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[ CAS No. 330794-10-0 ] {[proInfo.proName]}

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Chemical Structure| 330794-10-0
Chemical Structure| 330794-10-0
Structure of 330794-10-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 330794-10-0 ]

CAS No. :330794-10-0 MDL No. :MFCD23379585
Formula : C17H25BClNO4 Boiling Point : -
Linear Structure Formula :- InChI Key :AWETUPVLWRHMIY-UHFFFAOYSA-N
M.W : 353.65 Pubchem ID :22346952
Synonyms :

Calculated chemistry of [ 330794-10-0 ]

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.59
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 98.17
TPSA : 56.79 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 4.1
Log Po/w (WLOGP) : 3.8
Log Po/w (MLOGP) : 2.37
Log Po/w (SILICOS-IT) : 2.5
Consensus Log Po/w : 2.55

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.47
Solubility : 0.012 mg/ml ; 0.0000338 mol/l
Class : Moderately soluble
Log S (Ali) : -5.0
Solubility : 0.00355 mg/ml ; 0.00001 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -5.52
Solubility : 0.00106 mg/ml ; 0.00000301 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.44

Safety of [ 330794-10-0 ]

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 [ 330794-10-0 ]

* 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 [ 330794-10-0 ]

[ 330794-10-0 ] Synthesis Path-Downstream   1~22

  • 1
  • [ 330794-09-7 ]
  • [ 73183-34-3 ]
  • [ 330794-10-0 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate; In dichloromethane; N,N-dimethyl-formamide; b Tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate A mixture of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (2.10 g, 0.00685 mol), diboron pinacol ester (2.09 g, 0.00822 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.17 g, 0.00021 mol) and potassium acetate (2.02 g, 0.02055 mol) in N,N-dimethylformamide (50 ml) was heated at 80 C. under a nitrogen atmosphere for 6 hours. The solvent was removed under reduced pressure. The residue was triturated with heptane (70 mL) and the resulting solids were removed by filtration through a pad of celite. The heptane was removed in vacuo to give tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a grey solid (1.93 g, 0.00546 mol). 1H NMR (DMSO-d6, 400 MHz) delta 8.65 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 1.47 (s, 9H), 1.29 (s, 12H).
With potassium acetate; In dichloromethane; N,N-dimethyl-formamide; B. Tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate A mixture of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (2.10 g, 0.00685 mol), diboron pinacol ester (2.09 g, 0.00822 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.17 g, 0.00021 mol) and potassium acetate (2.02 g, 0.02055 mol) in N,N-dimethylformamide (50 ml) was heated at 80 C. under a nitrogen atmosphere for 6 hours. The solvent was removed in vacuo. The residue was triturated with heptane (70 mL) and the resulting solids were removed by filtration through a pad of Celite OR 521. The heptane was removed in vacuo to give tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a grey solid (1.93 g, 0.00546 mol): 1H NMR (DMSO-d6 400 MHz) delta 8.65 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 1.47 (s, 9H), 1.29 (s, 12H).
With potassium acetate; In dichloromethane; N,N-dimethyl-formamide; B. Tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate A mixture of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (2.10 g, 0.00685 mol), diboron pinacol ester (2.09 g, 0.00822 mol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.17 g, 0.00021 mol) and potassium acetate (2.02 g, 0.02055 mol) in N,N-dimethylformamide (50 ml) was heated at 80 C. under a nitrogen atmosphere for 6 hours. The solvent was removed in vacuo. The residue was triturated with heptane (70 mL) and the resulting solids were removed by filtration through a pad of Celite 521. The heptane was removed in vacuo to give tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a grey solid (1.93 g, 0.00546 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.65 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 1.47 (s, 9H), 1.29 (s, 12H).
With potassium acetate; In dichloromethane; N,N-dimethyl-formamide; b) Tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate A mixture of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (2.10 g, 0.00685 mol), diboron pinacol ester (2.09 g, 0.00822 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.17 g, 0.00021 mol) and potassium acetate (2.02 g, 0.02055 mol) in N,N-dimethylformamide (50 ml) was heated at 80 C. under a nitrogen atmosphere for 6 hours. The solvent was removed under reduced pressure. The residue was triturated with heptane (70 mL) and the resulting solids were removed by filtration through a pad of celite. The heptane was removed in vacuo to give tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a grey solid (1.93 g, 0.00546 mol). 1H NMR (DMSO-d6, 400 MHz) delta 8.65 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 1.47 (s, 9H), 1.29 (s, 12H).
With potassium acetate; In dichloromethane; N,N-dimethyl-formamide; B. Tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate A mixture of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (2.10 g, 0.00685 mol), diboron pinacol ester (2.09 g, 0.00822 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.17 g, 0.00021 mol) and potassium acetate (2.02 g, 0.02055 mol) in N,N-dimethylformamide (50 ml) was heated at 80 C. under a nitrogen atmosphere for 6 hours. The solvent was removed in vacuo. The residue was triturated with heptane (70 mL) and the resulting solids were removed by filtration through a pad of Celite 521. The heptane was removed in vacuo to give tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a grey solid (1.93 g, 0.00546 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.65 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 1.47 (s, 9H), 1.29 (s, 12H).
With potassium acetate; In dichloromethane; N,N-dimethyl-formamide; B. Tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate A mixture of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (2.10 g, 0.00685 mol), diboron pinacol ester (2.09 g, 0.00822 mol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.17 g, 0.00021 mol) and potassium acetate (2.02 g, 0.02055 mol) in N,N-dimethylformamide (50 ml) was heated at 80 C. under a nitrogen atmosphere for 6 hours. The solvent was removed in vacuo. The residue was triturated with heptane (70 mL) and the resulting solids were removed by filtration through a pad of Celite 521. The heptane was removed in vacuo to give tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a grey solid (1.93 g, 0.00546 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.65 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 1.47 (s, 9H), 1.29 (s, 12H).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In DMF (N,N-dimethyl-formamide); at 80.0℃; for 6.0h; [0648] A mixture of tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (2.10 g, 0.00685 mol), diboron pinacol ester (2.09 g, 0.00822 mol), [1,1'-bis(diphenylphosphino)ferro-cene]dichloropalladium(II) complex with dichloromethane (1:1) (0.17 g, 0.00021 mol) and potassium acetate (2.02 g, 0.02055 mol) in N,N-dimethylformamide (50 ml) was heated at 80 C. under a nitrogen atmosphere for 6 hours. The solvent was removed in vacuo. The residue was triturated with heptane (70 mL) and the resulting solids were removed by filtration through a pad of Celite 521. The heptane was removed in vacuo to give tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate as a grey solid (1.93 g, 0.00546 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.65 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 1.47 (s,9H), 1.29 (s, 12H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90.0℃; for 4.0h;Inert atmosphere; step 2: A 10 L 4-necked round-bottom flask was purged and maintained under a nitrogen atmosphere then charged with tert-butyl N-(4-bromo-2-chlorophenyl)carbamate (477 g, 1.00 equiv, crude), dioxane (3500 mL), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (371 g, 1.46 mol, 1.00 equiv), KOAc (428 g, 4.36 mol, 3.00 equiv), and Pd(dppf)Cl2 (18 g, 24.60 mmol, 0.02 equiv). The resulting solution was stirred at 90 C. for 4 h. This reaction was repeated for 1 more time. The solids were filtered out and the product was used in the next step without further purification.

