* 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.
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 14, p. 2358 - 2363
2
[ 252331-63-8 ]
[ 726136-49-8 ]
[ 226942-29-6 ]
[ 75416-51-2 ]
Yield
Reaction Conditions
Operation in experiment
22%
With water; sodium carbonate In methanolHeating / reflux
To a solution of methanol (20 mL) and saturated sodium carbonate solution (20 mL) are added a mixture of l-(6-Bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone and l-(8-bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (3 g, 9.7 mmol). The reaction mixture is refluxed overnight, concentrated and the residue is extracted with dichloromethane. The combined organic layers are washed with water and brine, dried over sodium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (silica gel, 230-400 mesh) using 0-2percent methanol in chloroform as eluent to obtain 8-bromo-l,2,3,4-tetrahydro-isoquinoline as colorless viscous oil (first fraction, 0.45 g, 22percent) and 6-Bromo-l,2,3,4-tetrahydro-isoquinoline as white solid (second fraction, 1.0 g, 48percent). MS m/z 211.9 (M+l)
With water; sodium carbonate In methanolHeating / reflux
To a solution of methanol (20 mL) and saturated sodium carbonate solution (20 mL) are added a mixture of l-(6-Bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone and l-(8-bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (3 g, 9.7 mmol). The reaction mixture is refluxed overnight, concentrated and the residue is extracted with dichloromethane. The combined organic layers are washed with water and brine, dried over sodium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (silica gel, 230-400 mesh) using 0-2percent methanol in chloroform as eluent to obtain 8-bromo-l,2,3,4-tetrahydro-isoquinoline as colorless viscous oil (first fraction, 0.45 g, 22percent) and 6-Bromo-l,2,3,4-tetrahydro-isoquinoline as white solid (second fraction, 1.0 g, 48percent). MS m/z 211.9 (M+l)
NaBH4 (3.46 g, 91.51 mmol) was slowly added to a mixture of 6-bromoisoquinoline (4.76 g, 22.88 mmol) and acetic acid (90 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added water, and the mixture was adjusted to pH 8 with 8N aqueous sodium hydroxide solution. The mixture was extracted 3 times with ethyl acetate/THF mixed solution (3:1). The organic layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, solvent gradient; 20→90percent ethyl acetate/hexane) to give 6-bromo-1,2,3,4-tetrahydroisoquinoline (3.26 g, 15.37 mmol, 67.2percent) as a colorless oil. 1H NMR (300 MHz, CDCl3):δ 1.63(1H,s), 2.77(2H,t,J=6.0 Hz), 3.11(2H,t,J=5.9 Hz), 3.95(2H,s), 6.85-6.90(1H,m), 7.21-7.26(2H,m).
Reference：
[1] Patent: EP3192791, 2017, A1, . Location in patent: Paragraph 0593
[2] Patent: WO2013/80222, 2013, A1, . Location in patent: Page/Page column 39
[3] Applied Catalysis A: General, 2018, vol. 560, p. 37 - 41
6
[ 147497-32-3 ]
[ 226942-29-6 ]
Reference：
[1] Patent: US5977134, 1999, A,
[2] Patent: EP1724263, 2006, A1, . Location in patent: Page/Page column 40
Boc2O (3.52 g, 16.14 mmol) was added to a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (3.26 g, 15.37 mmol) in THF (45 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→8percent ethyl acetate/hexane) to give tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.05 g, 16.18 mmol, quant.) as a colorless oil. 1H NMR (300 MHz, CDCl3):δ 1.49(9H,s), 2.80(2H,t,J=5.9 Hz), 3.62(2H,t,J=5.9 Hz), 4.51(2H,s), 6.97(1H,d,J=8.7 Hz), 7.28-7.32(2H,m).
87%
With triethylamine In dichloromethane at 0 - 35℃; for 16 h;
To a stirred solution of 122a (700 mg, 3.31 mmol) in anhydrous DCM (10 ml) was added triethylamine (0.92 ml, 6.63 mmol) and di-tert-butyl dicarbonate (1.44 g, 6.63 mmol) at 0°C. The reaction mixture was stirred at 20-35°C for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the reaction mixture was diluted with water (30 ml) and extracted with dichloromethane (2 x 30 ml). The combined organic layers were washed with brine (30 ml), followedby drying over anhydrous Na2S04 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 10percent ethyl acetate/pet ether as an eluentto get the desired compound as an oily liquid (900 mg, 87percent). NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 7.36 (dd, J = 7.8, 1.9 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 1H), 4.45 (s, 2H), 3.52 (t, J = 5.9 Hz, 2H), 2.77 (t, J = 5.9 Hz, 2H), 1.47 (s, 9H).
