* 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.
Multi-step reaction with 4 steps
1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 25 °C
2: p-toluenesulfonyl chloride / 2 h / 25 °C
3: ethanolamine / 10 h / 25 °C
4: triethylamine; dmap / dichloromethane / 8 h / 25 °C
With chromium(VI) oxide; sulfuric acid In water at 20℃; for 48h;
4-Bromoisoquinoline-6-carboxylic acid
To a solution of 10 g (45.03 mmol) of 4-bromo-6-methyl-isoquinoline in a mixture of 100 mL of concentrated sulfuric acid and 100 mL of water is added 13.51 g (135.09 mmol) of chromium trioxide at 20°C. The mixture is stirred at this temperature for 48 h. The precipitated solid is collected by filtration,washed with water and dried to give 5.39 g of the desired product as a white solid.MS (ESI+): 251.9, 253.9 [M+H].‘H NMR (400 MHz, DMSO-d6) ppm: 9.44 (s, 1H), 8.86 (s, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.24 (dd, J = 8.5, 1.5 Hz, 1H).
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 20h;
To a stirred solution of 100 mg (0.45 mmol) of 4-bromo-6-methyl-isoquinoline in 4 mL of CCL4 are added22 mg (0.09 mmol) of benzoyl peroxide and 176 mg (0.99 mmol) ofNBS. The reaction mixture is heatedto 80°C for 20h. Then the mixture is cooled down to rt, diluted with EA, washed with water and brine, dried over Na2SO4, concentrated to give 171 mg of the crude 4-bromo-6-(dibromomethyl)isoquinoline as a yellow solid.This intermediate is dissolved in a mixture of 3 mL of ethanol and 3 mL of water and 153 mg (0.9 mmol)of AgNO3 are added. The reaction mixture is stirred at 100°C for lh. The solvent is evaporated underreduced pressure and the residue is purified by column chromatography (PE/EA = 1/3) to give 56 mg of the desired product as a white semisolid.MS (ESI+): 299.9 [M+H].‘H NMR (400 MHz, CDC13) ppm: 10.31 (s, 1H), 9.29 (s, 1H), 8.87 (s, 1H), 8.67 (s, 1H), 8.26-8.12 (m,2H).
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 25℃; for 4h;
A solution of 220mg (1.00 mmol) of 4-bromo-6-(bromomethyl)isoquinoline (CAS 98331-27-2) and 513 mg (3.50 mmol) of mCPBA in 4 mL of DCM is stirred at 25°C for 4 h. The solvent is evaporated and theresidue is diluted with EA, washed with saturated NaHCO3 solution and water, dried over Na2SO4, concentrated to give 235 mg of the crude 4-bromo-6-methyl-2-oxido-isoquinolin-2-ium as a grey solid. The crude intermediate is dissolved in 5 ml. of pyridine and 376mg (1.98 mmol) of TsC1 is added. The reaction mixture is stirred at 25°C for 2 h. The pyridine was removed under reduced pressure to afford 285 mg of the crude 4-bromo-6-methyl-1-pyridin-1-ium-1-yl-isoquinoline as a grey solid.Then the crude intermediate in 10 ml. of 2-aminoethanol is stirred at 25°C for 10 h. The solution is poured onto cracked ice, and the solids are isolated by filtration and dried under vacuum to afford 130 mg of the crude 4-bromo-6-methyl-isoquinolin-1-amine as a grey solid.This intermediate is dissolved in 5 mL of DCM and 239 mg (1.09 mmol) of Boc2O. 153 jiL (1.10 mmol) of TEA, 67 mg (0.55 mmol) of DMAP are added. The resultant solution is stirred at 25°C for 8h. Thesolvent was removed and the residue was purified by silica gel column chromatography (PE/EA = 10/1, Rf = 0.4) to give 111 mg of tert-butyl N-(4-bromo-6-methyl- 1 -isoquinolyl)-N-tert-butoxycarbonylcarbamate as a light yellow solid.MS (ESI+): 437.1 [M+H].‘H NMR (400 MHz, DMSO-d6) ppm: 8.65 (s, 1H), 7.95 (s, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.95 (dd, J1.2 Hz, J2 = 8.8 Hz, 1H), 2.61 (s, 3H), 1.29 (s, 18H).
