dried (MgS04), filtered and concentrated. Purification via flash chromatography (12g silica gel, 5-40% EtO Ac/heptane) affords 5-methoxy-2-(3-methyl- l,2,4-thiadiazol-5-yl)-benzaldehyde which is used without further purification.
  • 61
  • [ 872-31-1 ]
  • [ 139962-95-1 ]
  • [ 1001920-47-3 ]
YieldReaction ConditionsOperation in experiment
97% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) In toluene at 100℃; Inert atmosphere;
  • 62
  • [ 1397691-95-0 ]
  • [ 139962-95-1 ]
  • [ 1397691-96-1 ]
YieldReaction ConditionsOperation in experiment
76.9% With potassium fluoride In tetrahydrofuran; water at 20℃; for 14h; Inert atmosphere; 3 Synthesis Example 3 2-(5-Amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde (7) Under an argon atmosphere, to a solution of allylpalladium(II) chloride dimer (160 mg, 437 μmol) in anhydrous THF (30 mL) was added 2-(di-tert-butylphosphino)-1-phenylindole (295 mg, 874 μmol) at room temperature, followed by stirring at room temperature for 10 minutes. Subsequently, to the mixture were successively added 2-amino-3-benzyl-5-bromo-6-chloropyrazine (5) (2.60 g, 8.74 mmol), 2-formyl-4-methoxyphenylboronic acid (6) (3.14 g, 17.4 mmol), potassium fluoride (2.60 g, 44.8 mmol) and water (160 μL, 8.88 mmol) at room temperature. The mixture was stirred overnight (14 hours) at room temperature without further treatment. After to this was added water, the product was extracted with ethyl acetate (*3). The combined organic extract was washed successively with water (*1) and brine (*1), and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1) to give 2-(5-amino-6-benzyl-3-chloropyrazin-2-yl)-5-methoxybenzaldehyde (7) (2.37 g, 6.70 mmol, 76.9%) as a reddish brown solid. TLC Rf=0.27 (n-hexane/ethyl acetate=3/1); 1H NMR (500 MHz, CDCl3) δ 3.92 (s, 3H), 4.13 (s, 2H), 4.66 (s, 2H), 7.21-7.25 (m, 3H), 7.27-7.31 (m, 1H), 7.32-7.37 (m, 2H), 7.51-7.55 (m, 2H), 9.92 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 40.4, 55.7, 111.2, 120.7, 127.4, 128.4 (2C), 129.2 (2C), 132.5, 132.7, 135.7, 135.8, 137.8, 139.1, 144.1, 151.5, 160.0, 191.0.
76.9% With potassium fluoride; bis(η3-allyl-μ-chloropalladium(II)); di‐tert‐butyl‐(1‐phenylindol‐2‐yl)phosphane In tetrahydrofuran; water at 20℃; for 14h; Inert atmosphere;
76.9% With potassium fluoride; bis(η3-allyl-μ-chloropalladium(II)); di‐tert‐butyl‐(1‐phenylindol‐2‐yl)phosphane In tetrahydrofuran; water at 20℃; for 14h; Inert atmosphere; 3 Synthesis Example 3: 2-(5-Amino-6-benzyl-3-chloropyrazin-2-yl) -5-methoxybenzaldehyde (7) Underan argon atmosphere, allylpalladium (II) chloride dimer (160 mg, 437 μmol) wasdissolved in anhydrous THF (30 mL), which 2- (di-tert-butylphosphino) at roomtemperature -1-phenylindole (295 mg, 874 μmol) was added, and after it isstirred for 10 minutes at room temperature,2-amino-3-benzyl-5-bromo-6-chloropyrazine (5) (2.60 g, 8.74 mmol),2-formyl-4-methoxyphenylboronic acid ( 6) (3.14 g, 17.4 mmol), potassiumfluoride (2.60 g, 44.8 mmol), water (160 μL, were sequentially added at roomtemperature 8.88 mmol), was as it is at room temperature overnight (14 hours)stirring. Water was added thereto and the product was extracted with ethylacetate (× 3). The organic layer was washed with water (× 1) and saturatedbrine (× 1), and dried over anhydrous sodium sulfate. After filtration, thefiltrate was concentrated under reduced pressure, and the residue was purifiedby silica gel flash column chromatography (n- hexane / ethyl acetate = 3/1), 2-(5-amino-6-benzyl-3-chloropyrazin-2-yl) -5-methoxybenzaldehyde (7) (2.37 g,6.70 mmol, 76.9%) was obtained as a red-brown solid
