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[ CAS No. 915411-02-8 ]

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Chemical Structure| 915411-02-8
Chemical Structure| 915411-02-8
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Product Details of [ 915411-02-8 ]

CAS No. :915411-02-8 MDL No. :MFCD08059264
Formula : C13H17BN2O2 Boiling Point : 404.1±18.0°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :244.10 g/mol Pubchem ID :-
Synonyms :

Safety of [ 915411-02-8 ]

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 [ 915411-02-8 ]

  • Downstream synthetic route of [ 915411-02-8 ]

[ 915411-02-8 ] Synthesis Path-Downstream   1~15

  • 1
  • [ 73183-34-3 ]
  • [ 186407-74-9 ]
  • [ 915411-02-8 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate In dimethyl sulfoxide at 80℃; for 4h; 6 Reference Example 6 Indazole-4-Boronate Ester (70) : Route 2 (70)To a solution of 3 -bromo-2 -methyl aniline (5.0g, 26.9mmol) in chloroform(5OmL) was added potassium acetate (1.05eq., 28.2mmol, 2.77g). Acetic anhydride (2.0eq., 53.7mmol, 5.07mL) was added with concurrent cooling in ice-water. The mixture was then stirred at room temperature for 10 minutes after which time a white gelatinous solid formed. 18-Crown-6 (0.2eq., 5.37mmol, 1.42g) was then added followed by wo-amyl nitrite (2.2eq., 59.1mmol, 7.94mL) and the mixture was heated under reflux for 18 h. The reaction mixture was allowed to cool, was partitioned between chloroform (3 * 10OmL) and saturated aqueous sodium hydrogen carbonate EPO (10OmL). The combined organic extracts were washed with brine (10OmL), separated and dried (MgSO4).The crude product was evaporated onto silica and purified by chromatography eluting with 20%- »40% EtO Ac-petrol to give the iV-acetyl indazole (73) (3.14g, 49%) as an orange solid followed by the indazole (74) (2.13g, 40%) as a pale orange solid.73: 1H NMR (400 MHz, CDCl3) 2.80 (3H, s), 7.41 (IH, t, J=7.8Hz), 7.50 (IH, d, J=7.8Hz), 8.15 (IH, s), 8.40 (IH, d, J=7.8Hz). 74: 1H NMR (400 MHz, CDCl3) 7.25 (IH, t, J=7.3Hz), 7.33 (IH, d, J=7.3Hz), 7.46 (IH, d, J=7.3Hz), 8.11 (IH, s), 10.20 (IH, br s),To a solution of the iV-acetyl indazole (3.09g, 12.9mmol) in MeOH (5OmL) was added 6N aqueous HCl (3OmL) and the mixture was stirred at room temperature for 7 h. The MeOH was evaporated and the mixture partitioned between EtOAc (2 x 5OmL) and water (5OmL). The combined organic layers were washed with brine (5OmL), separated and dried (MgSO4). The solvent was removed by evaporation under reduced pressure to give an orange solid (2.36 g, 93%).To a solution of the 4-bromoindazole (500 mg, 2.54mmol) and bis(pinacolato)diboron (1.5 eq., 3.81mmol) in DMSO (2OmL) was added potassium acetate (3.0 eq., 7.61mmol, 747 mg; dried in drying pistol) and PdCl2(dppf)2 (3 mol%, 0.076mmol, 62 mg). The mixture was degassed with argon and heated at 8O0C for 40 h. The reaction mixture was allowed to cool and partitioned between water (5OmL) and ether (3 x 5OmL). The combined organic layers were washed with brine (5OmL), separated and dried (MgSO4). The crude material was purified by chromatography eluting with 30%-»40% EtO Ac-petrol to give an inseparable 3:1 mixture of the boronate ester (369 mg, 60%) and indazole (60 mg, 20%); this was isolated as a yellow gum which solidified upon standing to furnish (70) as an off- white solid.1H NMR (400 MHz, ^6-DMSO) (70) 1.41 (12H, s), 7.40 (IH, dd, J=8.4Hz, 6.9Hz), 7.59 (IH, d, J=8.4Hz), 7.67 (IH, d, J=6.9Hz), 10.00 (IH, br s), 8.45 (IH, s), and EPO indazole: 7.40 (IH, t), 7.18 (IH, t, J=7.9Hz), 7.50 (IH, d, J=9.1Hz), 7.77 (IH, d, J=7.9Hz), 8.09 (IH, s). Impurity at 1.25.
