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[ CAS No. 1025708-31-9 ]

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Chemical Structure| 1025708-31-9
Chemical Structure| 1025708-31-9
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Product Details of [ 1025708-31-9 ]

CAS No. :1025708-31-9 MDL No. :MFCD08669562
Formula : C11H14BN3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W :231.06 g/mol Pubchem ID :-
Synonyms :

Safety of [ 1025708-31-9 ]

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

Application In Synthesis of [ 1025708-31-9 ]

  • Downstream synthetic route of [ 1025708-31-9 ]

[ 1025708-31-9 ] Synthesis Path-Downstream   1~24

  • 1
  • [ 1025708-31-9 ]
  • [ 1272353-93-1 ]
  • [ 1272354-91-2 ]
YieldReaction ConditionsOperation in experiment
49% With potassium carbonate In 1,4-dioxane; water at 90℃; for 16h; Inert atmosphere; 165 To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4- amine (0.22 g, 0.65 mmol) in 1,4-dioxane (10 mL) and ¾0 (2 mL) under nitrogen was added 2-cyanopyrimidin-5-ylboronic ester (0.22 g, 0.97 mmol), and potassium carbonate (0.18 g, 1.30 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 min. After this time, (l,l'-bis(diphenylphosphino)- ferrocene)palladium (II) chloride dichloromethane complex (0.048 mg, 0.06 mmol) was added and the reaction mixture was again degassed with nitrogen for 10 min.After this time, the reaction mixture was stirred heated to 90 °C where it stirred for 16 h. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature and then quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer was extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over a2S04, filtered and concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography using adichloromethane / methanol mixture as the eluent to afford Example 165 (0.13 g, 49 % yield) as a brown solid. XH NMR (400 MHz, DMSO-i¾) δ (ppm): 9.86 (s, 2H), 8.22 (d, 1H, J=6.4 Hz), 7.94 (dd, 1H, J =1.6 Hz J=8.4 Hz), 7.89 (dd, 1H, J= 3.2 Hz, J=11.2 Hz), 7.74 (dt, 1H, J =1.6 Hz, 8 Hz,), 7.63-7.50 (m, 5H),7.40-7.32 (m, 2H), 7.25 (dd, 1H, J=5.2 Hz, 6.8 Hz), 7.08 (br t, 1H, J= 4Hz), 4.76 (d, 2H, J=4.4 Hz). LCMS Method U: retention time 1.85 min; [M+l] = 416.0; HPLC Method A4: purity 97.6%, retention time = 23.30 min.
49% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In water; N,N-dimethyl-formamide at 90℃; for 4h; Inert atmosphere;
  • 2
  • [ 1025708-31-9 ]
  • [ 1354290-08-6 ]
  • [ 1354286-57-9 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; tricyclohexylphosphine In 1,4-dioxane; water at 90℃; for 19h; Inert atmosphere; 103 N-(5-Bromo-2-morpholinopyridin-4-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)- quinolin-4-amine (56.7 mg, 0.11 mmol), 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaboro- lan-2-yl)pyrimidine-2-carbonitrile (53.6 mg, 0.23 mmol), tricyclohexylphosphine (6.7 mg, 0.024 mmol), and tris(dibenzylideneacetone)dipalladium (0) (11.1 mg, 0.012 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.22 mL, 0.29 mmol) were added by syringe. The resulting reaction was heated to 90 °C and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-40% of a premixed solution of 89:9: 1 DCM: MeOH: ammonium hydroxide in DCM) to afford a light yellow solid that was further purified with HPLC ( 10-90% of 0.1 % TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5-(4-(5,7-difluoro-3-methyl-2-(pyridin-2- yl)quinolin-4-ylamino)-6-moi holinopyridin-3-yl)pyrimidine-2-carbonitrile.NMR (400 MHz, DMSO-d6) δ ppm 9.05 (2 H, s), 8.72 (1 H, ddd, J=4.9, 1.8, 1.0 Hz), 8.43 (1 H, br. s.), 8.04 (1 H, td, J=7.7, 1.8 Hz), 7.97 (1 H, s), 7.90 (1 H, dt, J=7.9, 1.1 Hz), 7.72 (1 H, m), 7.57 (2 H, m), 5.67 (1 H, s), 3.60 (4 H, t, J=4.7 Hz), 3.32 (4 H, m), 2.30 (3 H, s). Mass Spectrum (pos.) m/e: 537.1 (M+H)+.
