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[ CAS No. 1926172-50-0 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 1926172-50-0
Chemical Structure| 1926172-50-0
Chemical Structure| 1926172-50-0
Structure of 1926172-50-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1926172-50-0 ]

CAS No. :1926172-50-0 MDL No. :MFCD19443358
Formula : C13H15BrN2O Boiling Point : -
Linear Structure Formula :- InChI Key :QYBLJMHBINRKQM-UHFFFAOYSA-N
M.W : 295.18 Pubchem ID :71307646
Synonyms :

Calculated chemistry of [ 1926172-50-0 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.46
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 71.86
TPSA : 27.05 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.74
Log Po/w (XLOGP3) : 3.39
Log Po/w (WLOGP) : 3.48
Log Po/w (MLOGP) : 3.11
Log Po/w (SILICOS-IT) : 3.14
Consensus Log Po/w : 3.17

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.13
Solubility : 0.0218 mg/ml ; 0.0000739 mol/l
Class : Moderately soluble
Log S (Ali) : -3.64
Solubility : 0.0681 mg/ml ; 0.000231 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.21
Solubility : 0.018 mg/ml ; 0.0000611 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.02

Safety of [ 1926172-50-0 ]

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 [ 1926172-50-0 ]

* 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 [ 1926172-50-0 ]

[ 1926172-50-0 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 110-87-2 ]
  • [ 926922-40-9 ]
  • 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
95.3% With toluene-4-sulfonic acid; In dichloromethane; at 15℃; for 2h; To a mixture of 4-bromo-5- methyl-lH-indazole (3 g, 14.2 mmol) and 3,4-dihydro-2H-pyran (2.39 g, 28.4 mmol, 2.60 mL) in DCM (30 mL) was added TsOH*H20 (270 mg, 1.42 mmol) and the mixture stirred at 15 C for 2 hours. After completion, the reaction mixture was concentrated under vacuum and the residue purified by column chromatography using 5- 20& EtO Ac/Petroleum Ether as eluent to give 4-bromo-5-methyl-l-tetrahydropyran-2-yl-indazole (4 g, 13.6 mmol, 95.3% yield) as white solid. MR (400 MHz, chloroform-d) delta 8.01 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.70 (dd, J=2.8, 9.2 Hz, 1H), 4.05 - 3.96 (m, 1H), 3.79 - 3.70 (m, 1H), 2.66 - 2.44 (m, 4H), 2.25 - 2.04 (m, 2H), 1.84 - 1.56 (m, 3H).
95.3% With toluene-4-sulfonic acid; In dichloromethane; at 15℃; for 2h; To a mixture of <strong>[926922-40-9]4-bromo-5-methyl-1H-indazole</strong> (3 g, 14.2 mmol) and 3,4-dihydro-2H-pyran (2.39 g, 28.4 mmol, 2.60 mL) in DCM (30 mL) was added TsOH*H 2O (270 mg, 1.42 mmol) and the mixture stirred at 15° C. for 2 hours. After completion, the reaction mixture was concentrated under vacuum and the residue purified by column chromatography using 5 20& EtOAc/Petroleum Ether as eluent to give 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (4 g, 13.6 mmol, 95.3% yield) as white solid. 1H NMR (400 MHz, chloroform-d) delta 8.01 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 5.70 (dd, J=2.8, 9.2 Hz, 1H), 4.05-3.96 (m, 1H), 3.79-3.70 (m, 1H), 2.66-2.44 (m, 4H), 2.25-2.04 (m, 2H), 1.84-1.56 (m, 3H).
80% With pyridinium p-toluenesulfonate; In dichloromethane; at 28 - 30℃; for 18h; This reaction was run in two parallel batches. To a stirred solution of <strong>[926922-40-9]4-bromo-5-methyl-1H-indazole</strong> (100 g, 474 mmol, 1.0 eq) in DCM (1 L) was added PPTS (11.9 g, 47.4 mmol, 0.1 eq) at 28 C. Then DHP (119.6 g, 1.4 mol, 3.0 eq) was added in one portion. The mixture was stirred at 30 C. for 18 hours. TLC analysis (20% EtOAc/petroleum ether) showed complete consumption of starting material. The two batches were combined together for work-up. The reaction was quenched with H2O (1.5 L) and the layers were separated. The aqueous layer was extracted with DCM (1 L). The combined organics were washed with H2O (1 L) and brine (1 L), dried over Na2SO4, and concentrated to dryness. The residue was triturated with petroleum ether (300 mL) to provide 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 b) as an off-white solid (223 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.00 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 5.84 (dd, J=9.6, 2.5 Hz, 1H), 3.87 (d, J=12.4 Hz, 1H), 3.73 (ddd, J=11.5, 7.7, 6.0 Hz, 1H), 2.45 (s, 3H), 2.43-2.31 (m, 1H), 2.09-1.90 (m, 2H), 1.83-1.66 (m, 1H), 1.57 (dt, J=9.3, 3.9 Hz, 2H). LCMS (ESI) m/z 295, 297 (M+H).
80% With pyridinium p-toluenesulfonate; In dichloromethane; at 28 - 30℃; for 18h; This reaction was carried out in two parallel batches. To a stirred solution of <strong>[926922-40-9]4-bromo-5-methyl-1H-indazole</strong> (23) (100 g, 474 mmol) in DCM (1 L) was added PPTS (12 g, 47 mmol) at 28 C., then DHP (120 g, 1.4 mol) was added in one portion at 28 C. After the addition, the resulting mixture was stirred at 30 C. for 18 hours. TLC (EtOAc/petroleum ether, 1:5) showed the starting material was consumed. The two batches were combined together for work-up. The reaction was quenched with H2O (1.5 L) and the layers separated, and the aqueous layer extracted with DCM (14 The combined organic layers were washed with H2O (14 brine (1 L), dried over Na2SO4 and concentrated to dryness. The residue was triturated with petroleum ether (300 mL) and gave 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (24) as an off-white solid (223 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.00 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 5.84 (dd, J=9.6, 2.5 Hz, 1H), 3.87 (d, J=12.4 Hz, 1H), 3.73 (ddd, J=11.5, 7.7, 6.0 Hz, 1H), 2.45 (s, 3H), 2.43-2.31 (m, 1H), 2.09-1.90 (m, 2H), 1.83-1.66 (m, 1H), 1.57 (dt, J=9.3, 3.9 Hz, 2H). LCMS (ESI) m/z 295, 297 (M+H).

