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CAS No. : | 893566-75-1 | MDL No. : | MFCD08752230 |
Formula : | C14H18BrNO2 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | GKXSAKJDUDGJFB-UHFFFAOYSA-N |
M.W : | 312.20 | Pubchem ID : | 59463272 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
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* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 6-bromo-1,2,3,4-tetrahydroisoquinoline and 8-bromo-1,2,3,4-tetrahydroisoquinoline (22.1 mmol) in THF (100 mL) was added DIPEA (22.1 mmol) and BOC2O (24 mmol). The reaction mixture was allowed to stir at rt over the weekend and then concentrated. Water (5 mL) was added to the residue and the pH was adjusted to 2 by the addition of 1N H3PO4. The mixture was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (6.04 g, 88%) as a yellow oil. | ||
Dry THF (50 mL) and DIPEA (1.3 mL, 7.5 mmol) were added followed by BOC- anhydride (1.8 g, 8.2 mmol). The mixture was stirred overnight at RT. The volatiles were evaporated and the residue was taken up in water. The pH was adjusted to 2 with IM phosphoric acid and the product was extracted twice with EtOAc. The combined organic phases were washed with brine made slightly alkaline with saturated sodium bicarbonate, dried, filtered and concentrated. The crude product was purified by column chromatography with EtOAc-heptanes (1:50 through 1:20) to give 2.24 g (96%) of a 3:1 mixture of the title product and fert-butyl 8-bromo-3,4-dihydroisoquinoline-2(lH)- carboxylate. EPO <DP n="26"/>LC-MS m/z 256/258 (M-56);1H NMR (CDCl3) delta 7.31 (dd, IH), 7.30 (br s, IH), 6.98 (d, IH), 4.52 (s, 2H), 3.63 (t, 2H), 2.81 (t, 2H) and 1.50 (s, 9H) ppm (6-isomer).1H NMR (CDCl3) delta 7.42 (dd, IH), 7.12-7.01 (m's, 2H), 4.55 (s, 2H), 3.64 (t, 2H), 2.84 (t, 2H) and 1.51 (s, 9H) ppm (8-isomerV | ||
Dry THF (50 mL) and DIPEA (1.3 mL, 7.5 mmol) were added followed by BOC- anhydride (1.8 g, 8.2 mmol). The mixture was stirred at RT overnight. The volatiles were i5 evaporated and the residue was taken up in water. The pH was adjusted to 2 with IM phosphoric acid and the product was extracted twice with EtOAc. The combined organic phases were washed with brine made slightly alkaline with saturated sodium bicarbonate, dried, filtered and concentrated. The crude product was purified by column chromatography with EtOAc-heptanes (1:50 through 1:20) to give 2.24 g (96%) of a 3:120 mixture of the title product and tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(lH)- carboxylate. LC-MS mlz 256, 258 (M-56);1H NMR (CDCl3) delta 7.31 (dd, IH), 7.30 (br s, IH), 6.98 (d, IH), 4.52 (s, 2H), 3.63 (t, 2H),2.81 (t, 2H) and 1.50 (s, 9H) ppm (6-isomer).25 11HH N NMMRR ( (CCDDCCll33)) delta delta 77..4422 ( (dddd,, I IHH)),, 77..112-7.01 (m, 2H), 4.55 (s, 2H), 3.64 (t, 2H), 2.84 (t, 2H) and 1.51 (s, 9H) ppm (8-isomer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃; for 4h; | A solution of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate and <strong>[893566-75-1]tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate</strong> (19.5 mmol), bis(pinacolato)diboron (21.4 mmol) and potassium acetate (61 mmol) in DMF (100 mL) was degassed. To this solution was added PdCl2dppf (1:1 complex with DCM, 0.8 mmol). The reaction mixture was heated at 85 C. for 4 hr and then allowed to cool to room temperature and diluted with EtOAc. The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LCMS: (FA) ES+360 (for each). | |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 81℃; | tert-Butyl 