  • 63
  • [ 1402799-01-2 ]
  • [ 139962-95-1 ]
  • [ 1402796-52-4 ]
YieldReaction ConditionsOperation in experiment
75% With sodium carbonate In 1,2-dimethoxyethane; water Microwave irradiation; 57 Reaction scheme 3 above shows a general process for synthesizing compounds 57, 60, 61 and 79 of the present invention, and other compounds of the present invention can also be prepared according to reaction scheme 3 above. The starting material compound 7 is allowed to react with compound 4, acetic acid and sodium cyanoborohydride to synthesize compound 8 which is then allowed to react with triphosgen, thereby preparing compound 9. The obtained compound 9 can be subjected to a Suzuki reaction (Morris, G. A., et al., Tetrahedron Lett., 2001, 42, 2093) with various boronic acids, thereby preparing desired compounds.; As shown in reaction scheme 3, intermediated was synthesized. The obtained intermediate 9 (0.13 g, 0.20 mmol) was subjected to a Suzuki reaction with boronic acid (58 mg, 0.33 mmol), thus obtaining Compound 57 (0.11 g, 75%) as brown oil.1H NMR (400 MHz, CDC13); atropisomer mixture; δ 10.05 (s, 0.49H), 10.00 (s, 0.47H), 7.86 (s, 1H), 7.73 (s, 2H), 7.37-7.42 (m, 1H), 7.70-7.17 (m, 2H), 5.62-5.64 (m, 1H), 3.83-4.03 (m, 2H), 3.86 (d, J= 3.0, 3H), 2.15-2.39 (m, 4H), 1.72-1.88 (m, 4H), 3.82 (d, J= 3.4, 3H), 2.03-2.38 (m, 4H), 1.75 (d, J= 3.8, 4H), 0.37-0.42 (m, 3H). MS (ESI) m/z 542 (M+ + H).
  • 64
  • [ 1274070-41-5 ]
  • [ 139962-95-1 ]
  • [ 1415130-26-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In 1,4-dioxane; water at 80℃; for 16h; 60.A Ethyl 3-(5-bromopicolinamido)propanoate (1.0 g, 3.3 mmol), (2-formyl-4-methoxyphenyl)boronic acid (896 mg, 5.0 mmol), Pd(dppf)Cl2 (364 mg, 0.5 mmol), and K2CO3 (918 mg, 6.6 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL) and heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
  • 65
  • [ 25187-00-2 ]
  • [ 139962-95-1 ]
  • [ 1433030-01-3 ]
YieldReaction ConditionsOperation in experiment
100% With tris-(dibenzylideneacetone)dipalladium(0); potassium fluoride dihydrate; tri tert-butylphosphoniumtetrafluoroborate In tetrahydrofuran at 40℃; for 12h; Inert atmosphere;
  • 66
  • [ 139962-95-1 ]
  • [ 170456-80-1 ]
  • [ 1432521-47-5 ]
YieldReaction ConditionsOperation in experiment
93% With triphenylphosphine; cesium fluoride; bis(dibenzylideneacetone)-palladium(0) In 1,2-dimethoxyethane at 90℃; for 18h; Inert atmosphere; General Procedure B: Suzuki-Miyaura Coupling General procedure: An oven-dried heavy wall pressure vessel was cooled under Ar. To this flask was sequentially added aryl halide 6 or 9, the boronic acid, catalyst, ligand, and cesium fluoride, all under an Ar atmosphere. The flask was then purged with Ar for an additional 5 minutes, and DME was added via syringe under Ar. The flask was further purged with Ar for 1 minute, then sealed under Ar, placed in an oil bath pre-heated to 90 °C and left overnight. After cooling to room temperature, the reaction was diluted with Et2O, washed with brine, dried over MgSO4, and the solvent removed in vacuo. The crude products were purified by column chromatography.
