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With triethylamine;mercury dichloride; In dichloromethane; at 20℃; for 16.0h;
A mixture of <strong>[623586-00-5](R)-benzyl 3-methylpiperazine-1-carboxylate</strong> (4.8 g, 20.5 mmol) from step (a) above, 1,3-bis(tertbutoxycarbonyl)-2-methylisothiourea (6.5 g, 23 mmol, Aldrich), and triethylamine (3.4 mL, 24.6 mmol, Aldrich) in DCM (140 mL) was added mercury(II)chloride (5.8 g, 21.6 mmol, Aldrich). The reaction mixture was stirred at RT for 16 h. Then, the mixture was filtered and the solid was washed with DCM (2*100 mL). The combined filtrates were concentrated in vacuo and the residue was purified on silica gel using ISCO Combiflash system with DCM/2M methanolic ammonia gradient to give the title compound as a white solid. MS (ESI, positive ion) m/z: 477 (M+1).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16.0h;
A solution of (R)-2-methylpiperazine (7 g, 70 mmol, Aldrich) in DCM (200 mL) and DIEA (6.7 mL, 38.5 mmol, Aldrich) was added benzyl chloroformate (5 mL, 35 mmol, Aldrich) dropwise at 0 C. The mixture was then warmed up to RT and was stirred for 16 h. The solvents were removed and the residue was purified on silica gel using ISCO Combiflash system with DCM/2M methanolic ammonia gradient to give the title compound as light yellow oil. MS (ESI, positive ion) m/z: 235 (M+1).
(2R,5S)-tert-butyl 5-(((R)-4-((benzyloxy)carbonyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium carbonate; sodium iodide; In acetonitrile; at 80℃; for 18.0h;
To a solution of (2 ,5 )-tert-butyl 5-(chloromethyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-lH-pyrrolo[3,2-b]pyridin-l-yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylate ( 8.67 g, 15.91 mmol, obtained as described in WO 2012/143726) in acetonitrile (50.0 mL) and was added (R)- benzyl 3-methylpiperazine-l-carboxylate (4.10 g, 17.50 mmol, commercially available from, for example, Fluorochem), sodium iodide (0.238 g, 1.591 mmol) and potassium carbonate (6.59 g, 47.7 mmol) and the reaction was stirred at 80 C for 18 hours. The volatiles were removed in vacuo, the reaction was diluted in 100 mL DCM and was washed with 100 mL saturated sodium bicarbonate solution and 100 mL water. The aqueous layer was washed with an additional 2 x 100 mL DCM, and the combined organic layers were washed with 100 mL brine and passed through a Biotage phase separator. The volatiles were removed in vacuo. The residue was dissolved in 25 mL DCM and loaded onto 340g KP-Sil SNAP cartridge and purified by flash chromatography: 2% methanol in DCM for lcolumn volume, 10 column volumes gradient 2% to 12% methanol in DCM and 2 column volumes 12% methanol in DCM. Compound eluted at 7 column volumes to afford the title compound (9.26 g, 12.5 mmol, 78 % yield). LCMS RT= 1.05 min, ES+ve 743.
(2R,5S)-tert-butyl 5-(((R)-4-(6-(4-(((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-4-yl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(5-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethoxy)pyrimidin-2-yl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(6-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)nicotinoyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(6-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)nicotinoyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(6-(4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)nicotinoyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)acetyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
2-((2R,5R)-2-(((R)-4-(5-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethoxy)pyrimidin-2-yl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethanone tetrakis(trifluoroacetate)[ No CAS ]
2-((2R,5R)-2-(((R)-4-(2-(2-(2-(2-((6-(tert-butylsulfonyl)-4-((5-fluoro-1H-indazol-3-yl)amino)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethanone pentakis(trifluoroacetate)[ No CAS ]
2-((2R,5R)-2-(((R)-4-(6-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)nicotinoyl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethanone pentahydrochloride[ No CAS ]
2-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-1-yl)-1-((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)ethanone[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(6-(4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-1-yl)nicotinoyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carbonyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 5-(((R)-4-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)propyl)piperidin-1-yl)pyrimidine-5-carbonyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate[ No CAS ]
(2R,5S)-tert-butyl 4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methylpiperazin-1-yl)methyl)piperazine-1-carboxylate[ No CAS ]
2-((2R,5R)-2-(((R)-4-(6-(4-(((6-(tert-butylsulfonyl)-4-((3,4-dimethyl-1H-pyrazol-5-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-1-yl)pyrimidin-4-yl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethanone tetrakis(trifluoroacetate)[ No CAS ]