6-( 4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-vD-3 ,4-dihvdroisoquinoline- 2(liD-carboxylate is A 3:1 mixture (0.49 g, 1.6 mmol) of fert-butyl 6-bromo-3,4-dihydroisoquinoline-2(lH)- carboxylate and tert-butyl 8~bromo-3,4-dihydroisoquinoline-2(li/)- carboxylate, bis(pinacolato)diborane (0.45 g, 1.8 mmol), PdCl2 x dppf (0.039 g, 0.048 mmol), potassium acetate (0.48 g, 4.8 mmol) and DMF (8.0 mL) was heated at 81 C ' WeligKtyThe~slve1alphat^30 twice with EtOAc. The organic phase was dried, filtered and concentrated. Column chromatography with EtO Ac-heptanes (1:10 through 1:4) gave 0.24 g of a 4:1 mixture of EPO <DP n="25"/>the title product and ter/-butyl 8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2(lH)-carboxylate.1H NMR (CDCl3) delta 7.62 (d, IH), 7.60 (s, IH), 7.13 (d, IH), 4.59 (s, 2H), 3.64 (t, 2H), 2. .85 (t, 2H), 1.50 (s, 9H) and 1.35 (s, 12H) ppm (6-isomer). 1H NMR (CDCl3) delta 7.69 (d, IH), 7.24-7.14 (m's, 2H), 4.88 (s, 2H), 3.64 (t, 2H), 2.85 (t, 2H), 1.50 (s, 9H) and 1.35 (s, 12H) ppm (8-isomef). | |
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 81℃; | A 3:1 mixture (0.49 g, 1.6 mmol) of tert-mty 6-bromo-3,4-dihydroisoquinoline-2(lH)- carboxylate and fert-butyl 8-bromo-3,4-dihydroisoquinoline-2(lH)- carboxylate, bis(pinacolato)diborane (0.45 g, 1.8 mmol), PdCl2 x dppf (0.039 g, 0.048 mmol), potassium acetate (0.48 g, 4.8 mmol) and DMF (8.0 mL) was heated at 81 0C overnight. The solvent was evaporated, the residue taken up in water-brine and washed twice with EtOAc. The organic phase was dried, filtered and concentrated. Column chromatography with EtOAc-heptanes (1:10 through 1:4) gave 0.24 g of a 4:1 mixture of the title product and tert-butyl 8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4- dihydroisoquinoline-2( lH)-carboxylate.1H NMR (CDCl3) delta 7.62 (d, IH), 7.60 (s, IH), 7.13 (d, IH), 4.59 (s, 2H), 3.64 (t, 2H)5 2.85 (t, 2H), 1.50 (s, 9H) and 1.35 (s, 12H) ppm (6-isomer). 1H NMR (CDCl3) delta 7.69 (d, IH), 7.24-7.14 (m, 2H)5 4.88 (s, 2H), 3.64 (t, 2H), 2.85 (t, 2H), 1.50 (s, 9H) and 1.35 (s, 12H) ppm (8-isomer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 85℃; for 2h;Inert atmosphere; Sealed tube; | A vial was charged with N-(2,4-dimethoxybenzyl)-l-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-N-(l,2,4-thiadiazol-5-yl)-lH-indole-6-sulfonamide (Intermediate H)(0.188 g, 0.330 mmol), tert-butyl 8-bromo-3,4-dihydroisoquinoline- 2(lH)-carboxylate (0.257 g, 0.824 mmol), potassium phosphate (0.315 g, 1.483 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.027 g, 0.033 mmol). DMF (2.197 ml) was added, and the vial was flushed with argon, sealed, and stirred at 85 °C for two hours. Additional tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (Oakwood Inc., West Columbia, South Carolina ) (0.257 g, 0.824 mmol) was added and the reaction was stirred at 85 °C for two hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40g silica gel column (Teledyne Isco, Lincoln, NE) , gradient elution 0 to 100percent EtOAc:Hex) to afford tert- butyl 8-(6-( -(2,4-dimethoxybenzyl)-N-(l,2,4-thiadiazol-5-yl)sulfamoyl)-l-methyl-lH- indol-3-yl)-3,4-dihydroisoquinoline-2(lH)-carboxylate as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.5% | With triethylamine; In tetrahydrofuran; at 25℃; for 1h; | To a solution of 8-bromo-l,2,3,4-tetrahydroisoquinoline HCl salt (3.50 g, 14.1 mmol, 1 eq) in tetrahydrofuran (50 mL) was added triethylamine (2.85 g, 28.2 mmol, 3.9 mL, 2 eq.) and B0C2O (3.10 g, 14.2 mmol, 1.01 eq.). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with H20 (50 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give Example 121A (4.20 g, yield = 95.5percent). [0215] NMR (400MHz, CDCb) delta 7.41 (d, J=7.6 Hz, 1H), 7.12 - 7.01 (m, 2H), 4.54 (s., 2H), 3.64 (t, J=5.2 Hz, 2H), 2.84 (t, J=5.2 Hz, 2H), 1.51 (s, 9H). |