  • 67
  • [ 466639-53-2 ]
  • [ 139962-95-1 ]
  • [ 1459238-33-5 ]
YieldReaction ConditionsOperation in experiment
62% With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In tetrahydrofuran at 20℃; Inert atmosphere; 1 4.5 General procedure for the preparation of biarylcarboxaldehydes (28a-c) General procedure: The mixture of 2-formylphenyl boronic acid 26a-c (1.0equiv), 2-bromo-1-iodo-4-methoxybenzene 27 (2.0equiv), and 5mol% PdCl2(PPh3)2 in THF (5mL) was stirred under Ar atmosphere at room temperature. A solution of 2N K2CO3 (25mL) was then transferred into the reaction via syringe until the reaction turned a brown-red solution. The reaction was allowed to stir at room temperature overnight. After checking by TLC, the reaction was quenched with water and partitioned with EtOAc to obtain the dark-brown crude oil. The crude product was purified by flash chromatography or preparative thin layer chromatography (EtOAc/Hexane) to obtain the product.
  • 68
  • [ 93839-16-8 ]
  • [ 139962-95-1 ]
  • 1-(8-fluoro-2-methoxyphenanthren-9-yl)ethanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tetrakis(triphenylphosphine) palladium(0); caesium carbonate In ethanol; toluene at 150℃; for 0.166667h; Microwave irradiation; General procedure for the synthesis of intermediates 9i and 9j General procedure: To a thick-well borosilicate glass vial (10 mL) was added phenyl propanone starting materials (0.20 g, 0.94 mmol), 4-methoxy-2-formyl boronic acid (0.20 g, 1.12 mmol), Pd (PPh3)4 (0.043 g, 4mol %), Cs2CO3 ( 0.91 g, 2.82 mmol) and S-Phos (0.022 g, 6 mol%) sequentially in a toluene: ethanol (4 mL:2 mL) mixture. The reaction vial was then sealed and placed in a microwave reactor and irradiated with 60-80 W power at 150 °C for 10 min. The reaction mixture was then cooled to room temperature and diluted with excess ethyl acetate. The resulting solution was filtered through celite and concentrated in vacuo. The crude solid was purified by column chromatography (10-15% ethyl acetate/hexane).
  • 69
  • [ 139962-95-1 ]
  • diethyl (1-bromonaphthalen-2-yl)phosphonate [ No CAS ]
  • (-)-diethyl 1-(2-formyl-4-methoxyphenyl)naphthalen-2-ylphosphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); (R)-(+)-2-(dicyclohexylphosphino)-2'-methoxy-1,1'-binaphthyl In toluene at 50℃; for 56h; Inert atmosphere; enantioselective reaction;
  • 70
  • [ 139962-95-1 ]
  • diethyl (1-bromonaphthalen-2-yl)phosphonate [ No CAS ]
  • diethyl 1-(2'-formyl-4'-methoxyphenyl)naphthalen-2-ylphosphonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); (R)-[6,6'-(2S,3S-butadioxy)]-2-di-(3,5-di-methylphenyl)phosphino-(1,1')-biphenyl In tetrahydrofuran at 40℃; for 60h; Inert atmosphere; Glovebox; enantioselective reaction;
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0) In toluene at 50℃; Inert atmosphere;
  • 71
  • [ 1571136-59-8 ]
  • [ 139962-95-1 ]
  • [ 1571136-48-5 ]
YieldReaction ConditionsOperation in experiment
87% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene at 150℃; for 0.166667h; Sealed tube; Microwave irradiation;
  • 72
  • [ 1571136-60-1 ]
  • [ 139962-95-1 ]
  • [ 1571136-53-2 ]
YieldReaction ConditionsOperation in experiment
85% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene at 150℃; for 0.166667h; Sealed tube; Microwave irradiation;
  • 73
  • [ 884855-68-9 ]
  • [ 139962-95-1 ]
  • [ 1571136-41-8 ]
YieldReaction ConditionsOperation in experiment
93% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene at 150℃; for 0.166667h; Sealed tube; Microwave irradiation;
  • 74
  • [ 1589518-11-5 ]
  • [ 139962-95-1 ]
  • [ 1589546-19-9 ]
YieldReaction ConditionsOperation in experiment
87% With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); (R)-(+)-2-(dicyclohexylphosphino)-2'-methoxy-1,1'-binaphthyl In toluene at 50℃; enantioselective reaction;
  • 75
  • N-(1-(2-bromophenyl)-2-cyanoallyl)benzamide [ No CAS ]
  • [ 139962-95-1 ]
  • [ 1611486-19-1 ]
YieldReaction ConditionsOperation in experiment
81% Stage #1: N-(1-(2-bromophenyl)-2-cyanoallyl)benzamide; 2-formyl-4-methoxyphenylboronic acid With sodium carbonate In 1,4-dioxane; water for 0.25h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 80℃; General procedure: 4.2. General procedure for the synthesis of 3aA-3jA, 3aB-aE, 3bE as exemplified for 3aA: A suspension of 1a (0.20 g, 0.59 mmol), 2-formylphenylboronic acid 2A (0.09 g, 0.65 mmol), 2(M) aq Na2CO3 (0.13 g, 1.18 mmol) in dioxane (3 mL) was degassed under N2 for 15 min. Then a weighed amount of Pd(PPh3)4 (0.03 g, 0.03 mmol) was added to it and the reaction mixture was transferred to an oil bath and heated at 80 °C until all the starting materials were consumed. The excess 2-propanol was evaporated under reduced pressure and the crude mixture was worked up with EtOAc (3*10 mL). Thereafter the combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and evaporated under reduced pressure to yield the crude product as brown oil, which after chromatographic purification [silica gel, hexane/EtOAc (80:20)] yielded the pure 3aA (0.18 g, 79%) as a white solid.