  • 3
  • [ 14080-23-0 ]
  • [ 73183-34-3 ]
  • [ 1025708-31-9 ]
YieldReaction ConditionsOperation in experiment
54% With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 3,4,7,8-Tetramethyl-o-phenanthrolin In tetrahydrofuran at 20 - 80℃; for 19h; Inert atmosphere; Glovebox;
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 3,4,7,8-Tetramethyl-o-phenanthrolin In tetrahydrofuran at 80℃; for 24h; Glovebox; Inert atmosphere; Sealed tube;
  • 4
  • [ 1025708-31-9 ]
  • [ 1620828-38-7 ]
  • [ 1620827-63-5 ]
YieldReaction ConditionsOperation in experiment
10 mg With palladium diacetate; sodium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water at 100℃; for 6h; Inert atmosphere; 43 Example 43 5-(5-((4S,6S)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4- yl)thiophen-3-yl)pyrimidine-2-carbonitrile Example 43 5-(5-((4S,6S)-2-Amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-l,3-oxazin-4- yl)thiophen-3-yl)pyrimidine-2-carbonitrile To a solution of (4S,6S)-4-(4-bromothiophen-2-yl)-4-methyl-6-(trifluoromethyl)-5,6- dihydro-4H-l,3-oxazin-2-amine (XXIX-1) (50 mg) in 1 ,2-dimethoxyethane (1.0 ml) was added subsequently 2-cyanopyrimidine-5-boronic acid pinacolester (34 mg), triphenylphosphine (10 mg) and an aqueous solution of Na2CC>3 (2N, 0.2 ml). The mixture was flushed with argon for 5 min, treated with palladium(II)acetate (5 mg) and heated at 100 °C for 6 h. The mixture was evaporated and purified by chromatography (NH2-phase from Biotage, gradient EtOAc in heptane, 0% to 100% EtOAc) followed by another chromatography (Si02, gradient MeOH in dichloromethane, 0% to 10% MeOH) to give the title compound (10 mg) as a colorless foam. MS: m/z = 368.5 [M+H]
  • 5
  • [ 1025708-31-9 ]
  • 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine [ No CAS ]
  • 5-({6-[3-(difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
53% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In ethanol; benzene at 125℃; for 0.25h; Microwave irradiation; Sealed tube; Inert atmosphere; 1 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile Example 1 5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile Into a 5 mL microwave vial was combined 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine (Intermediate 1, 176.00 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), tetrakis(triphenylphosphine)palladium(0) (56.63 mg, 0.05 mmol), and sodium bicarbonate (1.38 mL, 1.15 mol/L; 1.59 mmol). The vial was sealed, purged with nitrogen and heated to 125° C. under microwave conditions for 15 minutes. Water was removed from the reaction with a pipette, and the crude reaction mixture was filtered thru CELITE, and washed with EtOAc (3*5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-30%, EtOAc/hexanes) afforded the title compound as a white solid (100 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.19 (dd, J=2.3, 7.8 Hz, 1H), 7.04-6.61 (m, 1H), 4.49 (q, J=7.0 Hz, 2H), 4.30-4.25 (m, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=384.15.