  • 2
  • [ 915411-02-8 ]
  • [ 885618-31-5 ]
  • [ 885618-38-2 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In ethanol; water; toluene at 120℃; for 1h; Irradiation; 8 Reference Example 8: Preparation of 2-(lH-Indazol-4-yl)-4-morpholin-4- vI-thienof3,2-dlpyrimidine-6-carbaldehvde (71) EPO A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6- carbaldehyde (66) (lOOmg, 0.35mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan- 2-yl)-lH-indazole (70) (95mg, 0.39mmol) and sodium carbonate (112mg) were suspended in toluene (2.5mL), ethanol (1.5mL) and water (0.7mL). To this was added bis(triphenylphosphine)palladium(II) chloride (13.5mg) and the reaction vessel was flushed with argon. The reaction mixture was microwaved at 12O0C for 1 h and then partitioned between DCM and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography to yield the title compound 71 (97mg).
  • 3
  • [ 915411-02-8 ]
  • [ 885618-54-2 ]
  • 2-(1H-indazol-4-yl)-6-(4-methylpiperazin-1-yl-methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With sodium carbonate In ethanol; water; toluene at 130℃; for 2h; Irradiation; 2 Example 2: 2-(lH-IndazoI-4-yl)-6-(4-methvI-piperazin-l-ylmethyl)-4- morpholin-4-yl-thieno[3,2-dlpyrimidine (59) by Route 2 Indazole-4-boronate ester (2.0eq., 0.82mmol), 2-Chloro-6-(4-methyl- piperazin-1-yl methyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (compound 72 prepared in Reference Example 4: 150mg, 0.41mmol) and sodium carbonate (3.0eq., 130mg) were combined in a mixture of toluene (2mL), ethanol (ImL) and water (0.5mL). PdCl2(PPh3 )2 (O.leq.) was added and the reaction mixture was flushed with Argon, and then heated in a microwave reactor at 13O0C for 2 h. Following extraction EPO (DCM/brine) and flash column chromatography, the product was isolated as a white solid (149mg, 81%)
  • 4
  • [ 73183-34-3 ]
  • [ 53857-58-2 ]
  • [ 915411-02-8 ]
YieldReaction ConditionsOperation in experiment
74% With potassium acetate In dimethyl sulfoxide at 100℃; for 48h; 9.a.iii A round bottom flask was charged with 7-bromoindazole (200 mg, 1.01 mmol), bis(pinacolato)diboron (335 mg, 1.32 mmol), potassium acetate (285 mg, 3.03 mmol) and Pd(dppf)Cl2 CH2Cl2 complex (41 mg, 0.05 mmol). Dry DMSO (4 mL) was added under argon and the mixture was heated to 100° C. for 48 h. The reaction mixture was then cooled to rt, filtered over Hyflo and the filter cake washed with TBME (50 mL). Brine (20 mL) was added to the filtrate and the layers were separated. The aqueous layer was extracted with TBME (2×25 mL) and the combined organics were washed with water (2×20 mL), dried (Na2SO4) and concentrated to provide the crude product (323 mg). Flash chromatography over SiO2 (16 g, AcOEt/heptane 1:4) provided the pure indazole 7-pinacol boronate (181 mg, 74%).
74% With potassium acetate In dimethyl sulfoxide at 100℃; for 48h; 9.a.iii (iii) Indazole 7-pinacol boronate. A round bottom flask was charged with 7-bromoindazole (200 mg, 1.01 mmol), bis(pinacolato)diboron (335 mg, 1.32 mmol), potassium acetate (285 mg, 3.03 mmol) and Pd(dppf)Cl2 CH2Cl2 complex (41 mg, 0.05 mmol). Dry DMSO (4 mL) was added under argon and the mixture was heated to 100° C. for 48 h. The reaction mixture was then cooled to rt, filtered over Hyflo and the filter cake washed with TBME (50 mL). Brine (20 mL) was added to the filtrate and the layers were separated. The aqueous layer was extracted with TBME (2×25 mL) and the combined organics were washed with water (2×20 mL), dried (Na2SO4) and concentrated to provide the crude product (323 mg). Flash chromatography over SiO2 (16 g, AcOEt/heptane 1:4) provided the pure indazole 7-pinacol boronate (181 mg, 74%).