  • 2
  • [ 330794-10-0 ]
  • trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
  • trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80.0℃; for 22.0h; [0650] A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), <strong>[330794-10-0]tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate</strong> (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80 C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80 C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol): [0651] 1H NMR (DMSO-d6, 400 MHz) delta 8.76 (s, 1H), 8.23 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.57 (dd, 1H), 4.58-4.71 (m, 1H), 2.15 (s, 3H), 1.89-2.61 (m, 15H), 1.49 (s, 9H), 1.40-1.48 (m, 2H); TLC (dichloromethane/methanol=90:10) Rf 0.13, MS: MH+ 541.
  • 3
  • [ 14221-01-3 ]
  • [ 330794-10-0 ]
  • [ 461699-32-1 ]
  • trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With ammonium hydroxide; sodium carbonate; In methanol; 1,2-dimethoxyethane; dichloromethane; water; c Trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), <strong>[330794-10-0]tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate</strong> (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(O) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80 C., after which time additional tetrakis(triphenylphosphine)palladium(O) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80 C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3*75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.76 (s, 2H), 8.23 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.57 (dd, 1H), 4.58-4.71 (m, 1H), 2.15 (2, 3H), 1.89-2.61 (m, 15H), 1.49 (s, 9H), 1.40-1.48 (m, 2H);
With ammonium hydroxide; sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In methanol; 1,2-dimethoxyethane; dichloromethane; water; C. Trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), <strong>[330794-10-0]tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate</strong> (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(O) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80 C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80 C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3*75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol): 1H NMR (DMSO-d6 400 MHz) delta 8.76 (s, 1H), 8.23 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.57 (dd, 1H), 4.58-4.71 (m, 1H), 2.15 (s, 3H), 1.89-2.61 (m, 15H), 1.49 (s, 9H), 1.40-1.48 (m, 2H); TLC (dichloromethane/methanol =90:10) Rf 0.13, MS: M+541.
With ammonium hydroxide; sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In methanol; 1,2-dimethoxyethane; dichloromethane; water; C. Trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), <strong>[330794-10-0]tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate</strong> (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(O) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80 C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80 C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3*75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.76 (s, 1H), 8.23 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.57 (dd, 1H), 4.58-4.71 (m, 1H), 2.15 (s, 3H), 1.89-2.61 (m, 15H), 1.49 (s, 9H), 1.40-1.48 (m, 2H); TLC (dichloromethane/methanol=90:10) Rf 0.13, MS: M+ 541.
  • 4
  • [ 330794-10-0 ]
  • [ 461699-32-1 ]
  • trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With ammonium hydroxide; sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In methanol; 1,2-dimethoxyethane; dichloromethane; water; c) Trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), <strong>[330794-10-0]tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate</strong> (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80 C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80 C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3*75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.76 (s, 2H), 8.23 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.57 (dd, 1H), 4.58-4.71 (m, 1H), 2.15 (2, 3H), 1.89-2.61 (m, 15H), 1.49 (s, 9H), 1.40-1.48 (m, 2H);