  • 6
  • [ 1025708-31-9 ]
  • 2-[(3,5-difluoropyridin-2-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl trifluoromethanesulfonate [ No CAS ]
  • 5-{2-[(3,5-difluoropyridin-2-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
31 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 70℃; for 1h; Inert atmosphere; 44.5 Production of 5-{2-[(3,5-difluoropyridin-2-yl)methoxy]-6,7-dihydr o-5H-cyclopenta[b]pyridin-4-yl}pyrimidine-2-carboni trile [Step 5] Production of 5-{2-[(3,5-difluoropyridin-2-yl)methoxy]-6,7-dihydr o-5H-cyclopenta[b]pyridin-4-yl}pyrimidine-2-carboni trile To 2-[(3,5-difluoropyridin-2-yl)methoxy]-6,7-dihydro-5 H-cyclopenta[b]pyridin-4-yl trifluoromethanesulfonate (50 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri midine-2-carbonitrile (31 mg), Pd(dppf)Cl2·CH2Cl2 (10 mg) and potassium carbonate (50 mg) was added 1,4-dioxane/water (3/1, 1 mL), and the mixture was degassed, then stirred under Ar atmosphere at 70°C for 1 hour. After the reaction mixture was allowed to return to room temperature, the mixture was added with water and ethyl acetate, and subjected to extraction. The organic layer was dried over anhydrous sodium sulfate, filtered off and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (31 mg) as a white solid. [MS (ESI) m/z 366.3 (M+H)+]
  • 7
  • [ 1025708-31-9 ]
  • [ 145343-76-6 ]
  • 2-chloro-4-(2-cyanopyrimidin-5-yl)benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate In 1,2-dimethoxyethane; water at 100℃; for 2h; 22.A Step A. 2-Chloro-4-(2-cyanopyrimidin-5 -yl)benzoic acid Step A. 2-Chloro-4-(2-cyanopyrimidin-5 -yl)benzoic acidA mixture of 2-chloro-4-iodobenzoic acid (0.28 g, 0.99 mmol),5 -(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (0.41 g, 1.8 mmol), andK3P04 (0.64 g, 3.0 mmol) in DME (4.2 mL) and water (1.4 mL) was stirred at 100 °C for 2 h.After cooling the mixture, it was diluted with water and CH2C12 and filtered. The aqueous layerwas washed with CH2C12 and neutralized with iN aq. HC1. The precipitate was collected and dried to give the title compound. MS (ESI) mlz = 260, 262 (M+H)‘H NMR (300 MHz, DMSO-d6) (5 (ppm): 9.46 (2H, s), 8.15 (1H, d, J= 1.4 Hz), 8.00-7.89 (2H,m)
With potassium phosphate In 1,2-dimethoxyethane; water at 100℃; for 2h; 17.A Step A. 2-Chloro-4-(2-cyanopyrimidin-5-yl)benzoic acid A mixture of 2-chloro-4-iodobenzoic acid (0.28 g, 0.99 mmol), (0992) 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (0.41 g, 1.8 mmol), and K3PO4 (0.64 g, 3.0 mmol) in DME (4.2 mL) and water (1.4 mL) was stirred at 100 °C for 2 h. After cooling the mixture, it was diluted with water and CH2CI2 and filtered. The aqueous layer was washed with CH2CI2 and neutralized with IN aq. HC1. The precipitate was collected and dried to give the title compound. MS (ESI) m/z = 260, 262 (M+H) (0993) 1H NMR (300 MHz, OMSO-d6) δ (ppm): 9.46 (2H, s), 8.15 (1H, d, J = 1.4 Hz), 8.00-7.89 (2H, m)
YieldReaction ConditionsOperation in experiment
1.40 g With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 4h; 1 Step-i: - Preparation of 2-chloro-4-(4,4,5 ,5-tetramethyl- i ,3 ,2-dioxaborolan-2-yl)benzonitrile General procedure: The title compound was prepared following the procedure described in step-3 of Intermediate- 33 by using 4-bromo-2-chlorobenzonitrile (1.0 g, 4.61 mmo), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (1.29 g, 4.33 mmol), potassium acetate (0.9063 g, 9.23 mmol),Pd(dppf)C12 (0.190 g, 0.23 mmol) in 1,4-dioxane to afford 0.850 g of title compound :_To a solution of ethyl 4-amino-3-bromobenzoate (5.0 g, 20.66 mmol), (4- cyanophenyl)boronic acid (3.33 g, 22.72 mmol) and Pd(dppf)C12 (0.843 g, 1.03 mmoi) indiglyme (10 mL) was added K2C03 (4.27 g, 30.99 mmol). The reaction mixture was heated at80°C for 4 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 2.7 g of title product.