74% With potassium acetate In dimethyl sulfoxide at 100℃; for 48h; 9.a.iii [0226] (iii) Indazole 7-pinacol boronate. A round bottom flask was charged with 7-bromoindazole (200 mg, 1.01 mmol), bis(pinacolato)diboron (335 mg, 1.32 mmol), potassium acetate (285 mg, 3.03 mmol) and Pd(dppf)Cl2 CH2Cl2 complex (41 mg, 0.05 mmol). Dry DMSO (4 mL) was added under argon and the mixture was heated to 1000C for 48 h. The reaction mixture was then cooled to rt, filtered over Hyflo and the filter cake washed with TBME (50 mL). Brine (20 mL) was added to the filtrate and the layers were separated. The aqueous layer was extracted with TBME (2x25 mL) and the combined organics were washed with water (2x20 mL), dried (Na2SO4) and concentrated to provide the crude product (323 mg). Flash chromatography over SiO2 (16 g, AcOEt/heptane 1:4) provided the pure indazole 7-pinacol boronate (181 mg,
  • 5
  • [ 915411-02-8 ]
  • [ 915411-01-7 ]
YieldReaction ConditionsOperation in experiment
74% With hydrogenchloride; In water; at 80℃; for 20h; Indazole 7-pinacol boronate (247 mg, 1.01 mmol) was dissolved in 2 M aqueous HCl (5 mL) and the mixture was heated to 80 C. for 20 h. The reaction mixture was cooled to room temperature, neutralized with 1M NaOH solution (12 mL) to pH 6 and extracted with ethyl acetate (3×20 mL). The combined organics were washed with water (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the crude boronic acid (148 mg). The crude material was purified by flash chromatography (CH2Cl2/MeOH 95:5) to give 120 mg (74%) of the boronic acid of 7-bromoindazole.
74% (iv) Boronic acid of 7-bromoindazole. Indazole 7-pinacol boronate (247 mg, 1.01 mmol) was dissolved in 2 M aqueous HCl (5 mL) and the mixture was heated to 80 C. for 20 h. The reaction mixture was cooled to room temperature, neutralized with 1M NaOH solution (12 mL) to pH 6 and extracted with ethyl acetate (3×20 mL). The combined organics were washed with water (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the crude boronic acid (148 mg). The crude material was purified by flash chromatography (CH2Cl2/MeOH 95:5) to give 120 mg (74%) of the boronic acid of 7-bromoindazole.
74% [0227] (iv) Boronic acid of 7-bromoindazole. Indazole 7-pinacol boronate(247 mg, 1.01 mmol) was dissolved in 2 M aqueous HCl (5 mL) and the mixture was heated to 80C for 20 h. The reaction mixture was cooled to room temperature, neutralized with IM NaOH solution (12 mL) to pH 6 and extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with water (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the crude boronic acid (148 mg). The crude material was purified by flash chromatography (CH2Cl2ZMeOH 95:5) to give 120 mg (74%) of the boronic acid of 7-bromoindazole.
  • 6
  • [ 915411-02-8 ]
  • tert-butyl 3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonyl)azetidine-1-carboxylate [ No CAS ]
  • tert-butyl 3-((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(1H-indazol-7-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)phenyl)sulfonyl)azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 120℃; for 17h; 497.A Step A: tert-butyl 3 -((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-( 1H- indazol-7-yl)-3 -(2-(4-methoxybenzyl)-2H-tetrazol-5 -yl)phenyl)sulfonyl)azetidine- 1 -carboxylate A suspension of tert-butyl 3 -((2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-iodo-3 - (2-(4-methoxybenzyl)-2H-tetrazol-5 -yl)phenyl)sulfonyl)azetidine- 1 -carboxylate (500 mg, 0.537 mmol), sodium carbonate (171 mg, 1.61 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indazole (262 mg, 1.074 mmol) and tetrakis(triphenylphosphine)Pd(0) (62 mg, 0.054 mmol) in dioxane (4 ml) and water (1.0 ml) was degassed and heated at 120°C for 17 hr. The mixture was diluted with EtOAc, then washed with brine. The organic layer was dried (Mg504) and concentrated. The crude was chromatographed via silica gel chromatography 40g column, 0-20% MeOH in DCM) to give the desired product. LC/MS (M+H): 921.60.