  • 2
  • [ 1926172-50-0 ]
  • [ 2158300-20-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 100 °C / Inert atmosphere 2: dichloromethane / 12 h / 15 °C
Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 100 °C / Inert atmosphere 2: dichloromethane / 12 h / 15 °C
  • 3
  • [ 1926172-50-0 ]
  • [ 2158296-66-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 100 °C / Inert atmosphere 2: dichloromethane / 12 h / 15 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -40 - -20 °C
Multi-step reaction with 3 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 100 °C / Inert atmosphere 2: dichloromethane / 12 h / 15 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / -40 - -20 °C
  • 4
  • [ 1926172-50-0 ]
  • [ 2158300-31-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium t-butanolate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct / toluene / 10 h / 70 °C 2: 2,6-dimethylpyridine; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 1 h / 0 - 10 °C 3: triethylamine / dichloromethane / 0.5 h / 0 °C
Multi-step reaction with 3 steps 1: sodium t-butanolate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct / toluene / 10 h / 70 °C 2: trimethylsilyl trifluoromethanesulfonate; 2,6-dimethylpyridine / dichloromethane / 1 h / 0 - 10 °C 3: triethylamine / dichloromethane / 0.5 h / 0 °C
  • 5
  • [ 1926172-50-0 ]
  • [ 2158300-30-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium t-butanolate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct / toluene / 10 h / 70 °C 2: 2,6-dimethylpyridine; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 1 h / 0 - 10 °C
Multi-step reaction with 2 steps 1: sodium t-butanolate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct / toluene / 10 h / 70 °C 2: trimethylsilyl trifluoromethanesulfonate; 2,6-dimethylpyridine / dichloromethane / 1 h / 0 - 10 °C
  • 6
  • [ 1926172-50-0 ]
  • [ 2158296-70-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: sodium t-butanolate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct / toluene / 10 h / 70 °C 2: 2,6-dimethylpyridine; trimethylsilyl trifluoromethanesulfonate / dichloromethane / 1 h / 0 - 10 °C 3: triethylamine / dichloromethane / 0.5 h / 0 °C 4: toluene-4-sulfonic acid / acetonitrile / 1 h / 90 °C
Multi-step reaction with 4 steps 1: sodium t-butanolate; chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct / toluene / 10 h / 70 °C 2: trimethylsilyl trifluoromethanesulfonate; 2,6-dimethylpyridine / dichloromethane / 1 h / 0 - 10 °C 3: triethylamine / dichloromethane / 0.5 h / 0 °C 4: toluene-4-sulfonic acid / acetonitrile / 1 h / 90 °C
  • 7
  • [ 1926172-50-0 ]
  • [ 2158300-45-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 110 °C / Inert atmosphere 2: dichloromethane / 1 h / 15 °C
Multi-step reaction with 2 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 110 °C / Inert atmosphere 2: dichloromethane / 1 h / 15 °C
  • 8
  • [ 1926172-50-0 ]
  • [ 2158296-74-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 110 °C / Inert atmosphere 2: dichloromethane / 1 h / 15 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / -50 °C
Multi-step reaction with 3 steps 1: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); ruphos / toluene / 12 h / 110 °C / Inert atmosphere 2: dichloromethane / 1 h / 15 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / -50 °C
Multi-step reaction with 3 steps 1: caesium carbonate; ruphos; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 12 h / 110 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / -40 °C
  • 9
  • [ 1926172-50-0 ]
  • [ 2158300-15-1 ]
  • [ 2158300-18-4 ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 100℃; for 12h; Inert atmosphere; 148.A Step A: tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: To a solution of tert-butyl 2-(cyanomethyl)-4-[2-[[(2,S)-l- methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l- carboxylate (200 mg, 424 umol), 4-bromo-5-methyl-l-tetrahydropyran-2-yl-indazole (188 mg, 636 umol), RuPhos (39.6 mg, 84.8 umol) and CS2CO3 (414 mg, 1.27 mmol) in toluene (6 mL) was added Pd2(dba)3 (38.8 mg, 42.4 umol) and the reaction stirred at 100 °C for 12 hours under N2. Upon completion, the mixture was purified directly by silica gel chromatography (PE: EtOAc=3 : l to 0: 1) to give fert-butyl 2-(cyanomethyl)-4-[2-[[(25)-l-methylpyrrolidin-2- yl]methoxy]-7-(5-methyl-l-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (120 mg, 149 umol, 35.1% yield, 85.0% purity) as a brown solid. ES+APCI MS m/z 686.6 [M+H]+. MR (400MHz, CHLOROFORM-d) δ = 8.04 (d, J= 2.0 Hz, 1H), 7.33 - 7.29 (m, 2H), 5.70 (dd, J= 2.4, 9.2 Hz, 1H), 4.62 (br s, 1H), 4.39 (br s, 1H), 4.34 - 4.28 (m, 2H), 4.20 - 4.14 (m, 1H), 4.05 (br d, J= 12.0 Hz, 2H), 3.91 (br d, J= 12.4 Hz, 1H), 3.81 - 3.72 (m, 1H), 3.53 (br t, J= 4.8 Hz, 2H), 3.27 (br d, J= 10.8 Hz, 2H), 3.10 (br d, J= 6.8 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.90 - 2.65 (m, 5H), 2.59 (br d, J= 10.2 Hz, 1H), 2.50 (s, 3H), 2.43 (s, 3H), 2.35 - 2.26 (m, 1H), 2.23 - 2.15 (m, 1H), 2.11 (br s, 2H), 1.90 - 1.65 (m, 7H), 1.54 (s, 9H).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 100℃; for 12h; Inert atmosphere; 148.A Example 148 2-[4-[7-(5-methyl-1H-indazol-4-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methox- y]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2-- yl]acetonitrile Step A: tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-- 1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- -4-yl]piperazine-1-carboxylate To a solution of tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetr- ahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (200 mg, 424 umol), 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (188 mg, 636 umol), RuPhos (39.6 mg, 84.8 umol) and Cs 2CO 3 (414 mg, 1.27 mmol) in toluene (6 mL) was added Pd 2(dba) 3 (38.8 mg, 42.4 umol) and the reaction stirred at 100° C. for 12 hours under N 2. Upon completion, the mixture was purified directly by silica gel chromatography (PE:EtOAc=3:1 to 0:1) to give tert-butyl 2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-- 1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- -4-yl]piperazine-1-carboxylate (120 mg, 149 umol, 35.1% yield, 85.0% purity) as a brown solid. ES+APCI MS m/z 686.6 [M+H] +. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.04 (d, J=2.0 Hz, 1H), 7.33-7.29 (m, 2H), 5.70 (dd, J=2.4, 9.2 Hz, 1H), 4.62 (br s, 1H), 4.39 (br s, 1H), 4.34-4.28 (m, 2H), 4.20-4.14 (m, 1H), 4.05 (br d, J=12.0 Hz, 2H), 3.91 (br d, J=12.4 Hz, 1H), 3.81-3.72 (m, 1H), 3.53 (br t, J=4.8 Hz, 2H), 3.27 (br d, J=10.8 Hz, 2H), 3.10 (br d, J=6.8 Hz, 1H), 3.06-2.96 (m, 1H), 2.90-2.65 (m, 5H), 2.59 (br d, J=10.2 Hz, 1H), 2.50 (s, 3H), 2.43 (s, 3H), 2.35-2.26 (m, 1H), 2.23-2.15 (m, 1H), 2.11 (br s, 2H), 1.90-1.65 (m, 7H), 1.54 (s, 9H).
  • 10
  • [ 1926172-50-0 ]
  • [ 2158300-25-3 ]
  • [ 2158300-29-7 ]
YieldReaction ConditionsOperation in experiment
48% With chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; sodium t-butanolate In toluene at 70℃; for 10h; 152.A Step A: tert-butyl 2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methylethoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: A mixture of tert-butyl 2-(cyanomethyl)-4-[2-[(lR)-2- (dimethylamino)- l-methyl-ethoxy]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine- 1-carboxylate (0.50 g, 1.09 mmol), 4-bromo-5-methyl-l-tetrahydropyran-2-yl-indazole (482 mg, 1.63 mmol), t-BuONa (314 mg, 3.26 mmol) and [2-(2-aminoethyl)phenyl]-chloro- palladium;dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (80.4 mg, 109 umol) in toluene (30 mL) was stirred at 70 °C for 10 hours. The mixture was diluted with water (10 mL) and the aqueous layer extracted with ethyl acetate (3 χ 20 mL). The organic layers were washed with saturated sodium chloride solution (30 mL), dried over Na2SC"4, filtered and concentrated under vacuum. The residue was purified by reverse phase flash [water (Formic Acid, 0.1 %.)/acetonitrile] to give tert-butyl 2-(cyanomethyl)-4-[2-[(lR)-2-(dimethylamino)-l-methyl- ethoxy]-7-(5-methyl-l-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]piperazine-l-carboxylate (0.40 g, 522 umol, 48.0 % yield) as a yellow solid. ES+APCI MS m/z 674.3 [M+H]+. 1H MR (400MHz, chloroform-d) δ = 8.03 (d, J= 1.6 Hz, 1H), 7.31 - 7.27 (m, 2H), 5.68 (dd, J= 2.4, 9.6 Hz, 1H), 5.31 (br s, 1H), 4.61 (br s, 1H), 4.28 (s, 2H), 4.08 - 3.94 (m, 3H), 3.86 (br d, J= 11.6 Hz, 1H), 3.79 - 3.71 (m, 1H), 3.52 (br t, J= 4.8 Hz, 2H), 3.24 (br d, J= 12.8 Hz, 2H), 3.04 - 2.91 (m, 1H), 2.87 - 2.67 (m, 5H), 2.65 - 2.47 (m, 2H), 2.41 (s, 3H), 2.32 (br s, 6H), 2.17 (br d, J= 4.0 Hz, 1H), 2.09 (br s, 1H), 1.77 (br t, J = 10.8 Hz, 3H), 1.52 (s, 9H), 1.36 (d, J= 6.0 Hz, 3H).