  • 9
  • [ 1025708-31-9 ]
  • [ 62875-84-7 ]
  • ethyl 4-amino-3-(2-cyanopyrimidin-5-yl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.500 g With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In diethylene glycol dimethyl ether at 80℃; for 4h; 2 Step-2: - Preparation of ethyl 4-amino-3 -(2-cyanopyrimidin-5-yl)benzoate The title compound was prepared following the procedure described in step-3 of Intermediate-33 by using 5-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (0.780 g,3.37 mmol), ethyl 4-amino-3-iodobenzoate (step-i of Intermediate-66, 1.17 g, 4.05 mmol),Pd(dpp/)C12(O.137 g. 0.168 minol), diglyme (10 mL), K2C03 (0.931 g, 6.74 mmol) to afford0.500 g of title product. ‘H NMR (300 MHz, DMSO-d6): 8.09-8.04 (t, J = 6.6 Hz, 1H), 7.73-7.70 (t, J = 8.1 Hz, 1H), 7.60-7.57 (t, J = 7.8 Hz, 1H), 5.03 (s, 2H), 3.30-3.19 (q, J = 7.5 Hz,4H), 1.17-1.13 (t, J= 7.5 Hz, 3H), 1.04-0.99 (t, J= 7.2 Hz, 3H); MS [M+Hj: 380:_To a solution of ethyl 4-amino-3-bromobenzoate (5.0 g, 20.66 mmol), (4- cyanophenyl)boronic acid (3.33 g, 22.72 mmol) and Pd(dppf)C12 (0.843 g, 1.03 mmoi) indiglyme (10 mL) was added K2C03 (4.27 g, 30.99 mmol). The reaction mixture was heated at80°C for 4 h. The reaction mass was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 2.7 g of title product. ‘H NMR (300 MHz, DMSO-d6): 7.92-7.89 (d, J = 7.8 Hz, 2H), 7.69-7.67 (d, J = 8.7 Hz, 1H), 7.63-7.60 (d, J = 7.8 Hz, 2H),7.56 (s, 1H), 6.8 1-6.78 (d, J = 8.4Hz, 1H), 5.83 (br s, 2H), 4.22-4.20 (q, J = 6.9 Hz, 2H),1.28-1.23 (t, J= 7.5 Hz, 3H).
  • 10
  • [ 1025708-31-9 ]
  • [ 17823-40-4 ]
  • 5-(4-cyano-2,3,5,6-tetrafluorophenyl)pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; at 115℃; for 16h; A mixture of <strong>[17823-40-4]4-bromo-2,3,5,6-tetrafluorobenzonitrile</strong> (0.44 g, 1.73 mmol), 2-cyanopyrimidine-5-boronic acid pinacol ester (0.40 g, 1.73 mmol), Pd2(dba)3 (0.09g, 0.1 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.08 g, 0.2 mmol) and K3PO4 (0.575 g, 2.5 mmol) in anhydrous toluene (20 mL) was degassed and heated at 115 C for 16 hours. The resulting mixture was poured into ethyl acetate (100 mL), after filtered off precipitate, the solution was loaded on silica gel and purified by flash column using eluents of ethyl acetate/hexane (10% to 30%). The desired fractions were collected and concentrated to give white solid Compound22 (0.12 g, in 25% yield).