  • 7
  • [ 915411-02-8 ]
  • 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(methylsulfonyl)benzenesulfonamide [ No CAS ]
  • 3-(1H-indazol-7-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6-(methylsulfonyl)benzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water at 80℃; for 3h; Inert atmosphere; 332.B Step B: 3 -( 1H-indazol-7-yl)-N,N-bis(4-methoxybenzyl)-2-(2-(4- methoxybenzyl)-2H-tetrazol-5 -yl)-6-(methylsulfonyl)benzenesulfon-amide To a mixture of 3 -iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H- tetrazol-5-yl)-6-(methyl-sulfonyl)benzenesulfonamide (0.20g, 0.25 mmol) in H20 (2.00 mL) and dioxane (10 mL), was added 7-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1H-indazole (0.12g, 0.51 mmol) ,Na2CO3 (81 mg, 0.76 mmol) and Pd(dppf)C12 CH2C12 (41 mg, 0.05 mmol) under nitrogen. The resulting mixture was stirred at 80°C for 3 hr.The reaction mixture wasconcentrated under reduced pressure, the residue was purified by a silica gel column, eluted withethyl acetate/petroleum ether (1:50 1:1) to afford the title compound:LCMS calc’d forC39H37N707S2 [M + 1]780 found 780; ‘H NMR(400 MHz, DMSO-d6) ö 13.04 (s, 1H), 8.80 (d, J= 8.4 Hz, 1H), 8.34 (d, J= 8.4 Hz, 1H), 8.15 (s, 1H), 7.05-6.99 (m, 5H), 6.87-6.85 (m, 5H), 6.78-6.76 (m, 1H), 6.66-6.64 (m, 2H), 6.49-6.46 (m, 1H), 4.92-4.75 (m, 2H), 4.60-4.56 (m, 2H), 4.06-3.97 (m, 2H), 3.81(s, 3H), 3.77 (s, 9H).
  • 8
  • [ 915411-02-8 ]
  • 6-(chloromethyl)-N4-cyclopropyl-N2-methylpyridine-2,4-dicarboxamide [ No CAS ]
  • 6-((1H-indazol-7-yl)methyl)-N4-cyclopropyl-N2-methylpyridine-2,4-dicarboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.666667h; Inert atmosphere; Microwave irradiation;
44.9% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.666667h; Microwave irradiation; 8 6-((1H-indazol-7-yl)methyl)-N4-cyclopropyl-N2-methylpyridine-2,4-dicarboxamide 6-(Chloromethyl)-N4-cyclopropyl-N2-methylpyridine-2,4-d icarboxamide (66 mg, 0.247 mmol) was combined with 7-(4,4,5,5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)- 1 H-indazole (68 mg, 0.279 mmol),potassium carbonate (104 mg, 0.753 mmol) and PdCI2(dppf) (34 mg, 0.046 mmol) in 1,4-dioxane (2 mL) and water (1 mL) in a 2 mL microwave vial. This was heated at 120 °C for 40 mm. The solution was filtered through Celite, partitioned betweeen EtOAc (10 mL) and water (10 mL), extracted with further EtOAc (2 x 10 mL), dried through a hydrophobic frit and concentrated to give 240 mg of a brown oil. This was purified by chromatography on Si02 (Biotage SNAP 25 g, eluting with O-100%ethyl acetate / cyclohexane). The desired fractions were concentrated to give 6-((1H-indazol-7- yl)methyl)-N4-cyclopropyl-N2-methylpyrid ine-2,4-d icarboxamide (43 mg, 0.111 mmol, 44.9 % yield) as a pale brown solid.LCMS (2 mm Formic): Rt = 0.80 mi [MH]+ = 350.5
  • 9
  • [ 915411-02-8 ]
  • 3-(1H-indazol-7-yl)-5-(pyridin-3-ylamino)-phenol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water / 20 h / 80 °C 1.2: 20 °C / pH 6 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 48 h / Heating / reflux 3.1: methyl-phenyl-thioether; trifluoroacetic acid / 15 h / 20 °C 3.2: pH 7