48% With chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) methyl-t-butyl ether adduct; sodium t-butanolate In toluene at 70℃; for 10h; 152.A Example 152 2-[4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl-1H-indazol-4-- yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoyl-piperazin-2- -yl]acetonitrile Step A: tert-butyl 2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl- -1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido [3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate A mixture of tert-butyl 2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-5,6,7,8-tet- rahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate (0.50 g, 1.09 mmol), 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (482 mg, 1.63 mmol), t-BuONa (314 mg, 3.26 mmol) and [2-(2-aminoethyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (80.4 mg, 109 umol) in toluene (30 mL) was stirred at 70° C. for 10 hours. The mixture was diluted with water (10 mL) and the aqueous layer extracted with ethyl acetate (3 20 mL). The organic layers were washed with saturated sodium chloride solution (30 mL), dried over Na 2SO 4, filtered and concentrated under vacuum. The residue was purified by reverse phase flash [water (Formic Acid, 0.1%.)/acetonitrile] to give tert-butyl 2-(cyanomethyl)-4-[2-[(1R)-2-(dimethylamino)-1-methyl-ethoxy]-7-(5-methyl- -1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidi- n-4-yl]piperazine-1-carboxylate (0.40 g, 522 umol, 48.0% yield) as a yellow solid. ES+APCI MS m/z 674.3 [M+H] +. 1H NMR (400 MHz, chloroform-d) δ=8.03 (d, J=1.6 Hz, 1H), 7.31-7.27 (m, 2H), 5.68 (dd, J=2.4, 9.6 Hz, 1H), 5.31 (br s, 1H), 4.61 (br s, 1H), 4.28 (s, 2H), 4.08-3.94 (m, 3H), 3.86 (br d, J=11.6 Hz, 1H), 3.79-3.71 (m, 1H), 3.52 (br t, J=4.8 Hz, 2H), 3.24 (br d, J=12.8 Hz, 2H), 3.04-2.91 (m, 1H), 2.87-2.67 (m, 5H), 2.65-2.47 (m, 2H), 2.41 (s, 3H), 2.32 (br s, 6H), 2.17 (br d, J=4.0 Hz, 1H), 2.09 (br s, 1H), 1.77 (br t, J=10.8 Hz, 3H), 1.52 (s, 9H), 1.36 (d, J=6.0 Hz, 3H).
  • 11
  • [ 1926172-50-0 ]
  • [ 2158300-42-4 ]
  • [ 2158300-43-5 ]
YieldReaction ConditionsOperation in experiment
65% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 110℃; for 12h; Inert atmosphere;
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 110℃; for 12h; Inert atmosphere; 155.C Step C: tert-butyl 4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate: To a mixture of tert-butyl 4-[2-[[(2,S)-l-methylpyrrolidin-2-yl]methoxy]-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (200 mg, 462 umol) and 4- bromo-5-methyl-l-tetrahydropyran-2-yl-indazole (204 mg, 694 umol) in toluene (4 mL) was added Pd2(dba)3 (63.5 mg, 69.4 umol), RuPhos (43.2 mg, 92.5 umol) and Cs2C03 (301 mg, 925 umol) and the mixture stirred at 110 °C for 12 hours under N2. After completion, the reaction mixture was partitioned between water (10 mL) and EtOAc and the layers separated. The aqueous layer was subsequently extracted with EtOAc (2 x 10 mL) and the combined organics were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5/l to Ethyl acetate/MeOH=10/l) to give tert-butyl 4-[2-[[(2(S)- 1 -methylpyrrolidin-2-yl]methoxy] -7-(5-methyl- 1 -tetrahydropyran-2-yl- indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine-l-carboxylate (240 mg, 310 umol, 67.1% yield, 83.6% purity) as brown oil. ES+APCI MS m/z 647.6 [M+H]+.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 110℃; for 12h; Inert atmosphere; 155.C Step C: tert-butyl 4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy] tetrahydropyran-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-- 4-yl]piperazine-1-carboxylate To a mixture of tert-butyl 4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6,7,8-tetrahydropyrido[3,4- -d]pyrimidin-4-yl]piperazine-1-carboxylate (200 mg, 462 umol) and 4-bromo-5-methyl-1-tetrahydropyran-2-yl-indazole (204 mg, 694 umol) in toluene (4 mL) was added Pd 2(dba) 3 (63.5 mg, 69.4 umol), RuPhos (43.2 mg, 92.5 umol) and Cs 2CO 3 (301 mg, 925 umol) and the mixture stirred at 110° C. for 12 hours under N 2. After completion, the reaction mixture was partitioned between water (10 mL) and EtOAc and the layers separated. The aqueous layer was subsequently extracted with EtOAc (2 10 mL) and the combined organics were dried over Na 2SO 4, filtered and concentrated. The residue was purified by column chromatography (SiO 2, Petroleum ether/Ethyl acetate=5/1 to Ethyl acetate/MeOH=10/1) to give tert-butyl 4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-7-(5-methyl-1-tetrahydropyra- n-2-yl-indazol-4-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazine- -1-carboxylate (240 mg, 310 umol, 67.1% yield, 83.6% purity) as brown oil. ES+APCI MS m/z 647.6 [M+H] +.
  • 12
  • [ 376581-24-7 ]
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With palladium diacetate; triphenylphosphine; sodium hydroxide In methanol; water at 100℃; for 0.0166667h; Flow reactor;
  • 13
  • 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole [ No CAS ]
  • [ 406463-06-7 ]
  • C22H21N3O [ No CAS ]
  • 14
  • [ CAS Unavailable ]
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With palladium diacetate; triphenylphosphine; sodium hydroxide In methanol; water at 100℃; for 0.0166667h; Flow reactor;
  • 15
  • [ 1926172-50-0 ]
  • [ 2368909-90-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; sodium t-butanolate; ammonia; bis(tri-ortho-tolylphosphine)palladium(0) / tetrahydrofuran / 100 °C / Inert atmosphere; Sealed tube 2: SK-CC02-A; lithium tert-butoxide / tetrahydrofuran; toluene / 20 h / 110 - 115 °C / Inert atmosphere
  • 16
  • [ CAS Unavailable ]
  • [ 1926172-50-0 ]
  • [ 2022976-34-5 ]
YieldReaction ConditionsOperation in experiment
95% With n-butyllithium In tetrahydrofuran at -78 - -65℃; for 3.5h; 20.2 Step 2: Synthesis of compound 20-3 To a cooled (-78 ) solution of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5.0 g, 17.00 mmol, 1.0 eq. ) in anhydrous THF (30 mL) was added B (O-iPr)3(6.4 g, 34.00 mmol, 2.0 eq. ) . Then n-BuLi (2.5 mol/L in THF, 13.0 mL, 31.46 mmol, 1.85 eq. ) was added dropwise to above solution over a period of 30 min, maintaining the reaction temperature between -70 and -65 . After addition, the reaction was stirred at -78 for 3 h. LCMS analysis showed starting material was consumed and desired product formed. The reaction mixture was quenched with a solution of saturated aq. NH4Cl (20 mL) and diluted with MTBE (30 mL) . The layers was separated and the aqueous layer was extracted with MTBE (30 mL × 3) . The combined organics were washed with brine (50 mL) , dried over anhydrous Na2SO4and concentrated. The residue was dissolved in MTBE (10 mL) . Petroleum ether was added dropwise to the solution at 0 . A white solid precipitated during the petroleum ether addition. The resultant suspension was filtered and the filter cake was washed with petroleum ether (30 mL) . The filter cake was dried under vacuum to obtain (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) boronic acid (4.2 g, 95%) .[0743]LCMS (ESI, m/z) : [M+1]+= 261; RT = 1.242 min.
95% With n-butyllithium In tetrahydrofuran at -78 - -65℃; for 3.5h; 20.2 Step 2: Synthesis of compound 20-3 To a cooled (-78 ) solution of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (5.0 g, 17.00 mmol, 1.0 eq. ) in anhydrous THF (30 mL) was added B (O-iPr)3(6.4 g, 34.00 mmol, 2.0 eq. ) . Then n-BuLi (2.5 mol/L in THF, 13.0 mL, 31.46 mmol, 1.85 eq. ) was added dropwise to above solution over a period of 30 min, maintaining the reaction temperature between -70 and -65 . After addition, the reaction was stirred at -78 for 3 h. LCMS analysis showed starting material was consumed and desired product formed. The reaction mixture was quenched with a solution of saturated aq. NH4Cl (20 mL) and diluted with MTBE (30 mL) . The layers was separated and the aqueous layer was extracted with MTBE (30 mL × 3) . The combined organics were washed with brine (50 mL) , dried over anhydrous Na2SO4and concentrated. The residue was dissolved in MTBE (10 mL) . Petroleum ether was added dropwise to the solution at 0 . A white solid precipitated during the petroleum ether addition. The resultant suspension was filtered and the filter cake was washed with petroleum ether (30 mL) . The filter cake was dried under vacuum to obtain (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) boronic acid (4.2 g, 95%) .[0743]LCMS (ESI, m/z) : [M+1]+= 261; RT = 1.242 min.