  • 11
  • [ 1025708-31-9 ]
  • 2-chloro-7-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine [ No CAS ]
  • 5-(7-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2,3-b:4,5-c']dipyridin-2-yl)pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With potassium fluoride; tris-(dibenzylideneacetone)dipalladium(0); XPhos In 1,4-dioxane at 100℃; for 2h; Inert atmosphere; 41 5-(7-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2, 3-6:4, 5-c]dipyridin-2- yl)pyrimidine-2-carbonitrile (i48): 5-(7-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2, 3-6:4, 5-c]dipyridin-2- yl)pyrimidine-2-carbonitrile (i48): To a stirred solution of 2-chloro-7-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9/-/-pyrrolo[2,3- b:4,5-c]dipyridine (i47) (0.17 g, 0.468 mmol) and 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrimidine-2-carbonitrile (0.162 g, 0.702 mmol) in dioxane (15 mL), KF (0.135 g, 2.341 mmol) was added and the reaction was degassed with argon for 20 min. Pd2(dba)3 (0.043 g, 0.046 mmol) and X-phos (0.067 g, 0.14 mmol) were added and the mixture was further degassed for another 10 min. The reaction was heated at 100°C for 2h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure. The crude product was purified by silica gel (230:400 mesh) column chromatography using 0.5 % methanol in DCM to afford 5-(7-methoxy-9-((2-(trimethylsilyl)ethoxy)methyl)-9/-/- pyrrolo[2,3-b:4,5-c']dipyridin-2-yl)pyrimidine-2-carbonitrile (i48) (0.09 g, Yield 44%). 1H NMR (400 MHz, DMSO-d6) δ -0.18 (s, 9H), 0.86 (t, J = 7.9 Hz, 2H), 3.62 (t, J = 7.9 Hz, 2H), 3.97 (s, 3H), 5.92 (s, 2H), 7.06 (s, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.73 (d, J = 8.0 Hz, 1 H), 9.08 (s, 1 H), 9.80 (s, 2H). MS (ESI) m/e (M+1 )+: 433.05
  • 12
  • [ 15862-37-0 ]
  • [ 1025708-31-9 ]
  • 5-(5-bromo-3-nitropyridin-2-yl)pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
29% With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran; water at 65℃; Inert atmosphere; Sealed tube; 143.1 Step 1: 5-(5-Bromo-3-nitropyridin-2-yl)pyrimidine-2-carbonitrile To a 250 mL round bottom flask was added 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidine-2-carbonitrile (0.65 g, 2.81 mmol),2,5-dibromo-3- nitropyridine (0.793 g, 2.81 mmol) and 50 mL of THF. To this mixture was added 2M aqueous tripotassium phosphate (2.81 ml, 5.63 mmol) and PdCi2(dppf) CH2Ci2 (0.230 g, 0.281 mmol). The resulting solution was degassed by bubbling through argon gas while sonicating for 1 min. The flask was sealed and heated in an oil bath at 65°C overnight. The reaction mixture was concentrated to give a black residue. This material was purified on SiC (40 g) loaded on dry column in DCM and eluted using hexane (51 mL), 20% EtOAc/hexane (252 mL) , 20 to 50% EtOAc/hexane (357 mL, linear gradient). The product fractions gave the title compound (251 mg, 29%) as a white fluffy solid. NMR (400MHz, CDCh) δ 9.08 (d, J=2.0 Hz, 1H), 9.01 (s, 2H), 8.64 (d, J=2.0 Hz, 1H). LC/MS (306, [M+H]+). LCMS: Rt = 1.28 min; (ES): m/z (M+H)+ 306: (Waters Acquity SDS; Column Type: ACQUITY UPLC BEH C18 1.7μιη 2.1 x 50 mm; Run Time: 2.20 min; 0-100%B; Solvent A: 100% water /0.05%TFA; Solvent B: 100% ACN w/0.05%TFA; Flow: 0.8 mL/min;Detection: UV = 220 nm).