With ammonium hydroxide; sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In methanol; 1,2-dimethoxyethane; dichloromethane; water; C. Trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), <strong>[330794-10-0]tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate</strong> (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80 C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80 C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3*75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol): 1H NMR (DMSO-d6, 400 MHz) delta 8.76 (s, 1H), 8.23 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.57 (dd, 1H), 4.58-4.71 (m, 1H), 2.15 (s, 3H), 1.89-2.61 (m, 15H), 1.49 (s, 9H), 1.40-1.48 (m, 2H); TLC (dichloromethane/methanol=90:10) Rf 0.13, MS: M+ 541.
  • 5
  • [ 330794-10-0 ]
  • 2-chloro-4-(6-methylpyrazin-2-yl)aniline [ No CAS ]
  • 6
  • [ 330794-10-0 ]
  • 2-(3-chloro-4-iodophenyl)-6-methylpyrazine [ No CAS ]
  • 7
  • [ 330794-10-0 ]
  • [2-chloro-4-(6-methylpyrazin-2-yl)phenyl]boronic acid [ No CAS ]
  • 8
  • [ 330794-10-0 ]
  • tert-butyl-3-(2-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethoxy)azetidine-1-carboxylate [ No CAS ]
  • 9
  • [ 330794-10-0 ]
  • tert-butyl-3-(2-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethoxy)azetidine-1-carboxylate [ No CAS ]
  • 10
  • [ 330794-10-0 ]
  • tert-butyl-3-(2-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)ethoxy)azetidine-1-carboxylate [ No CAS ]
  • 11
  • [ 330794-10-0 ]
  • 8-(2-(azetidin-3-yl-oxy)ethyl)-6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
  • 12
  • [ 330794-10-0 ]
  • tert-butyl-4-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)piperidine-1-carboxylate [ No CAS ]
  • 13
  • [ 330794-10-0 ]
  • 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-8-(piperidin-4-ylmethyl)pyrido[2,3-d]pyrimidin-7(8H)-one [ No CAS ]
  • 14
  • [ 330794-10-0 ]
  • [ 1432909-92-6 ]
  • 15
  • [ 330794-10-0 ]
  • 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-8-[[1-(2-hydroxyethyl)-4-piperidyl]methyl]pyrido[2,3-d]pyrimidin-7-one [ No CAS ]
  • 16
  • [ 330794-10-0 ]
  • 2-(3-chloro-4-iodophenyl)-3-methylpyrazine [ No CAS ]
  • 17
  • [ 330794-10-0 ]
  • [2-chloro-4-(3-methylpyrazin-2-yl)phenyl]boronic acid [ No CAS ]
  • 18
  • [ 95-58-9 ]
  • [ 330794-10-0 ]
  • tert-butyl-N-[2-chloro-4-(3-methylpyrazin-2-yl)phenyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
350 g With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; at 85.0℃;Inert atmosphere; step 3: A 10 L 4-necked round-bottom flask was purged and maintained under a nitrogen atmosphere and then charged with tert-butyl N-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate from step 2 (1.00 equiv), 2-chloro-3-methylpyrazine (187 g, 1.45 mol, 1.00 equiv), a solution of Na2CO3 (312 g, 2.92 mol, 2.00 equiv) in water (1460 mL) and (PPh3)4Pd(II) (10 g). The resulting solution was stirred overnight at 85 C. This reaction was repeated 1 more time. The reaction mixture was cooled to RT, diluted with 10 L of water and extracted with 10 L of EtOAc. The organic layer was washed with 3×10 L of water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified on a SiO2 column eluting with EtOAc/PE gradient (1:10 to 1:5) to afford 350 g (75%) of tert-butyl N-[2-chloro-4-(3-methylpyrazin-2-yl)phenyl]carbamate as a white solid.
  • 19
  • [ 38557-71-0 ]
  • [ 330794-10-0 ]
  • tert-butyl-N-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
340 g With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; at 85℃;Inert atmosphere; step 6: Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl N-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate, Na2CO3 (2 N, 2.90 L), <strong>[38557-71-0]2-chloro-6-methylpyrazine</strong> (236 g, 1.84 mol, 0.65 equiv; obtained in step 3), and Pd(PPh3)4 (20 g). The resulting solution was stirred overnight at 85 C. and cooled. The solids were filtered out and the filtrate was diluted with 3 L of water. The resulting solution was extracted with EtOAc (3×3 L). The organic layers were combined, washed with water (3×3 L) and brine (1×3 L), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc:PE (1:1) to afford 340 g (38%) of tert-butyl N-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]carbamate as a yellow solid.
  • 20
  • [ 38762-41-3 ]
  • [ 330794-10-0 ]
  • 21
  • [ 24424-99-5 ]
  • [ 330794-10-0 ]
  • 22
  • [ 330794-10-0 ]
  • (1R,5S,6S)-tert-butyl 6-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
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