76% With n-butyllithium In tetrahydrofuran at -70 - -65℃; for 4h; 2 Step 2: The reaction was carried out in two parallel batches. A stirred solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (210.0 g, 711.44 mmol, 1.0 eq) and B(O-iPr)3 (267.61 g, 1.42 mol, 2.0 eq) in THF (2.0 L) was cooled to -70° C. Then n-BuLi (526.5 mL, 1.32 mol, 1.85 eq) was added dropwise to above solution over a period of 3 hours, maintaining the reaction temperature between -70° C. and -65° C. After addition, the reaction mixture was stirred at -70° C. for 1 hour. TLC analysis (20% EtOAc/petroleum ether) showed consumption of the starting material. The mixture was quenched with a solution of saturated aq. NH4Cl (2.0 L) and diluted with MTBE (2.0 L). The layers were separated and the aqueous layer was extracted with MTBE (1.0 L). The combined organics were washed with brine (1.5 L), dried over anhydrous Na2SO4, filtered, and concentrated at 25° C. The residue was dissolved in MTBE (300 mL). Petroleum ether (1.2 L) was added dropwise to the solution at 20° C. (room temperature). A white solid precipitated during the petroleum ether addition. The resultant suspension was filtered and the filter cake was washed with petroleum ether (800 mL). The filter cake was dried under vacuum to provide [5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]boronic acid (Int-1) (280.0 g, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 2H), 7.89 (d, J=0.8 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 5.77 (dd, J=9.7, 2.6 Hz, 1H), 3.91-3.83 (m, 1H), 3.72 (ddd, J=11.5, 7.8, 6.2 Hz, 1H), 2.45 (s, 3H), 2.39 (ddd, J=16.2, 8.4, 3.8 Hz, 1H), 2.10-1.97 (m, 1H), 1.91 (dq, J=13.0, 3.4 Hz, 1H), 1.80-1.67 (m, 1H), 1.57 (dq, J=9.0, 4.6 Hz, 2H). LCMS (ESI) m/z 261 (M+H).
  • 17
  • [ 1926172-50-0 ]
  • [ 2368909-95-7 ]
  • [ 2368909-96-8 ]
YieldReaction ConditionsOperation in experiment
18% Stage #1: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole With n-butyllithium In tetrahydrofuran at -80℃; for 0.666667h; Stage #2: tert-butyl 4-(8-formylquinazolin-4-yl)piperazine-1-carboxylate In tetrahydrofuran at -80℃; for 3h; 4 Step 4 To a stirred solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (24) (940 mg, 3.2 mmol) in dry THF (28 mL) was added 2.4 M BuLi (1.6 mL, 3.8 mmol) drop-wise at -80° C. The resulting mixture was stirred at -80° C. for 40 minutes. Then, a solution of tert-butyl 4-(8-formylquinazolin-4-yl)piperazine-1-carboxylate (122) (436 mg, 1.27 mmol) in dry THF (5 mL) was added drop-wise. The resulting mixture was stirred at -80° C. for 3 hours. LCMS analysis showed about 50% of target compound was formed. The reaction was quenched with aqueous NH4Cl (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2*30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash chromatography, which was eluted with 0-60% EtOAc/petroleum ether, and gave tert-butyl 4-(8-{hydroxy[5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl}quinazolin-4-yl)piperazine-1-carboxylate (123) as a white solid (330 mg, 18% yield). 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.18 (d, J=15.0 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.58-7.45 (m, 1H), 7.28 (d, J=3.5 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.04 (s, 1H), 6.90-6.75 (m, 1H), 6.37 (br. s, 1H), 5.80-5.62 (m, 1H), 4.17-3.96 (m, 2H), 3.90-3.70 (m, 5H), 3.69-3.56 (m, 4H), 2.66-2.48 (m, 1H), 2.34 (s, 3H), 2.20-2.05 (m, 2H), 1.82-1.73 (m, 2H), 1.50 (s, 9H). LCMS (ESI) m/z 559 (M+H).
  • 18
  • [ 1926172-50-0 ]
  • [ 2219318-70-2 ]
YieldReaction ConditionsOperation in experiment
89% With (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine; bis(tri-ortho-tolylphosphine)palladium(0); ammonia; sodium t-butanolate In tetrahydrofuran at 100℃; Inert atmosphere; Sealed tube; 1 Step 1 A 2.5*10-3 M stock solution of the catalyst (4.1 mL) containing Pd[P(o-tol)3]2(7.3 mg) and CyPF-t-Bu (1-dicyclohexylphosphino-2-di-t-butylphosphinoethylferrocene) (5.6 mg) was added to a mixture of NaO-t-Bu (300 mg, 1.0 mmol) in THF (2.0 M) and 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (24) (300 mg, 1.0 mmol) in microwave vial under nitrogen. Ammonia (10.2 mL of a 0.5 M solution in dioxane) was added via a gas-tight syringe. The vial was sealed with a Teflon-lined cap and kept at 100° C. overnight. The crude reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine and concentrated under reduced pressure. The crude product was purified using silica gel (ISCO 12 g column) which was eluted with a 0-65% EtOAc/heptane gradient and gave 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (116) as light brown solid (209 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 6.97 (d, J=8.3 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 5.62 (dd, J=9.7, 2.4 Hz, 1H), 5.50 (s, 2H), 3.87 (d, J=12.2 Hz, 1H), 3.68 (ddd, J=11.4, 7.7, 6.0 Hz, 1H), 2.30-2.45 (m, 1H), 2.12 (s, 3H), 1.95-2.07 (m, 1H), 1.84-1.95 (m, 1H), 1.64-1.79 (m, 1H), 1.50-1.60 (m, 2H). LCMS (APCI) m/z 232 (M+H).
Multi-step reaction with 2 steps 1: caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane / 16 h / 110 °C / Inert atmosphere 2: hydrogen; palladium 10% on activated carbon / methanol / 16 h / 30 °C
  • 19
  • [ 1926172-50-0 ]
  • [ 2368909-31-1 ]
YieldReaction ConditionsOperation in experiment
89% With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; di-tert-butyl(2’,4’,6’-triisopropyl-[1,1‘-biphenyl]-2-yl)phosphine In 1,4-dioxane; water monomer at 95℃; 54.1 Step 1: Synthesis of compound 54-1 An aqueous solution (2 mL) of potassium hydroxide (861 mg, 15.35 mmol) was added to dioxane (18 mL), andthe compound 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-base)-1H-indazole (1.5 g, 5.12 mmol), Pd2(dba)3 (234 mg,0.26 mmol) and t-Bu-Xphos(217 mg, 0.51 mmol) were added in turn, stirring overnight at 95°C. The reaction mixturewas cooled to room temperature, added water to dilute, adjusted the pH to 2-3 with 2 N hydrochloric acid, extracted withethyl acetate, and washed with saturated brine once. The organic layer was dried, concentrated, and purified by columnchromatography (PE/EA=100:10) to obtain the target product (1.06 g, 89% yield).
89% With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; di-tert-butyl(2’,4’,6’-triisopropyl-[1,1‘-biphenyl]-2-yl)phosphine In 1,4-dioxane; water monomer at 95℃; 54.1 Step 1: Synthesis of compound 54-1 An aqueous solution (2 mL) of potassium hydroxide (861 mg, 15.35 mmol) was added to dioxane (18 mL), andthe compound 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-base)-1H-indazole (1.5 g, 5.12 mmol), Pd2(dba)3 (234 mg,0.26 mmol) and t-Bu-Xphos(217 mg, 0.51 mmol) were added in turn, stirring overnight at 95°C. The reaction mixturewas cooled to room temperature, added water to dilute, adjusted the pH to 2-3 with 2 N hydrochloric acid, extracted withethyl acetate, and washed with saturated brine once. The organic layer was dried, concentrated, and purified by columnchromatography (PE/EA=100:10) to obtain the target product (1.06 g, 89% yield).
80% With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; di-tert-butyl(2’,4’,6’-triisopropyl-[1,1‘-biphenyl]-2-yl)phosphine In 1,4-dioxane; water monomer at 29 - 95℃; for 18h; Inert atmosphere; 2 Step 2: A solution of KOH (85.5 g, 1525 mmol) in H2O (450 mL) was added to dioxane (1.8 L) at 29° C., followed by 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (24) (150 g, 508 mmol), Pd2(dba)3 (18.6 g, 20.3 mmol) and t-Bu-Xphos (17.3 g, 40.6 mmol). The resultant mixture was degassed and refilled with nitrogen three times. The resultant mixture was heated at 95° C. for 18 hours. TLC (petroleum ether/EtOAc=4:1) gave no starting material. The reaction mixture was cooled to 30° C. and evaporated to dryness. The residue was partitioned between MTBE (500 mL) and H2O. The aqueous layer was extracted with MTBE (500 mL) and the combined organic layers were discarded. The aqueous phase was acidified to pH=2-3 using 2 N HCl and extracted with EtOAc (2×1 L). The combined organic layers were washed with H2O (0.8 L) and brine (1 L), dried over Na2SO4 and evaporated to dryness. The residue was triturated with petroleum ether (500 mL) which gave 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (25) as an off-white solid (95 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.65 (dd, J=9.6, 2.6 Hz, 1H), 4.11-3.98 (m, 1H), 3.73 (td, J=11.1, 2.7 Hz, 1H), 2.55 (dddd, J=13.6, 11.8, 9.8, 4.0 Hz, 1H), 2.30 (s, 3H), 2.19-2.09 (m, 1H), 2.08-1.95 (m, 1H), 1.81-1.67 (m, 2H), 1.66-1.55 (m, 1H). LCMS (ESI) m/z 233 (M+H).