74.7%
With triethylamine In dichloromethane at 20℃; for 12 h;
To a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (1.00 g, 4.72 mmol) in DCM (20 mL) was added TEA (1.314 mL, 9.43 mmol) followed by di-tertbutyldicarbonate (1.31 mL, 5.66 mmol) and the reaction mixture was stirred at ambient temperature for 12 h. The reaction was quenched with water and extracted with DCM (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by CombiFlash (Redi sep-12 g, 15 percent EtOAc/n-hexanes) to obtain Intermediate 1-22 (1.10 g, 74.7 percent), as alight brown liquid. ‘HNIVIR (300 MHz, DMSO-d6) ö ppm 1.42 (s, 9 H), 2.77 (t, J 5.85 Hz, 2 H), 3.52 (t, J= 5.85 Hz, 2 H), 4.45 (s, 2 H), 7.14 (d, J= 7.93 Hz, 1 H), 7.33-7.40 (m, 2 H). LCMS (MethodE): retention time 3.41 mi [M+H] 316.0.
2.9 g
With triethylamine In tetrahydrofuran at 20℃; for 3 h;
A mixture of 6-bromo-l,2,3,4-tetrahydroisoquinoline (2 g, 9.43 mmol), Boc20 (2.26 g, 2.41 mL, 10.4 mmol) and Et3N (1.91 g, 2.63 mL, 18.9 mmol) in THF (30 mL) was stirred at rt. For 3 hrs. The resulting mixture was diluted with aqueous Na2C03 solution and extracted with EA (30 mL) twice. The combined organic layer was washed with brine, dried over aqueous Na2S04, filtered, and concentrated in vacuo to afford tert-butyl 6-bromo-3,4-dihydro-lH- isoquinoline-2-carboxylate (2.9 g) as white solid which was directly used in the next step without any further purification
To a mixture of <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> 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).
With water; sodium carbonate; In methanol;Heating / reflux;
To a solution of methanol (20 mL) and saturated sodium carbonate solution (20 mL) are added a mixture of l-(6-Bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone and l-(8-bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (3 g, 9.7 mmol). The reaction mixture is refluxed overnight, concentrated and the residue is extracted with dichloromethane. The combined organic layers are washed with water and brine, dried over sodium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (silica gel, 230-400 mesh) using 0-2percent methanol in chloroform as eluent to obtain 8-bromo-l,2,3,4-tetrahydro-isoquinoline as colorless viscous oil (first fraction, 0.45 g, 22percent) and 6-Bromo-l,2,3,4-tetrahydro-isoquinoline as white solid (second fraction, 1.0 g, 48percent). MS m/z 211.9 (M+l)
With water; potassium carbonate; In methanol; at 20℃;
Potassium carbonate (66.2 mmol) was added in one portion to a solution of 6-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline and 8-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (17.6 mmol) in MeOH (130 mL) and water (45 mL). The reaction mixture was allowed to stir at rt overnight and then diluted with EtOAc (150 mL). The mixture was washed with brined, dried over Na2SO4, filtered, and concentrated to give 6-bromo-1,2,3,4-tetrahydroisoquinoline and 8-bromo-1,2,3,4-tetrahydroisoquinoline (5.0 g, 100percent) as a white solid.
[00986]Part C. Preparation of 6-bromo-l,2,3,4-tetrahydroisoquinoline.; [00987] To a solution of the product from Part B (9.5g, 30.8mmol) in methanol (231ml) and water (77ml) at room temperature was added potassium carbonate (8.52g, 61.7mmol) and the reaction was stirred at room temperature for 30min. The reaction was diluted with water and 25percent isopropanol in chloroform and the pH was adjusted to 9 with IN HCl. The mixture was extracted twice with 25percent isopropanol in chloroform. The combined organic layers were dried overmgSO4, filtered and concentrated to give the title compound, contaminated with the 8-bromo isomer (6.55g, quantitative).
With ethanol; ammonia; water; at 20 - 60℃;
This mixture was stirred with absolute EtOH (100 mL) and 25percent ammonium hydroxide (10 mL) at 60 °C for 4 h. More 25percent ammonium hydroxide (15 mL) was added and stirring continued at RT overnight. The volatiles were evaporated to leave the crude amine as a white solid. LC-MS mlz 212/214 (M+l).
With ethanol; ammonia; water; at 20 - 60℃;
The above material was stirred with absolute EtOH (100 mL) and 25percent ammonium hydroxide (10 mL) at 60 0C for 4 h. More 25percent ammonium hydroxide (15 mL) was added io and stirring continued at RT overnight. The volatiles were evaporated to leave the crude amine as a white solid. LC-MS mlz 212, 214 (M+l).