  • 13
  • [ 1025708-31-9 ]
  • 5-(dimethyl-1H-1,2,3-triazol-5-yl)-8-[(S)-oxan-4-yl(phenyl)methyl]-3,8,10,12-tetraazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene-11-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / tetrahydrofuran; water / 65 °C / Inert atmosphere; Sealed tube 2: 1,2-bis-(diphenylphosphino)ethane / 1,2-dichloro-benzene / 0.58 h / 160 °C 3: di-isopropyl azodicarboxylate; triphenylphosphine / dichloromethane / 17 h / Cooling with ice 4: copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere; Sealed tube
  • 14
  • [ 1025708-31-9 ]
  • 7-bromo-9H-pyrido[2’,3’:4,5]pyrrolo[2,3-d]pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / tetrahydrofuran; water / 65 °C / Inert atmosphere; Sealed tube 2: 1,2-bis-(diphenylphosphino)ethane / 1,2-dichloro-benzene / 0.58 h / 160 °C
  • 15
  • [ 1025708-31-9 ]
  • (S)-7-bromo-9-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-9H-pyrido[2’,3’:4,5]pyrrolo[2,3-d]pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / tetrahydrofuran; water / 65 °C / Inert atmosphere; Sealed tube 2: 1,2-bis-(diphenylphosphino)ethane / 1,2-dichloro-benzene / 0.58 h / 160 °C 3: di-isopropyl azodicarboxylate; triphenylphosphine / dichloromethane / 17 h / Cooling with ice
  • 16
  • [ 1025708-31-9 ]
  • 4-chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-yl trifluoromethanesulfonate [ No CAS ]
  • 5-(4-chloro-6-{hydroxy(1-methyl-1H-imidazol-5-yl)[6-(trifluoromethyl)pyridin-3-yl]methyl}-2-methoxyquinolin-3-yl)pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane at 65℃; for 15h;
  • 17
  • [ 1025708-31-9 ]
  • N-(5-bromo-4-fluoro-2-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide [ No CAS ]
  • N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3S,5R)-3,4,5-trimethylpiperazin-1-yl]phenyl]-6-oxo-4-(trifluoromethyl)-1H-pyridine-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II); sodium carbonate; XPhos In 1,4-dioxane; water at 120℃; for 1h; Inert atmosphere; Microwave irradiation; 31.2 N-[5-(2-cyanopyrimidin-5-yl)-4-fluoro-2-[(3S, 5RJ-3, 4, 5-trimethylpiperazin-1- yl]phenyl]-6-oxo-4-(trifluoromethyl)-lH-pyridine-3-carboxamide To a 5 mL microwave vial charged with N-(5-bromo-4-fluoro-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-l,6-dihydropyridine-3- carboxamide (29.85 mg, 0.059 mmol), prepared according to the method described in Example 29), 2-cyanopyrimidine-5-boronic acid pinacol ester (40.9 mg, 0.177 mmol), sodium carbonate, anhydrous (62.6 mg, 0.591 mmol) and XPhos (5.63 mg, 0.012 mmol), XPhos Pd G2 (9.30 mg, 0.012 mmol) was added in water (1846 μ) / 1,4-dioxane (1108 μ) to give a white suspension that was stirred for 5 min, degassed, purged with N2, and microwaved for 60 min at 120 °C. The solvent was evaporated and 15 ml of DCM was added. The suspension was sonicated and the organic phase was removed and concentrated (3X). The crude black oil was purified using a Biotage column, (100-0%, CH2C12: 10% MeOH in CH2C12 + NH4Ac; in 10 min and isocratic for 5min using KP-SIL lOg column. Collected at 0% of the CH2C12) to yield an impure product. The product was freeze dried for 2 days to yield the crude product that was purified via preparatory HPLC. The fractions were evaporated and the concentrate was slowly passed through a ionic exchange column Rxn CX 6cc with MeOH and NH4OH. The product was lyophilized to yield 8.1 mg (26% yield) of the title compound. -NMR (500 MHz, MeOD) δ 9.14 (s, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.96 (s, 1H), 7.16 (d, J = 12.4 Hz, 1H), 6.92 (s, 1H), 3.15 (d, J = 11.6 Hz, 2H), 2.65 (t, J = 11.2 Hz, 2H), 2.61 - 2.54 (m, 2H), 2.39 (s, 3H), 2.03 (s, 1H), 1.17 (d, J = 6.1 Hz, 6H); LCMS [M+H]+ 530.