  • 20
  • [ 1926172-50-0 ]
  • [ 2413124-59-9 ]
  • [ 2413124-60-2 ]
YieldReaction ConditionsOperation in experiment
18% With sodium t-butanolate In 1,4-dioxane for 20h; Inert atmosphere; Reflux; 1 4-(7-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1-(((S)-1-methylpyrrolidin-2-yl)methyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester(1-6) Add 1-5 (379 mg, 0.812 mmol) to a 100 mL single-mouth bottle.4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (311 mg, 1.056 mmol),Sodium tert-butoxide (195 mg, 2.03 mmol), Ruphos-Pd-G3 (134 mg, 0.16 mmol) and Dioxane (20 mL),After Ar substitution protection, the temperature was raised to reflux and stirred for 20 hours. After LC-MS monitors the reaction,The system was quenched with water, EA (20 mL*2) was extracted, and the organic phase was washed with saturated sodium chloride and dried.preparing a purified pre-TLC (DCM / MeOH / NH4OH = 20/1 / 0.02) to give a pale brown oil 1-6 (100mg, yield 18%),
  • 21
  • [ 1926172-50-0 ]
  • [ 2413124-64-6 ]
  • [ 2413124-65-7 ]
YieldReaction ConditionsOperation in experiment
47% With sodium t-butanolate In 1,4-dioxane for 20h; Inert atmosphere; Reflux; 2 4-(6-Chloro-8-methoxy-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1-(((S)-1-methylpyrrolidin-2-yl)methyl)-2-oxo-1,2-dihydroquinazolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (53-5) Add 53-4 (638mg, 1.118mmol) to a 100mL single-mouth bottle.4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (428 mg, 1.453 mmol),Sodium tert-butoxide (268 mg, 2.79 mmol), Ruphos-Pd-G3 (184 mg, 0.22 mmol) and Dioxane (20 mL),After Ar substitution protection, the temperature was raised to reflux and stirred for 20 hours.After LC-MS was monitored, the system was quenched with water and extracted with EA (20 mL*2).The organic phase is washed with saturated sodium chloride and dried.preparing a purified pre-TLC (DCM / MeOH / NH4OH = 20/1 / 0.02) to give a pale brown oil 53-5 (371mg, yield 47%),
  • 22
  • [ 1926172-50-0 ]
  • [ 2412425-04-6 ]
  • [ 2412425-44-4 ]
YieldReaction ConditionsOperation in experiment
61% With tris-(dibenzylideneacetone)dipalladium(0); RuPhos; caesium carbonate In toluene at 90℃; for 8h; Inert atmosphere; 19 Compound 19-1 To a mixture of benzyl (25 -2-(cyanomethyl)-4-[2-[[(25)-l- methylpyrrolidin-2-yl]methoxy]-6,7,8,9-tetrahydro-5//-pynmido[4,5-c]azepin-4-yl]piperazine-l- carboxylate (800 mg, 1.54 mmol, 1.0 eg), 4-bromo-5-methyl-l- tetrahydropyran-2-yl-indazole (545 mg, 1.85 mmol, 6.31 pL, 1.2 eg), CS2CO3 (1.50 g, 4.62 mmol, 3.0 eg) an RuPhos (287 mg, 616 pmol, 0.4 eg) in toluene (20 mL) was added Pd2(dba)3 (282 mg, 308 pmol, 0.2 eg) under N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred under N2 at 90 °C for 8 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash [water (0.1% FA)/acetonitrile]. The desired fractions were collected and NaHC03 added to pH ~7, (0734) concentrated under vacuum to remove MeCN and extracted with ethyl acetate (2 x 40 mL). The organic layers were dried over Na2S() i and concentrated under vacuum to give benzyl (2S)-2- (cyanomethyl)-4-[2-[[(2,S)-l-methylpyrrolidin-2- yl]methoxy]-8-(5-methyl-l-tetrahydropyran-2- yl-indazol-4-yl)-5, 6, 7, 9-tetrahydropyrimido[4,5-c]azepin-4-yl]piperazine-l -carboxylate (700 mg, 935 pmol, 61% yield, 98% purity) as a yellow solid. LCMS [ESI, M+l]: 734. (0735) [0425] 'H NMR (400MHz, chloroform-d) d = 8.04 (d, 7=2.4 Hz, 1H), 7.43 - 7.33 (m, 5H), 7.26 - 7.16 (m, 2H), 5.67 (dd, 7=2.4, 9.6 Hz, 1H), 5.26 - 5.17 (m, 2H), 4.70 (br s, III), 4.54 - 4.38 (m, 2H), 4.35 (dd, 7=4.8, 10.8 Hz, 1 H), 4.20 - 4.08 (m, 2H), 4.03 (br d, .7=10.0 Hz, 1H), 3.82 (br d, 7=12.4 IIz, 1H), 3.77 - 3.70 (m, 1H), 3.66 (br d, 7=13.2 Hz, 1H), 3.61 - 3.53 (m, 1H), 3.50 - 3.40 (m, 1 H), 3.33 (br s, HI), 3.23 (br d, 7=1 1 .6 Hz, 1 H), 3.07 (br t, 7=7.6 Hz, 1H), 3.01 - 2.82 (m, 4H), 2.81 - 2.73 (m, HI), 2.68 - 2.51 (m, 2H), 2.45 (s, 3H), 2.26 (d, 7=1.2 Hz, 4H), 2.19 - 2.13 (m, 1H), 2.08 (br s, 1 H), 2.04 - 1.96 (m, 2H), 1.86 - 1.78 (m, 2H), 1.73 - 1.60 (m, 3H).
  • 23
  • [ 1926172-50-0 ]
  • [ 73183-34-3 ]
  • [ 1698028-42-0 ]
YieldReaction ConditionsOperation in experiment
67.3% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In 1,4-dioxane; dichloromethane at 100℃; Inert atmosphere; 1.4 Step 4: Synthesis of compound 1H Compound 1H-2 (550mg, 1.85mmol) was added to dioxane (10ml), KOAc (364mg, 3.7mmol) and pinacol diborate (705mg, 2.8mmol) were added, and the reaction solution was replaced with nitrogen After three times, Pd(dppf)Cl2 in dichloromethane complex (159mg, 0.19mmol) was added sequentially. The obtained reaction solution was replaced with nitrogen again three times and then stirred at 100°C overnight. After TLC showed that the reaction was over, the reaction solution was concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 (V:V volume ratio)) to obtain compound 1H (429 mg, light yellow) Transparent liquid), the yield is 67.3%.
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 100℃; S-13.2 Step 2: Synthesis of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. To a solution of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (116 g, 0.39 mol, 1.0 eq) in dioxane (1000 mL) was added KOAc (116 g, 1.20 mol, 3.0 eq), B2Pin2(129 g, 0.53 mol, 1.3 eq), Pd(dppf)Cl2(29 g, 0.04 mol, 0.1 eq) and the resulting mixture was degassed and purged with N2 (3x). The reaction mixture was stirred at 100 °C overnight. TLC indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography to afford the title compound. LCMS (m/z): 343.3 [M+H]+
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 100℃; S-13.2 Step 2: Synthesis of 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole. To a solution of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole (116 g, 0.39 mol, 1.0 eq) in dioxane (1000 mL) was added KOAc (116 g, 1.20 mol, 3.0 eq), B2Pin2(129 g, 0.53 mol, 1.3 eq), Pd(dppf)Cl2(29 g, 0.04 mol, 0.1 eq) and the resulting mixture was degassed and purged with N2 (3x). The reaction mixture was stirred at 100 °C overnight. TLC indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure and the residue was purified using silica gel chromatography to afford the title compound. LCMS (m/z): 343.3 [M+H]+
  • 24
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
70% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In 1,4-dioxane; water at 120℃; for 1h; Inert atmosphere; Microwave irradiation; 43.1 Step 1: Add tert-butyl (S)-2-(cyanomethyl)-4-(1-(2-isopropylphenyl)-2-oxy-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate to a 100mL three-necked round bottom flask (0.25g, 0.51mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (300mg, 1.0mmol), Pd2(dba)3 (92mg, 0.1mmol), RuPhos (47 mg, 0.1 mmol), cesium carbonate (490 mg, 1.5 mmol), 20 mL dioxane and 4 mL water. The system was replaced with nitrogen three times, and then protected with a nitrogen ball. React for 1 hour under microwave conditions at 120 degrees, add 50mL ethyl acetate to the reaction solution, wash 3 times with 50mL saturated brine, dry and concentrate, and the crude product is purified by a fast silica gel column. (2S)-2-(cyanomethyl)-4-(1-(2-isopropylphenyl)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl) -1H-Indazol-4yl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, Y: 70%).