94% | With triethylamine; In dichloromethane; at 20℃; for 1.5h; | To the solution of 8-bromo-1,2,3,4-tetrahydroiso- quinoline HC1 (1 g, 4.72 mmol) in DCM (20 mE) was added 13oc20 (1030mg, 4.72 mmol) andNEt3 (960mg, 9.43 mmol). The mixture was stirred at 20° C. for 1 .5 h. The mixture was concentrated in vacuo to afford crude product (2000 mg). The crude was purified by silica gel chromatography eluted withEtOAc in petroleum ether from 0 to 30percent to afford the desiredproduct (1.36 mg, 94percent). ?H NMR (400 MHz, CDC13) oe ppm7.42 (d, J=7.5 Hz, 1H), 7.14-6.97 (m, 2H), 4.61-4.48 (m, 2H),3.64 (t, J=5.4 Hz, 2H), 2.90-2.75 (m, 2H), 1.50 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
450 mg | With copper(l) iodide; trans-N,N-dimethylcyclohexanediamine; sodium iodide; In 1,4-dioxane; at 110℃; for 40h;Inert atmosphere; Sealed tube; | A mixture of tert-butyl 8-bromo-3,4-dihydroiso- quinoline-2(1H)-carboxylate (500 mg, 1.60 mmol), Nal (720 mg, 4.80 mmol), Cul (45.8 mg, 0.240 mmol) and trans-N,Ndimethylcyclohexanediamine (68 mg, 0.48 mmol) in dioxane (10 mE) was purged with N2 for 10 mm. The resulting yellow suspension was stirred at 110° C. in a sealed tube for 20 hrs. ECMS showed 50percent conversion, therefore additional Nal (720 mg, 4.80 mmol), Cul (45.8 mg, 0.24 mmol) and trans-N,N-dimethylcyclohexanediamine (68 mg, 0.40 mmol) was added followed by N2 purging for 10 mm. The resulting yellow suspension was stirred at 110° C. in a sealed tube for 20 hrs. The mixture was poured into water (20 mE) and extracted with EtOAc (10 mEx3). The extract was concentrated in vacuo to afford crude material which was purified by silica gel chromatography eluted with EtOAc in petroleum ether from 0 to 20percent to afford the product (450 mg, 78percent) as a light yellow oil. ECMS [M-tBu]304; 1H NMR (400 MHz, CDCl3) oe ppm 7.70 (d, J=8.0 Hz, 1H), 7.12 (d, J=7.0 Hz, 1H), 6.94-6.82 (m, 1H), 4.44 (m, 2H), 3.62 (t, J=5.5 Hz, 2H), 2.81 (br. s., 2H), 1.50 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Example 144: 1,1,1,3,3,3-Hexafluoropropan-2-yl 1-((2-ethyl-1,2,3,4-tetrahydroisoquinolin-8- yl)methyl)-1,8-diazaspiro[4.5]decane-8-carboxylate Step 1: Preparation of ter -but l 8-form l-1,2,3,4-tetrah droisoquinoline-2-carboxylate A flask was charged with <strong>[893566-75-1]tert-butyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate</strong> (3.11 g, 9.93 mmol, 1.00 equiv) and THF (50 mL) under nitrogen. The reaction mixture was cooled to?78 ^C and n-butyllithium (2.5 M in hexane, 6 mL, 15.1 mmol, 1.50 equiv) was added dropwise. The reaction mixture was stirred at?78 ^C for 2 h, then DMF (1.46 g, 19.9 mmol, 2.00 equiv) was added dropwise. The resulting solution was stirred for 2 h at?78 ^C, quenched with aq. NH4Cl (10 mL) and diluted with EtOAc (100 mL). The mixture was washed with H2O (3 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column (1:5 EtOAc/petroleum ether) to provide 1.81 g (69percent yield) of tert-butyl 8-formyl-1,2,3,4- tetrahydroisoquinoline-2-carboxylate as a yellow solid. LCMS (ESI, m/z): 262 [M+H]+. | |