  • 18
  • [ 1025708-31-9 ]
  • tert-butyl (1-(1'-((4-(2-cyanopyrimidin-5-yl)isoquinolin-3-yl)methyl)-2'-oxospiro[azetidine-3,3'-indolin]-1-yIcarbonyl)cyclopropyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; 1,2-dimethoxyethane / 16 h / 90 °C / Inert atmosphere; Sealed tube 2.1: caesium carbonate / acetonitrile / 0.17 h / 20 °C 2.2: 16 h / 70 °C
  • 19
  • [ 1025708-31-9 ]
  • 5-(3-((1-(1-aminocyclopropanecarbonyl)-2'-oxospiro[azetidine-3,3'-indolin]-1'-yl)methyl)isoquinolin-4-yl)pyrimidine-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; 1,2-dimethoxyethane / 16 h / 90 °C / Inert atmosphere; Sealed tube 2.1: caesium carbonate / acetonitrile / 0.17 h / 20 °C 2.2: 16 h / 70 °C 3.1: dihydrogen peroxide; potassium carbonate / water; dimethyl sulfoxide / 1 h / 0 - 20 °C 3.2: 8 h / 20 °C
  • 20
  • 4-iodo-3-methyl-isoquinoline [ No CAS ]
  • [ 1025708-31-9 ]
  • 5-(3-(bromomethyl)isoquinolin-4-yl)pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 16h; Inert atmosphere; Sealed tube; 2.a Step a) 5-(3-(Bromomethvnisoauinolin-4-vnpyrimidine-2-carbonitrile (2a) A stirred solution of 4-iodo-3-methylisoquinoline (1 .5 g), 5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrimidine-2-carbonitrile (1 .67 g) and sodium carbonate (1 .47 g) in 1 ,2- dimethoxyethane (20 mL) and water (5 mL) was purged with argon for 5 minutes. [1 ,1 '- Bis(diphenylphosphino)ferrocene]palladium(ll) chloride FontWeight="Bold" FontSize="10" CH2CI2 (0.40 g) was added and the reaction mixture was purged again with argon for 10 minutes. The reaction mixture was stirred in sealed tube at 90 °C for 16 h, then filtered through Celite. The filtrate was diluted with water (25 mL) and extracted with ethyl acetate (2x40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced. The afforded crude was purified by column chromatography using 100-200 silica mesh and eluted with 25-28% EtOAc : p. ether. Fractions containing desired product were concentrated under reduced pressure which gave the title compound (700 mg, 45%) as a solid. MS (ES+) 247.1 [M+H]+.
  • 21
  • [ 1025708-31-9 ]
  • 1-[(2S)-4-[(2-[[(tert-butyldimethylsilyl)oxy]methyl]phenyl)methyl]-6-chloro-2-cyclopropyl-2,3-dihydroquinoxalin-1-yl]ethanone [ No CAS ]
  • (S)-5-(1-acetyl-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)-2-cyclopropyl-1,2,3,4-tetrahydroquinoxalin-6-yl)pyrimidine-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.3% With [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; caesium carbonate In 1,2-dimethoxyethane at 110℃; for 2h; Microwave irradiation; Inert atmosphere; 1B.1 Step 1: Synthesis of (S)-5-(l-acetyl-4-(2-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)-2- cyclopropyl-l,2,3,4-tetrahydroquinoxalin-6-yl)pyrimidine-2-carbonitrile To a stirred solution of l-[(2S)-4-[(2-[[(tert-butyldimethylsilyl)oxy]methyl]phenyl)methyl]-6- chloro-2-cyclopropyl-2,3-dihydroquinoxalin-l-yl]ethanone (600.00 mg, 1.24 mmol, 1.00 equiv) in DME(12.00 ml) was added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine-2- carbonitrile (571.53 mg, 2.47 mmol, 2.00 equiv), CS2CO3 (1.20 g, 3.71 mmol, 3.00 equiv) and BrettPhos Pd G3 (112.11 mg, 0.12 mmol, 0.10 equiv) in portions at room temperature. The final reaction mixture was irradiated with microwave radiation for 2 h at 110 degrees C under N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE: EA = 3:1 to afford 5-[(2S)-l-acetyl-4-[(2-[[(tert-butyldimethylsilyl)oxy]methyl]phenyl)methyl]-2-cyclopropyl-2,3- dihydroquinoxalin-6-yl]pyrimidine-2-carbonitrile (550.00 mg, 80.30%) as a yellow oil. LC/MS: mass calcd. For C32H39N5O2S1: 553.29, found: 554.40 [M+H]+.