  • 25
  • [ 1926172-50-0 ]
  • [ 2576726-67-3 ]
  • [ 2576726-68-4 ]
YieldReaction ConditionsOperation in experiment
40% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In 1,4-dioxane at 115℃; for 1.5h; Inert atmosphere; Microwave irradiation; 1.3 Step 3: Add (S)-4-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[ 3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (35mg, 0.075mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (40mg, 0.117mmol), cesium carbonate (49mg, 0.15mmol), Pd2(dba)3 (10mg, 0.011mmol), Ruphos (10mg, 0.022mg) and 1 mL of dioxane, replaced with nitrogen, used a microwave reactor at 115°C, stirred for 90 min, cool to room temperature, add 20 mL ethyl acetate and 10 mL water, separate the layers, dry the organic phase and concentrate. Column chromatography (methanol/dichloromethane: 0-8%) to obtain (3S)-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (20 mg, Y: 40%).
  • 26
  • [ 1926172-50-0 ]
  • [ 2576726-71-9 ]
  • [ 2576726-72-0 ]
YieldReaction ConditionsOperation in experiment
25% With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate; ruphos In 1,4-dioxane at 130℃; for 1.5h; Inert atmosphere; Microwave irradiation; 2.3 Step 3: Add 4-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4- d] pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (120mg, 0.264mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (140mg, 0.476mmol), cesium carbonate (172mg, 0.53mmol), RuphosPdG3 (42mg, 0.053mmol), Ruphos (49mg, 0.105mmol) and 1.5mL of dioxane, replaced with nitrogen, used a microwave reactor at 130°C, stirred for 90min, cool to room temperature, add 50 mL ethyl acetate and 20 mL water, separate the layers, dry the organic phase and concentrate, and column chromatography (methanol/dichloromethane: 0-8%) to obtain 4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1-(2-isopropylphenyl)tert-butyl Yl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (44mg, Y: 25%).
  • 27
  • [ 1926172-50-0 ]
  • [ 2576726-75-3 ]
  • [ 2576726-76-4 ]
YieldReaction ConditionsOperation in experiment
23% With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate; ruphos In 1,4-dioxane; water at 110℃; for 1.16667h; Inert atmosphere; Microwave irradiation; 3.3 Step 3: Add (S)-3-methyl-4-(2-oxo-1-phenyl-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (100mg, 0.24mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (106mg, 0.36mmol), cesium carbonate (156mg, 0.489mmol), Ruphos-Pd-G3 (80mg, 0.096mmol), Ruphos (45mg, 0.096mg), dioxane 4mL water, nitrogen replacement, microwave heating at 110 °C stirring reaction 70min, cool to room temperature, add 20 mL ethyl acetate and 20 mL water, separate layers, dry the organic phase and concentrate, and column chromatography (methanol/dichloromethane: 0-8%) to obtain (S)-3-methyl-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxo -1-(tert-butyl)phenyl-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (36 mg, Y: 23%).
  • 28
  • [ 1926172-50-0 ]
  • [ 2576726-79-7 ]
  • [ 2576726-80-0 ]
YieldReaction ConditionsOperation in experiment
52% With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate; ruphos In 1,4-dioxane at 115℃; for 1.5h; Inert atmosphere; Microwave irradiation; 4.3 Step 3: Add (R)-4-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (260mg, 0.56mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (328mg, 1.16mmol), cesium carbonate (362mg, 1.16mmol), RuphosPd G3 (186mg, 0.222mmol), Ruphos (104mg, 0.222mg) and dioxane 1.5mL, replaced with nitrogen, used microwave reactor at 115°C, stirred for 90min, cool to room temperature, add 100 mL ethyl acetate and 40 mL water, separate the layers, dry the organic phase and concentrate, and column chromatography (methanol/dichloromethane: 0-8%) to obtain tert-butyl (3R)-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1-(2-isopropylbenzene (Yl)tert-butyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylpiperazine-1-formate (198 mg, Y: 52%).
  • 29
  • [ 1926172-50-0 ]
  • [ 2576726-92-4 ]
  • [ 2576726-93-5 ]
YieldReaction ConditionsOperation in experiment
84% With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate; ruphos In 1,4-dioxane at 110℃; for 1.5h; Inert atmosphere; Microwave irradiation; 7.6 Step 6: Add 3-ethyl-4-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido to a 25mL microwave tube [3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.41mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (183mg, 0.62mmol), cesium carbonate (266mg, 0.82mmol), Ruphos-Pd-G3 (102mg, 0.123mmol), Ruphos (57mg, 0.123mg), 8mL of dioxane, replaced with nitrogen, and stirred for 90min under microwave heating at 110°C, cool to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the layers, dry the organic phase and concentrate, and column chromatography (methanol/dichloromethane: 0-8%) to obtain 3-ethyl-4-(1-(2-isopropylphenyl)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (240 mg, Y: 84%).
  • 30
  • [ 1926172-50-0 ]
  • [ 2387444-11-1 ]
  • [ 2576726-96-8 ]
YieldReaction ConditionsOperation in experiment
48.6% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 120℃; for 2h; Inert atmosphere; Microwave irradiation; 8.3 Step 3: Add (2R,5S)-4-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyridino[3,4-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester to a 5mL microwave tube and (85mg, 0.177mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (90mg, 0.187mmol), cesium carbonate (123mg, 0.0.374mmol), Pd2(dba)3 (62mg, 0.075mmol), Ruphos (35mg, 0.075mg) and toluene 2mL, replaced with nitrogen, use a microwave reactor at 120°C, stir for 120min, Cool to room temperature, add 20 mL ethyl acetate and 10 mL water, separate the layers, dry the organic phase and concentrate, and column chromatography (methanol/dichloromethane: 0-10%) to obtain tert-butyl (2R,5S)-4-(1-(2-isopropylphenyl)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl))-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (60 mg, 0.086 mmol Y: 48.6%).
  • 31
  • [ 1926172-50-0 ]
  • [ 2576727-02-9 ]
  • [ 2576727-03-0 ]
YieldReaction ConditionsOperation in experiment
60 mg With methanesulfonato(2-dicyclohexylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl)(2’-methylamino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate; ruphos In 1,4-dioxane at 120℃; for 1h; Inert atmosphere; Microwave irradiation; 9.6 Step 6: Add 7-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4- d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (260mg, 0.41mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (222mg, 0.62mmol), cesium carbonate (268mg, 0.82mmol), Ruphos-Pd-G3 (170mg, 0.2mmol), Ruphos (93mg, 0.2mg), 8mL of dioxane, replaced with nitrogen, and stirred for 60min under microwave heating at 120°C, cool to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the layers, dry the organic phase and concentrate, and column chromatography (methanol/dichloromethane: 0-8%) to obtain tert-butyl 7-(1-(2-isopropylphenyl)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (60 mg, 0.085 mmol).
  • 32
  • [ 1926172-50-0 ]
  • [ 2576727-08-5 ]
  • [ 2576727-09-6 ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In 1,4-dioxane at 120℃; for 1h; Inert atmosphere; Microwave irradiation; 10.6 Step 6: Add 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyridine[3,4-]d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (140mg, 0.23mmol), to the 25mL microwave tube and 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (100mg, 0.34mmol), cesium carbonate (150mg, 0.46mmol), Pd2(dba)3 (76mg, 0.09mmol), Ruphos (43mg, 0.09mg), 8mL of dioxane, replaced with nitrogen, stirred under microwave heating at 120°C for 60min, cool to room temperature, add 30 mL ethyl acetate and 30 mL water, separate the layers, dry the organic phase and concentrate, and column chromatography (methanol/dichloromethane: 0-8%) to obtain 3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-(2-isopropylphenyl)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 110 mg crude product.
  • 33
  • [ 1926172-50-0 ]
  • [ 2576727-19-8 ]
  • [ 2576727-20-1 ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 120℃; for 1.01667h; Inert atmosphere; Microwave irradiation; 13.10 Step 10: Add 2-(cyanomethyl)-4-(1-(2-isopropylphenyl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[ 3,4-d)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (150mg, 0.3mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (180mg, 0.6mmol), tris(dibenzylideneacetone)dipalladium (56mg, 0.06mmol), a toluene (4 mL) mixture of RuPhos (28 mg, 0.06 mmol) and cesium carbonate (298 mg, 0.9 mmol) was placed in a microwave tube, and nitrogen was bubbled in for 1 min. The mixture was sealed and reacted at 120°C for 1 h under microwave irradiation. The reaction solution was concentrated and purified with a fast silica gel column to obtain a yellow solid 2-(cyanomethyl)-4-(1-(2-isopropylphenyl)-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (90 mg, P: 90%, Y: 42%).