  • 76
  • [ 1334217-99-0 ]
  • [ 139962-95-1 ]
  • 9-methoxy-5-nitro-3-(tetrahydro-2H-pyran-2-yl)-3H-pyrazolo[4,3-a]phenanthridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 3h; Reflux; 4.1.3 General procedure: A mixture of indazole 1 (100 mg, 0.26 mmol) in a 1:1:1 toluene/ethanol/H2O mixture (6 mL), Pd(PPh3)4 (10 mol%), Na2CO3 (2.5 equiv) and 2-formylboronic acid (57 mg, 0.38 mmol) was refluxed for 3 h. Water was added and the mixture was extracted with EtOAc. The combined organic fractions were dried over MgSO4 and evaporated. Column chromatography (cyclohexane/EtOAc, 2:1) provided compound 2 (81 mg, 0.23 mmol, 90%) as a brown powder.
  • 77
  • [ 132606-40-7 ]
  • [ 139962-95-1 ]
  • 3,10-dimethoxy-7,8-dihydro-8-hydroxy-7-methyl-indeno[1',2':4,5]pyrido[2,1-a]isoindol-5-one [ No CAS ]
  • 78
  • [ 139962-95-1 ]
  • [ 106-95-6 ]
  • [ 140-88-5 ]
  • ethyl (E)-4-(2-formyl-4-methoxyphenyl)but-2-enoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% Stage #1: 2-formyl-4-methoxyphenylboronic acid; allyl bromide With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In tetrahydrofuran for 4h; Reflux; Stage #2: ethyl acrylate With Grubbs catalyst first generation In dichloromethane at 40℃; PdCl2(PPh3)2 (2.5 mol%) and aqueous Na2CO3 (1.0 M, 2.0 eq.) solution were added to a solution of the boronic acid (3.0 mmol) and allyl bromide (1.2 eq.) in THF (0.2 M). The reaction mixture was heated to reflux and stirred for 4 hours. The reaction was quenched with H2O and extracted with DCM (x3). The combined organic layers were washed with brine, dried over MgSO4, and the solvent removed under reduced pressure, to afford the crude Suzuki cross-coupled product. Grubbs I catalyst (5.0 mol%) and ethyl acrylate (5.0 eq.) were added to a solution of the crude cross-coupled product in DCM was added Grubbs I catalyst (5.0 mol%) and ethyl acrylate (5.0 eq). The reaction was heated to 40 °C and stirred overnight. The solvent was removed under vacuum to afford the crude cross metathesis product (E)-ethylformylbutenoate. General procedure D was followed using (2-formyl-4-methoxyphenyl)boronic acid (540 mg, 3.0 mmol), followed by purification by column chromatography (eluent: DCM), to yield the title compound as a pale green oil in 63% yield (469 mg, 1.89 mmol). Rf (DCM) = 0.27; 1H NMR (300 MHz, CDCl3) δH: 10.14 (1H, s, CHO), 7.36 (1H, d, J = 2.7 Hz, ArH), 7.19-7.07 (3H, m, ArH, CH2CH=CH), 5.67 (1H, dt, J = 15.6, 1.7 Hz, CH2CH=CH), 4.15 (2H, q, J = 7.1 Hz, CH2CH3), 3.89 (2H, dd, J = 6.2, 1.7 Hz, ArCH2), 3.86 (3H, s, OCH3), 1.25 (3H, t, J = 7.1 Hz, CH2CH3); 13C{1H} NMR (75.5 MHz CDCl3) δC: 191.9, 166.5, 159.1, 147.3, 134.8, 132.8, 132.1, 122.7, 120.8, 116.4, 60.5, 55.7, 34.3, 14.4; I.R (thinfilm) ν max (cm-1): 1708 (C=O), 1693 (C=O), 1651 (C=C); HRMS (ESI): m/z calculated for C14H16O4: requires: 271.0946 for [M+Na]+; found: 271.0930
  • 79
  • [ 79-19-6 ]
  • [ 139962-95-1 ]