42% With [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate; caesium carbonate In 1,2-dimethoxyethane at 110℃; for 2h; Inert atmosphere; Sealed tube; Microwave irradiation;
  • 22
  • [ 1025708-31-9 ]
  • C21H19BrClFN4O4 [ No CAS ]
  • C26H21ClFN7O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
5.9 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In water at 100℃; for 2h; 52 Example 52 Compound 86 (20 mg, 0.038 mmol) was dissolved in 1,2-dioxane (0.2 mL), and then 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (11.4 mg, 0.049 mmol), PdCl2(dppf) (2.48 mg, 0.0038 mmol) and a 2 mol/L aqueous solution of potassium carbonate (38.0 ul, 0.076mmol) were added thereto, and the mixture was stirred at 100°C for 2 hours. After cooling, the reaction mixture was added to a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The extract was dried with sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain Compound (1-2-16) (5.9 mg, 0.0107mmol). Compound (1-2-16); Method B LC/MS retention time =1.82 min. MS (ESI) m/z =550.35 (M+H)+.
  • 23
  • [ 1025708-31-9 ]
  • benzyl ((R)-4-(4-bromophenyl)-1-((S)-1-(4-chloro-3 -(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)phenyl)-2-(((1-(trifluoromethyl)cyclopropyl)carbamoyl)oxy)ethyl)-4-neopentyl-5-oxoimidazolidin-2-ylidene)carbamate [ No CAS ]
  • C35H32ClF5N10O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / 1,4-dioxane; water / 1 h / 85 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 60 °C
  • 24
  • [ 1025708-31-9 ]
  • benzyl ((R)-4-(4-bromophenyl)-1-((S)-1-(4-chloro-3 -(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)phenyl)-2-(((1-(trifluoromethyl)cyclopropyl)carbamoyl)oxy)ethyl)-4-neopentyl-5-oxoimidazolidin-2-ylidene)carbamate [ No CAS ]
  • (S)-2-((R)-2-(((benzyloxy)carbonyl)imino)-4-(4-(2-cyanopyrimidin-5-yl)phenyl)-4-neopentyl-5-oxoimidazolidin-1-yl)-2-(4-chloro-3-(1-(difluoromethyl)-1H-1,2,4-triazol-5-yl)phenyl)ethyl (1-(trifluoromethyl)cyclopropyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 85℃; for 1h; 50 Preparation of Compound 167: To a solution of benzyl ((R)-4-(4-bromophenyl)- 1 -((5)-i -(4-chloro-3 -(1 -(difluoromethyl)- 1-1 ,2,4-triazol-5 -yl)phenyl)-2-(((i -(trifluoromethyl)cyclopropyl)carbamoyl)oxy)ethyl)-4-neopentyl-5 - oxoimidazolidin-2-ylidene)carbamate (0.03 g, 0.034 mmol) in dioxane (4 mL) and water (0.6 mL) were added 2-cyanopyrimidine-5-boronic acid pinacol ester (0.04 g, 0.017 mol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.0017 mol) and potassium carbonate (11 mg, 0.017 mmol) was stirred at 85 °C for 1 h. Thereaction mixture was treated with saturated ammonium chloride solution and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (EtOAc/hexanes) to give the product (S)-2-((R)-2- (((benzyloxy)carbonyl)imino)-4-(4-(2-cyanopyrimidin-5 -yl)phenyl)-4-neopentyl-5-oxoimidazolidin- 1 -yl)-2-(4-chloro-3-(i -(difluoromethyl)- 1-i ,2,4-triazol-5- yl)phenyl)ethyl (1 -(trifluoromethyl)cyclopropyl)carbamate. Then, this compound was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (3 mL). The mixture was heated at 60 °C for 2 h. The mixture was concentrated down and purified by reverse phase HPLC (acetonitrile/water, both containing 0.1% TFA) togive the product.
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