45% | Compound 14.2 (200 mg, 0.64 mmol) was dissolved in dry tetrahydrofuran (10 ml) andcooled to -78 O (dry ice, acetone). nButyllithium (2.4M in hexanes, 0.40 ml, 0.96 mmol) wasadded dropwise then the mixture was stirred at -78 00 for 1 h. Dry N,N-dimethylformamide (0.1 ml, 1.29 mmol) was added then stirring continued at 780C for 30 mm before allowing to RT for 1 h. The reaction mixture was quenched with water then extracted three times with ethyl acetate. The organic extract was dried over sodium sulfate, filtered and evaporated.The residue was purified via flash silica chromatography (DCM I EtOAc 5percent) to provide compound 14.3 (80 mg, 45percent) as a colourless oil. 1H NMR (CDCI3, 400 MHz) O 1.35 (5, 9H), 2.90 (m, 2H), 3.65 (m, 2H), 5.02 (5, 2H), 7.36 (m, 2H), 7.67 (t, 1H), 10.13 (5, 1H). UPLC-MS (short basic) rt 0.85 (262 [M+H]), 95percent pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.9% | With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere; | A mixture of Example 121A (4.50 g, 14.4 mmol, 1 eq.), Pd2(dba)3 (660 mg, 720.5 umol, 0.05 eq.), DPPF (799 mg, 1.44 mmol, 0.10 eq.) and Zn(CN)2 (1.86 g, 15.9 mmol, 1.10 eq.) in DMF (120 mL) was degassed and purged with N2 3 times. The mixture was stirred at 90 °C for 3 hours. The reaction mixture was filtered and diluted with H20 (100 mL) and extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give Example 121B (3.20 g, yield = 85.9percent) as a white solid. (0463) [0217] MR (400MHz, CDCb) delta 7.53 (d, J=7.6 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 4.77 (s., 2H), 3.69 (t, J=5.6 Hz, 2H), 2.87 (t, J=5.6 Hz, 2H), 1.51 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; at 0 - 20℃; for 0.5h; | Boc2O (25.73 g, 117.88 mmol) was added dropwise to a solution of intermediate 21 (25.00 g, 117.88 mmol) and TEA (32.83 mL, 236.00 mmol) in DCM (300 mL) at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes. Sat. citric acid was added to quench the reaction and layers were separated. The organic layer was washed with brine, dried over Mg504, filtered and evaporated in vacuo. The crude residue was purified by silica gel column (mobile phase: Petroleum ether/EtOAc, 3/1, v/v) to give 35 g of intermediate 22 (95percent yield). |
80% | With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; | 8-Bromo-1,2,3,4-tetrahydroisoquinoline 14.1 (200 mg, 0.804 mmol) was suspended in tetrahydrofuran (4 ml) and saturated sodium bicarbonate (2 ml) then di-t-butyl dicarbonate (263 mg, 1.21 mmol) was added as a solution in THF (2 ml) and the mixture was stirred atRT for 42 h. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic extract was dried over sodium sulfate, filtered and evaporated. The residue was purified via flash silica chromatography (heptane I DCM 0-80percent) to provide compound 14.2 (200 mg, 80percent) as a colourless oil. 1H NMR (ODd3, 400 MHz) O 1.30 (5, 9H), 2.82 (m, 2H), 3.63 (m, 2H), 4.60 (m, 2H), 7.05 (m, 2H), 7.39 (d, 1H). UPLC-MS (shortbasic) rt 1.01 (255, 257 [M-tBu+H]), 96percent pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 70℃; under 2068.65 Torr; for 4h; | Pd(OAc)2 (1.58 g, 7.05 mmol) was added to a mixture of intermediate 22 (22.00 g,70.47 mmol), DPPP (2.91 g, 7.05 mmol) and TEA (49.11 mL, 352.34 mmol) inMeOH/DMF solution (300 mL, 2:1, v/v). The resulting solution was stirred and pressurized to 40 psi with CO at 70 °C for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo.The crude residue was purified by column chromatography on silica gel (mobile phase gradient: from 91percent petroleum ether, 9percent EtOAc to 83percent petroleum ether, 17percent EtOAc) to give 12 g of intermediate 23 (59percent yield). |
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