  • 1-hydroxy-6-methoxybenzo[d][1,2,3]diazaborine-2(1H)-carbothioamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With formic acid In water for 2h; Reflux; General Synthesis of Diazaborines General procedure: The substituted 2-formylphenylboronic acid derivative (0.25 mol) was completely dissolved in hot H2O (20 mL) and the appropriate thiosemicarbazide (0.25 mol) and 5 drops of formic acid were added to the solution and the reaction mixture was heated under reflux for 2 h. Once the reaction had cooled to room temperature, the resulting precipitate was collected by suction filtration and washed with hexane (310 mL) to afford the desired diazaborine.
  • 80
  • [ 139962-95-1 ]
  • [ 6610-29-3 ]
  • 1-hydroxy-6-methoxy-N-methylbenzo[d][1,2,3]diazaborine-2(1H)-carbothioamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With formic acid In water for 2h; Reflux; General Synthesis of Diazaborines General procedure: The substituted 2-formylphenylboronic acid derivative (0.25 mol) was completely dissolved in hot H2O (20 mL) and the appropriate thiosemicarbazide (0.25 mol) and 5 drops of formic acid were added to the solution and the reaction mixture was heated under reflux for 2 h. Once the reaction had cooled to room temperature, the resulting precipitate was collected by suction filtration and washed with hexane (310 mL) to afford the desired diazaborine.
  • 81
  • [ 3766-55-0 ]
  • [ 139962-95-1 ]
  • N-allyl-1-hydroxy-6-methoxybenzo[d][1,2,3]diazaborine-2(1H)-carbothioamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With formic acid In water for 2h; Reflux; General Synthesis of Diazaborines General procedure: The substituted 2-formylphenylboronic acid derivative (0.25 mol) was completely dissolved in hot H2O (20 mL) and the appropriate thiosemicarbazide (0.25 mol) and 5 drops of formic acid were added to the solution and the reaction mixture was heated under reflux for 2 h. Once the reaction had cooled to room temperature, the resulting precipitate was collected by suction filtration and washed with hexane (310 mL) to afford the desired diazaborine.
  • 82
  • [ 139962-95-1 ]
  • [ 5351-69-9 ]
  • 1-hydroxy-6-methoxy-N-phenylbenzo[d][1,2,3]diazaborine-2(1H)-carbothioamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With formic acid In water for 2h; Reflux; General Synthesis of Diazaborines General procedure: The substituted 2-formylphenylboronic acid derivative (0.25 mol) was completely dissolved in hot H2O (20 mL) and the appropriate thiosemicarbazide (0.25 mol) and 5 drops of formic acid were added to the solution and the reaction mixture was heated under reflux for 2 h. Once the reaction had cooled to room temperature, the resulting precipitate was collected by suction filtration and washed with hexane (310 mL) to afford the desired diazaborine.
  • 83
  • [ 16182-15-3 ]
  • [ 139962-95-1 ]
  • 6-methoxy-2-[(2,4,6-trimethylphenyl)sulfonyl]-2,3,1-benzodiazaborinin-1(2H)-ol [ No CAS ]
  • 84
  • [ 2139-43-7 ]
  • [ 139962-95-1 ]
  • 2-[6-(1,3-dioxolan-2-yl)benzo[1,3]dioxol-5-yl]-5-methoxybenzaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
83% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 125℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation;
  • 85
  • [ 34824-58-3 ]
  • [ 139962-95-1 ]
  • 2'-(1,3-dioxolan-2-yl)-4-methoxybiphenyl-2-carbaldehyde [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 110℃; for 4h; Inert atmosphere;
Same Skeleton Products
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