Multi-step reaction with 3 steps
1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 25 °C
2: p-toluenesulfonyl chloride / 2 h / 25 °C
3: ethanolamine / 10 h / 25 °C
Multi-step reaction with 6 steps
1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 4 h / 25 °C
2.1: p-toluenesulfonyl chloride / 2 h / 25 °C
3.1: ethanolamine / 10 h / 25 °C
4.1: triethylamine; dmap / dichloromethane / 8 h / 25 °C
5.1: dibenzoyl peroxide; N-Bromosuccinimide / tetrachloromethane / 8 h / 100 °C
6.1: sodium hydride / N,N-dimethyl-formamide / 3 h / -20 - 25 °C
6.2: 2 h / -20 °C
Stage #1: 4-bromo-6-methylisoquinoline With n-butyllithium In tetrahydrofuran; hexane at -78 - -70℃; for 0.5h; Inert atmosphere;
Stage #2: Trimethyl borate In tetrahydrofuran; hexane at -70 - -40℃; for 1h;
Under Ar, to a cold (-78 °C) stirred solution of 6.8 mL of n-BuLi (10.8 mmol, 1.6M solution in hexane) in 40 ml of THF (dried over sodium) is added dropwise 2 g of 4-bromo-6-methylisoquinoline (9 mmol) in10 ml of THF (dried over sodium), the rate of addition is adjusted so as to keep the temperature of the reaction mixture below -70 °C. After stirring at this temperature for 30 mins, a solution 1.2 mL of trimethyl borate (10.8 mmol) in 5 mL of THF (dried over sodium) is slowly added while the temperature of the mixture is maintained between -70 °C and - 65 °C. The mixture is allowed to warm to -40 °C, and is stirred at this temperature for additional lh. The acetone/dry ice bath is removed and the reaction isallowed to warm to -20 °C when an aqueous 2 N hydrogen chloride solution is added. The mixture is allowed to reach room temperature, and the aqueous layer (pH 1) is collected and adjusted to pH 7 with an aqueous 5 N sodium hydroxide solution. The mixture is then saturated with NaC1, and extracted with THF. The combined extracts are dried over Na2SO4, concentrated under reduced pressure to provide 1.5 g of (6-methyl-4-isoquinolyl)boronic acid as an off-white solid.MS (ESI+): 188.1 [M+H].
With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; for 20h; Inert atmosphere;
30.A A. 4-(2-(Diphenylmethylene)hydrazinyl)-6-methylisoquinoline, 30a
A mixture of 4-bromo-6-methylisoquinoline (500 mg, 2.25 mmol), benzophenone hydrazone (442 mg, 2.25 mmol), BINAP (140 mg, 0.225 mmol), palladium(II) acetate (50.5 mg, 0.225 mmol), sodium tert-butoxide (325 mg, 3.38 mmol), and toluene (3 mL) was heated to 100° C. and stirred for 20 h under a N2 atmosphere before cooling to room temperature. The mixture was filtered and concentrated to give a black oil, which was purified by FCC (petroleum ether: ethyl acetate=30:70) to afford compound 30a (280 mg, 37%) as a yellow solid. LCMS (ESI): mass calcd. for C23H19N3 337.4, m/z found 338.0 [M+H]+.
With sodium azide; copper(II) sulfate heptahydrate; sodium carbonate; sodium L-ascorbate; <i>L</i>-proline In water; N,N-dimethyl-formamide at 85℃; Inert atmosphere;
General procedure for synthesis of amino isoquinolin derivatives(GP2) for compounds 48a-c
General procedure: Under argon atmospherethe appropriate bromo isoquinolin (1 eq.), L-proline (0.1 eq.), sodiumazide (1.3 eq.) and sodium carbonate (1.3 eq.)was dissolved ina 2:1 mixture of DMF and water. Subsequently, sodium ascorbate(1.3 eq.) and copper sulfate hepta hydrate (1 eq.) were added andthe reaction mixture was stirred over night at 85 C. After fullconversion (LCMS control) the mixture was cooled to room temperatureand EtOAc and sat. aqueous NaHCO3 solution were added.The mixture was extracted with EtOAc (3x), the combined organiclayers were dried over sodium sulfate and concentrated underreduced pressure to obtain the crude. The obtained products wereused as obtained without further purification.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