  • 34
  • [ 1926172-50-0 ]
  • [ 2649897-38-9 ]
  • [ 2649897-39-0 ]
YieldReaction ConditionsOperation in experiment
20% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In 1,4-dioxane at 140℃; for 1.5h; Inert atmosphere; Microwave irradiation; 42.9 Step 9: Add 4-(1-(2-isopropylphenyl)-6-methyl-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidine-4-yl)piperazine-1-carboxylic acid tert-butyl ester (100mg, 0.214mmoL), 4-bromo-5-methyl-1-(-(tetrahydro-2H-pyran-2-yl)-1H-indazole (95mg, 0.32mmol), Pd2(dba)3 (40mg, 0.043mmol), Ruphos (40mg, 0.085mmol) and cesium carbonate (139mg, 0.428mmol) were dissolved in 2ml of dry dioxane, replaced with nitrogen, and reacted in a microwave at 140°C for 1.5 hours. Reduce to room temperature, add 10ml of dichloromethane, filter, wash with water and saturated brine, concentrate, and obtain by column chromatography 4-(1-(2-isopropylphenyl)-6-methyl-7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-oxo-1,2,5,6,7,8-hexahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (29mg, Y: 20%).
  • 35
  • [ 1926172-50-0 ]
  • [ 2206736-98-1 ]
  • [ 2567927-92-6 ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In 1,4-dioxane at 85℃; for 5h;
  • 36
  • [ 1926172-50-0 ]
  • [ 2567927-78-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In 1,4-dioxane at 100℃; for 4h;
  • 37
  • [ 1926172-50-0 ]
  • [ 2206737-05-3 ]
  • [ 2664105-85-3 ]
YieldReaction ConditionsOperation in experiment
484 mg With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; Inert atmosphere; 29.B Step B:(2S)-2-(cyanomethyl)-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2 -[((S)-1-Methylpyrrolidin-2-yl)methoxy]-5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl}piperazine-1-carboxylic acid tert-butyl ester Under the protection of nitrogen, (S)-2-(cyanomethyl)-4-{2-[((S)-1-methylpyrrolidin-2-yl)methoxy]-5,6, 7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl}piperazine-1-carboxylic acid tert-butyl ester (380mg),4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (470mg), Cs2CO3 (787mg),Pd2(dba)3 (147mg) and Xantphos catalyst (185mg) were added to toluene (35ml) successively, and the temperature was raised to 100°C under the protection of nitrogen and stirred overnight.Cool to room temperature, concentrate under reduced pressure, add ethyl acetate to dissolve the residue,Filter through a pad of diatomaceous earth, wash with ethyl acetate, and concentrate the filtrate under reduced pressure.The residue was passed through silica gel column chromatography (MeOH/DCM=1/30)The product was purified (484 mg).
  • 38
  • [ 1926172-50-0 ]
  • [ 2158302-05-5 ]
  • [ 2648555-03-5 ]
YieldReaction ConditionsOperation in experiment
63% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In 1,4-dioxane at 95℃; for 4h; 110.1 Step 1: Synthesis of benzyl (2S)-2-(cyanomethyl)-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol- 4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1- carboxylate To a solution of (S)-benzyl 2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (7 g, 13.8 mmol, 1 equiv) in dioxane (105 mL) was added 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.17 g, 27.7 mmol, 2 equiv), RuPhos (1.29 g, 2.77 mmol, 0.2 equiv), Pd2(dba)3 (1.90 g, 2.08 mmol, 0.15 equiv) and Cs2CO3 (11.3 g, 34.6 mmol, 2.5 equiv). The resulting mixture was heated to 95 °C. After 4 h the reaction was cooled to room temperature, filtered through Celite, and washed with DCM (4 x 30 mL). The filtrate was washed with H2O (2 x 70 mL), sat. aq. NaCl (70 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (50→100% EtOAc/petroleum ether) to afford benzyl (2S)-2-(cyanomethyl)-4-(7-(5-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4- yl)piperazine-1-carboxylate (7.35 g, 63% yield) as an orange solid.1H NMR (400 MHz, Methanol-d4) δ 8.07 (s, 1H), 7.41 - 7.34 (m, 5H), 7.29 (br t, J = 8.3 Hz, 2H), 5.74 (br d, J = 8.3 Hz, 1H), 5.26 - 5.12 (m, 2H), 4.69 (br s, 1H), 4.33 (dq, J = 5.9, 11.2 Hz, 2H), 4.21 (s, 2H), 4.16 - 4.02 (m, 3H), 3.99 (br d, J = 11.6 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.53 - 3.45 (m, 2H), 3.28 (br s, 1H), 3.13 - 3.03 (m, 2H), 3.00 - 2.69 (m, 5H), 2.50 (s, 4H), 2.43 - 2.28 (m, 4H), 2.16 - 2.03 (m, 2H), 1.98 (br d, J = 13.2 Hz, 1H), 1.87 - 1.76 (m, 3H), 1.75 - 1.56 (m, 4H).
  • 39
  • [ 1926172-50-0 ]
  • [ 2637412-78-1 ]
  • [ 2677042-66-7 ]
YieldReaction ConditionsOperation in experiment
41% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 105℃; for 22h; 16.2 Second step(2S)-2-(cyanomethyl)-4-(6-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl esterSynthesis Add toluene (15.0mL) to the reaction flask,4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (259.1mg, 0.8777mmol),(2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylic acid benzyl ester (280.0mg, 0.5696mmol),XantPhos (103.2mg, 0.1730mmol), cesium carbonate (561.0mg, 1.72mmol) and Pd2(dba)3 (108.2mg, 0.1146mmol),Reacted at 105°C for 22h, filtered through Celite, added silica gel powder to the filtrate, and purified by column chromatography (DCM/MeOH(v/v)=5/1) to obtain the title compound as a light brown solid (165.0mg, 41%).
  • 40
  • [ 1926172-50-0 ]
  • [ 2617831-13-5 ]
  • [ 2750357-93-6 ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 100℃; for 48h; Inert atmosphere; S-3.1 Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(7-(5-methyl-lH- indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H- pyrimido[4,5-d]azepin-4-yl)piperazine-1-carboxylate. To a solution of tert-butyl (S)-2- (cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H- pyrimido[4,5-d]azepin-4-yl)piperazine-1-carboxylate (0.25 g, 0.51 mmol, 1.0 eq) in toluene (5 mL) was added 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-lH-indazole (0.18 g, 0.62 mmol, 1.2 eq), CS2CO3 (0.50 g, 1.55 mmol, 3.0 eq) under argon and degassed with argon for 10 min. To the reaction mixture, RuPhos (0.012 g, 0.025 mmol, 0.05 eq), Pd2(dba)3 (0.02 g, 0.025 mmol, 0.05 eq) were added under argon and stirred at 100 °C for 48 h. The reaction mixture was cooled to RT, filtered through Celite pad and washed with EtOAc. The combined filtrates were dried over Na2S04, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford the title compound.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 100℃; for 48h; Inert atmosphere; S-3.1 Step 1: Synthesis of tert-butyl (S)-2-(cyanomethyl)-4-(7-(5-methyl-lH- indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H- pyrimido[4,5-d]azepin-4-yl)piperazine-1-carboxylate. To a solution of tert-butyl (S)-2- (cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H- pyrimido[4,5-d]azepin-4-yl)piperazine-1-carboxylate (0.25 g, 0.51 mmol, 1.0 eq) in toluene (5 mL) was added 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-lH-indazole (0.18 g, 0.62 mmol, 1.2 eq), CS2CO3 (0.50 g, 1.55 mmol, 3.0 eq) under argon and degassed with argon for 10 min. To the reaction mixture, RuPhos (0.012 g, 0.025 mmol, 0.05 eq), Pd2(dba)3 (0.02 g, 0.025 mmol, 0.05 eq) were added under argon and stirred at 100 °C for 48 h. The reaction mixture was cooled to RT, filtered through Celite pad and washed with EtOAc. The combined filtrates were dried over Na2S04, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography to afford the title compound.