Multi-step reaction with 3 steps 1.1: hydrogenchloride; water / 20 h / 80 °C 1.2: 20 °C / pH 6 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 48.16 h / 20 °C / Heating / reflux 3.1: methyl-phenyl-thioether; trifluoroacetic acid / 15 h / 20 °C 3.2: pH 7
  • 10
  • [ 21443-96-9 ]
  • [ 915411-02-8 ]
  • 11
  • [ 2942-42-9 ]
  • [ 915411-02-8 ]
  • 12
  • [ 915411-02-8 ]
  • N-[1-(5-bromothiophen-2-yl)ethyl]-6,7-dimethoxy-2-methylquinazolin-4-amine [ No CAS ]
  • N-{1-[5-(1H-indazol-7-yl)thiophen-2-yl]ethyl}-6,7-dimethoxy-2-methylquinazolin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
12 mg With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 110℃; Inert atmosphere; 246 Example 246 N-{1 -[5-(1H-indazol-7-yl)thiophen-2-yl]ethyl}-6,7-dimethoxy-2-methylquinazolin-4-amine Under argon, N-[1 -(5-bromothiophen-2-yl)ethyl]-6,7-dimethoxy-2-methylquinazolin-4-amine (described in example 209; 20.0 mg, 49.0 μιτιοΙ), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-indazole (12.0 mg, 49.0 μηιοΙ), K2CO3 (27.1 mg, 196 μηιοΙ) and Pd(PPh3)4 (2.83 mg, 2.45 μιτιοΙ) in dioxane (500 μ) and H2O (100 μ) were stirred at 1 10°C overnight. H2O was added, the mixture extracted with DCM and the solvent removed in vacuo. Purification by preparative HPLC (basic conditions) gave the title compound as a white solid (12.0 mg, 53%). 1H-NMR (400 MHz, DMSO-de): δ [ppm] = 13.22 (br s, 1H), 8.19 (br d, 2H), 7.72 (d, 1H), 7.67 (s, 1H), 7.55 (br d, 1H), 7.42 (br d, 1H), 7.19 (br d, 1H), 7.14 (br t, 1H), 7.06 (s, 1H), 5.99 (quin, 1H), 3.88 (s, 3H), 3.88 (s, 3H), 2.45 (s, 3H), 1.75 (d, 3H). LC-MS (method 9): m/z: [M+H]+ = 446, Rt = 0.92 min.
  • 13
  • [ 915411-02-8 ]
  • tert-butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate [ No CAS ]
  • (S)-tert-butyl 4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane; water at 25 - 90℃; for 0.5h; Inert atmosphere; 117.A Step A: (S)-tert-butyl 4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-117a-1) To a mixture of (S)-tert-butyl-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.30 g, 0.44 mmol) in 1,4-dioxane (6.0 mL) and water (1.0 mL) were added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (159 mg, 0.653 mmol), potassium acetate (Int-43-1, 171 mg, 1.74 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (36 mg, 0.044 mmol) at 25° C. under a nitrogen atmosphere. The mixture was heated to 90° C. for 30 min. The mixture was allowed to cool to rt and quenched with water (10 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate gradient in petroleum ether) to afford (S)-tert-butyl-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-isopropylpyridin-3-yl)-6-fluoro-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-117a-1). MS (ESI): m/z 772 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.80 (d, J=5.1 Hz, 1H), 8.44 (d, J=7.4 Hz, 1H), 8.36 (dd, J=16.0, 12.5 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.56 (dd, J=5.1, 2.0 Hz, 1H), 7.31 (t, J 7.8 Hz, 1H), 5.14-4.94 (m, 1H), 4.53-4.33 (m, 1H), 4.20-4.09 (m, 1H), 4.01 (br d, J=13.3 Hz, 1H), 3.92-3.71 (m, 1H), 3.55-3.40 (m, 3H), 3.30-3.15 (m, 1H), 2.95-2.80 (m, 1H), 2.62-2.47 (m, 2H), 1.75 (br dd, J=13.5, 7.2 Hz, 1H), 1.69-1.59 (m, 1H), 1.55-1.49 (m, 12H), 1.25-1.19 (m, 3H), 0.89 (dd, J=6.7, 5.1 Hz, 3H), 0.65 (s, 9H), -0.17 (s, 3H), -0.22 (d, J=0.8 Hz, 3H).