  • 41
  • [ 1926172-50-0 ]
  • [ 68-12-2 ]
  • [ 2750910-96-2 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -70℃; for 2h; S-29.2 Step 2: Synthesis of 5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-4- carbaldehyde. To a solution of 4-bromo-5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (5.0 g, 16.93 mmol, 1.0 eq) in dry THL (60 mL) at -70 °C was added nBuLi (2.4 M in hexane; 8 mL, 20.10 mmol, 1.2 eq) and stirred for 30 min. Then DML (1.5 mL, 20.10 mmol, 1.2 eq) was added dropwise and stirred at -70 °C for 2 h. To the reaction mixture, EtOAc (150 mL) was added followed by ice cooled NH4CI (50 mL). The organic layer was washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the crude compound. The crude material was purified by silica gel chromatography to afford the title compound. LCMS (m/z): 245.1 [M+H]+
Stage #1: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -70℃; for 2h; S-29.2 Step 2: Synthesis of 5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole-4- carbaldehyde. To a solution of 4-bromo-5-methyl-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (5.0 g, 16.93 mmol, 1.0 eq) in dry THL (60 mL) at -70 °C was added nBuLi (2.4 M in hexane; 8 mL, 20.10 mmol, 1.2 eq) and stirred for 30 min. Then DML (1.5 mL, 20.10 mmol, 1.2 eq) was added dropwise and stirred at -70 °C for 2 h. To the reaction mixture, EtOAc (150 mL) was added followed by ice cooled NH4CI (50 mL). The organic layer was washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the crude compound. The crude material was purified by silica gel chromatography to afford the title compound. LCMS (m/z): 245.1 [M+H]+
  • 42
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
  • [ 2750929-31-6 ]
YieldReaction ConditionsOperation in experiment
87% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 110℃; for 16h; Inert atmosphere; 22.2 Step 2: Synthesis of compound 22-3 To a mixture of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (2 g, 6.80 mmol, 1.0 eq. ) in anhydrous dioxane (50 mL) was added BnNH2(2.18 g, 20.4 mmol 3 eq. ) , BINAP (423 mg, 0.68 mmol) and Cs2CO3(6.63 g, 20.4 mmol) , then followed by Pd2(dba)3(622 mg, 0.68 mmol) . The reaction mixture was stirred at 110 for 16 h under N2. LCMS analysis showed starting material was consumed and desired product was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5/1-2/1, v/v) to obtain N-benzyl-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (1.9 g, 87%) .[0827]LCMS: Rt: 1.813 min; MS m/z (ESI) : 322.1 [M+H]+.
87% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 110℃; for 16h; Inert atmosphere; 22.2 Step 2: Synthesis of compound 22-3 To a mixture of 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (2 g, 6.80 mmol, 1.0 eq. ) in anhydrous dioxane (50 mL) was added BnNH2(2.18 g, 20.4 mmol 3 eq. ) , BINAP (423 mg, 0.68 mmol) and Cs2CO3(6.63 g, 20.4 mmol) , then followed by Pd2(dba)3(622 mg, 0.68 mmol) . The reaction mixture was stirred at 110 for 16 h under N2. LCMS analysis showed starting material was consumed and desired product was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5/1-2/1, v/v) to obtain N-benzyl-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-amine (1.9 g, 87%) .[0827]LCMS: Rt: 1.813 min; MS m/z (ESI) : 322.1 [M+H]+.
  • 43
  • [ 1926172-50-0 ]
  • [ 2640938-07-2 ]
  • [ 2640938-08-3 ]
YieldReaction ConditionsOperation in experiment
74.1% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 120℃; for 1h; Inert atmosphere; Microwave irradiation; 2.9 Step 9: the tert-butyl (R)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthyridin-10(8H)-carboxylate (50 mg, 0.14 mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (83 mg, 0.28 mmol), cesium carbonate (136 mg, 0.42 mmol), Pd2(dba)3 (51 mg, 0.056 mmol), Ruphos (26 mg, 0.056 mmol) and toluene (6 mL) were added to a 5 mL microwave tube, subjected to nitrogen replacement, placed into a microwave reactor at 120°C, and stirred for 1 hour to react. The resulting reaction liquid was cooled to room temperature, and filtered. The filtrate was dried and concentrated. The resulting crude product was subjected to thin-layer chromatography on a plate (DCM/MeOH/ammonia water=100:5:1) to obtain tert-butyl (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthyridin-10(8H)-carboxylate (60 mg, Y: 74.1%). ES-API: [M+H]+=561.3.
With tris-(dibenzylideneacetone)dipalladium(0); nitrogen 2.9 Example 2 Step 9: the tert-butyl (R)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthyridin-10(8H)-carboxylate (50 mg, 0.14 mmol), 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (83 mg, 0.28 mmol), cesium carbonate (136 mg, 0.42 mmol), Pd2(dba)3 (51 mg, 0.056 mmol), Ruphos (26 mg, 0.056 mmol) and toluene (6 mL) were added to a 5 mL microwave tube, subjected to nitrogen replacement, placed into a microwave reactor at 120°C, and stirred for 1 hour to react. The resulting reaction liquid was cooled to room temperature, and filtered. The filtrate was dried and concentrated. The resulting crude product was subjected to thin-layer chromatography on a plate (DCM/MeOH/ammonia water=100:5:1) to obtain tert-butyl (8aR)-3-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1,2,3,4,8a,9,11,12-octahydropyrazino[1',2':4,5][1,4]oxazino[2,3-c][1,7]naphthyridin-10(8H)-carboxylate (60 mg, Y: 74.1%). ES-API: [M+H]+=561.3.
  • 44
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -78 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 12 h / 95 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 100 °C
  • 45
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -78 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 12 h / 95 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 100 °C 4.1: palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / toluene / 6 h / 110 °C / Inert atmosphere
  • 46
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -78 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 12 h / 95 °C / Inert atmosphere
  • 47
  • [ 1926172-50-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -78 °C / Inert atmosphere 1.2: -78 °C / Inert atmosphere 2.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 12 h / 95 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 100 °C 4.1: palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate / toluene / 6 h / 110 °C / Inert atmosphere 5.1: boron tribromide / dichloromethane / 2.5 h / -78 - 20 °C 5.2: 5 min / -20 - 0 °C
  • 48
  • [ CAS Unavailable ]
  • [ 1926172-50-0 ]
  • [ 2022976-34-5 ]
YieldReaction ConditionsOperation in experiment
78% Stage #1: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: triethyl borate In tetrahydrofuran; hexane at -78℃; Inert atmosphere; (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid To a solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (300 mg, 1.02 mmol) in THF (10 mL) under argon atmosphere at -78 , then 0.89 mL n-BuLi in hexane (1.6 M) was added dropwise to the reaction system. After stirring for 15 min, triethyl borate (209 mg, 1.43 mmol) was added, kept stirring for 2 h. Then put into 10 mL NH4Cl saturated aqueous solution to quench the reaction. The solvent was removed in vacuo and water (80 mL) was added. The pH of the aqueous phase was adjusted to 5 with 2N HCl and then extracted with ethyl acetate (80 mL), then was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM/MeOH = 30:1) to afford (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (206 mg, 0.79 mmol) as a pale yellow oil. Yield: 78.0%. LCMS-IT-TOF m/z 261.1 [M + H]+.
78% Stage #1: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere; Stage #2: triethyl borate In tetrahydrofuran; hexane at -78℃; Inert atmosphere; (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid To a solution of 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (300 mg, 1.02 mmol) in THF (10 mL) under argon atmosphere at -78 , then 0.89 mL n-BuLi in hexane (1.6 M) was added dropwise to the reaction system. After stirring for 15 min, triethyl borate (209 mg, 1.43 mmol) was added, kept stirring for 2 h. Then put into 10 mL NH4Cl saturated aqueous solution to quench the reaction. The solvent was removed in vacuo and water (80 mL) was added. The pH of the aqueous phase was adjusted to 5 with 2N HCl and then extracted with ethyl acetate (80 mL), then was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM/MeOH = 30:1) to afford (5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)boronic acid (206 mg, 0.79 mmol) as a pale yellow oil. Yield: 78.0%. LCMS-IT-TOF m/z 261.1 [M + H]+.
  • 49
  • [ 926922-40-9 ]
  • [ CAS Unavailable ]
  • [ 1926172-50-0 ]
YieldReaction ConditionsOperation in experiment
With p-toluenesulfonic acid monohydrate 47.1 Example 47 step 1: 4-bromo-5-methyl-1H-indazole (5 g, 23.8 mmol) was dissolved in dichloromethane (50 mL), and after cooling by ice water 3,4-dihydro-2H-pyran (4 g, 47.6 mmol) was added and then p-toluenesulfonic acid monohydrate (452 mg, 2.38 mmol) was added. The reaction was conducted at 10° C. for 1 h. The reaction solution was quenched by adding water, and the organic phase was washed with saturated sodium bicarbonate and brine and dried over sodium sulfate. The solvent was concentrated under reduced pressure to dryness to obtain crude product 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.5 g, Y: 100%). ES-API: [M+1]+=295.0
  • 50
  • [ 1926172-50-0 ]
  • [ 2615270-06-7 ]
YieldReaction ConditionsOperation in experiment
47.2 Example 47 step 2: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.5 g, 23.8 mmol) was dissolved in N,N-dimethylformamide (300 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane ditetrafluoro boronic acid (29.5 g, 83.3 mmol) was added. The temperature was warmed up to 70° C. and the reaction was conducted for 2 h. The reaction solution was cooled, quenched by adding water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The solvent was dried by rotary evaporation under reduced pressure, and purified by column (petroleum ether/ethyl acetate=3/1) to obtain 4-bromo-3-fluoro-5-methyl-1H-indazole (1.4 g, Y: 25.8%). ES-API: [M+MeOH]+=229.0
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