  • 14
  • [ 915411-02-8 ]
  • tert-butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate [ No CAS ]
  • tert-butyl (S)-4-(6-fluoro-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole; tert-butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane; water at 90℃; for 0.5h; Inert atmosphere; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 1.5h; Inert atmosphere; 3a.A; 3b.A Step A: tert-butyl (S)-4-(6-fluoro-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-3a) tert-Butyl (S)-4-(1-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)-2-isopropylpyridin-3-yl)-7-chloro-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (Int-1g) (71.4 mg, 0.101 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.037 g, 0.152 mmol), potassium acetate (0.040 g, 0.405 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (8.3 mg, 10.1 μmol) were added to a 20 mL scintillation vial equipped with magnetic stir bar, degassed under nitrogen, charged with dioxane (0.87 mL)/ water (0.15 mL), degassed three times under nitrogen and heated to 90° C. for 30 min. The reaction was cooled to room temperature, quenched with 2 mL 1:1 water/saturated ammonium chloride, extracted 1×25 mL EtOAc, washed with brine and concentrated in vacuo. The crude residue was taken up in 5 mL THF, charged with 1.0 M solution of TBAF in THF (0.506 mL, 0.506 mmol) and allowed to stir for 1.5 h at room temperature. The reaction was quenched with saturated NH4Cl, extracted 1×15 mL EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and purified on silica gel 0-100% 3:1 EtOAc/EtOH/DCM to provide tert-butyl (S)-4-(6-fluoro-1-(4-(3-hydroxypropoxy)-2-isopropylpyridin-3-yl)-7-(1H-indazol-7-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate. Int-3a MS (ESI) [M+H]+ m/z 673.
  • 15
  • [ 915411-02-8 ]
  • 6-bromo-N-(2-fluorophenyl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d’]dipyrimidin-2-amine [ No CAS ]
  • N-(2-fluorophenyl)-6-(1H-indazol-7-yl)-9,10-dihydro-8H-pyrido[1,6-a:2,3-d']dipyrimidin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
14% With 2,3-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine; potassium carbonate In 1,4-dioxane at 80℃; for 16h; 79.1 Step 1 : Synthesis of A-(2-fluorophenyl)-6-( l//-indazol-7-yl)-9, I O-dihydro-8//- pyrido[l,6-a:2,3-d']dipyrimidin-2-amine A solution of 6-bromo-N -(2-fluorophenyl)-9,10-dihydro-8//-pyrido[l,6-a:2,3- d']dipyrimidin-2-amine (40 mg, 0.11 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1/7-indazole (40 mg, 0.16 mmol), Pd(dppf)C12 (5 mg) and K2CO3 (44 mg, 0.34 mmol) in dioxane (20 mL) was stirred at 80 °C for 16 hours. The mixture was purified by Prep-HPLC (0.1% NH4HCO3) twice to give the product, which was not pure enough. Further purification by prep- TLC (DCM/MeOH = 2: 1) to afford A-(2-fhiorophenyl)-6-(l//-indazol-7-yl)-9,10-dihydro-8/7- pyrido[l,6-a:2,3-£/']dipyrimidin-2-amine (6.1 mg, 14 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 6 12.67 (s, 1H), 9.33 (s, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.87-7.78 (m, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.35-7.10 (m, 6H), 4.12-4.09 (m, 2H), 3.37-3.36 (m, 2H), 1.94-1.90 (m, 2H). LCMS (M+H+) m/z: 412.1.
14% With 2,3-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine; potassium carbonate In 1,4-dioxane at 80℃; for 16h; 79.1 Step 1 : Synthesis of A-(2-fluorophenyl)-6-( l//-indazol-7-yl)-9, I O-dihydro-8//- pyrido[l,6-a:2,3-d']dipyrimidin-2-amine A solution of 6-bromo-N -(2-fluorophenyl)-9,10-dihydro-8//-pyrido[l,6-a:2,3- d']dipyrimidin-2-amine (40 mg, 0.11 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1/7-indazole (40 mg, 0.16 mmol), Pd(dppf)C12 (5 mg) and K2CO3 (44 mg, 0.34 mmol) in dioxane (20 mL) was stirred at 80 °C for 16 hours. The mixture was purified by Prep-HPLC (0.1% NH4HCO3) twice to give the product, which was not pure enough. Further purification by prep- TLC (DCM/MeOH = 2: 1) to afford A-(2-fhiorophenyl)-6-(l//-indazol-7-yl)-9,10-dihydro-8/7- pyrido[l,6-a:2,3-£/']dipyrimidin-2-amine (6.1 mg, 14 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 6 12.67 (s, 1H), 9.33 (s, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.87-7.78 (m, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.35-7.10 (m, 6H), 4.12-4.09 (m, 2H), 3.37-3.36 (m, 2H), 1.94-1.90 (m, 2H). LCMS (M+H+) m/z: 412.1.
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