With hydrogenchloride; BH3; In tetrahydrofuran; methanol;
Step 1 Preparation of 6-bromo-1,2,3,4-tetrahydroisoquinoline A solution of 6-bromo-3,4-dihydro-1(1H)-isoquinolinone (Example 31, Step 1; 5.5 g, 1.0 mmol) in THF (25 mL) was treated with 1M BH3 in THF (5 mL, 5 mmol) and heated at reflux for 20 h. To the mixture was added MeOH (5 mL), the solvent removed and the residue heated with 2N HCl for 3 h. The reaction was cooled, made basic with aqueous NH4 OH and extracted with CH2 Cl2, dried and evaporated to give the title compound as a gum which was used as such.
The compound (2.253 g) obtained in Example 17-1 was dissolved in anhydrous THF (11 ml) and added with a 1 mol/l borane-THF complex/THF solution (manufactured by Kanto Chemical Co., Inc.) (55.4ml). The whole was refluxed overnight under heating. After the whole was left for cooling, methanol was added thereto and the solvent was distilled off. The resultant was added with 1 mol/l hydrochloric acid and refluxed under heating for 3 hours. After completion of the reaction, the solution was cooled with ice and added with a 1 mol/l sodium hydroxide aqueous solution and 27% ammonium water, followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was distilled off. The resultant was dissolved in anhydrous dichloromethane (40 ml), added with triethylamine (1.53 ml), and cooled with ice. Trifluoroacetic anhydride (1.55 ml) was added thereto and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the resultant was added with a saturated aqueous sodium hydrogen carbonate solution, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, thereby obtaining the subject compound (2.23 g) as a white solid. MS(FAB,Pos.):m/z=308,310[M+H]+
6-Bromo-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step 2 Preparation of 6-Bromo-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline Following the procedure described for Example 1, Step 6 but using <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> from Step 1 the title compound was obtained. Analysis for C21 H19 N4 Br Calcd. C, 61.92; H, 4.70; N,13.76 found C, 61.59; H, 4.65; N,13.49
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;
The compound (2.253 g) obtained in Example 17-1 was dissolved in anhydrous THF (11 ml) and added with a 1 mol/l borane-THF complex/THF solution (manufactured by Kanto Chemical Co., Inc.) (55.4ml). The whole was refluxed overnight under heating. After the whole was left for cooling, methanol was added thereto and the solvent was distilled off. The resultant was added with 1 mol/l hydrochloric acid and refluxed under heating for 3 hours. After completion of the reaction, the solution was cooled with ice and added with a 1 mol/l sodium hydroxide aqueous solution and 27% ammonium water, followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was distilled off. The resultant was dissolved in anhydrous dichloromethane (40 ml), added with triethylamine (1.53 ml), and cooled with ice. Trifluoroacetic anhydride (1.55 ml) was added thereto and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the resultant was added with a saturated aqueous sodium hydrogen carbonate solution, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, thereby obtaining the subject compound (2.23 g) as a white solid. MS(FAB,Pos.):m/z=308,310[M+H]+
To a solution of the acid structural unit S27 (1.5 g) in dichloromethane (5 ml/mmol) there was added at 0 C. diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.). The resulting reaction mixture was stirred for 15 min. at 23 C. It was then cooled to 0 C., and <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> (1.2 eq., dissolved in dichloromethane) was added dropwise. The reaction mixture was stirred for 16 h at 25 C. until the reaction was complete. The mixture was diluted with dichloromethane (100 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (5% ethyl acetate in dichloromethane). Yield: 80%
[00988]Part D. Preparation of 6-bromo-2-nitroso-l,2,3,4-tetrahydroisoquinoline.; [00989] To a solution of the product from Part C (6.55g, 30.9mmol) in acetic acid (61.8ml) and 3N aq. hydrochloric acid (10.29ml, 30.9mmol) at O0C was added 1.9M sodium nitrite (20.64ml, 39.2mmol) dropwise, and the reaction was stirred at room temperature overnight. The solvent was evaporated and the reaction was diluted with 25percent isopropanol in chloroform and sat NaHCO3. The aqueous layer was <n="181"/>extracted twice with 25percent isopropanol in chloroform. The combined organic layers were dried overmgSO4, filtered and concentrated to give the title compound, contaminated with the 8-bromo isomer(6.97 g, 94percent).
With sodium tetrahydroborate; acetic acid; at 10 - 35℃; for 1.5h;
NaBH4 (3.46 g, 91.51 mmol) was slowly added to a mixture of 6-bromoisoquinoline (4.76 g, 22.88 mmol) and acetic acid (90 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added water, and the mixture was adjusted to pH 8 with 8N aqueous sodium hydroxide solution. The mixture was extracted 3 times with ethyl acetate/THF mixed solution (3:1). The organic layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, solvent gradient; 20?90% ethyl acetate/hexane) to give 6-bromo-1,2,3,4-tetrahydroisoquinoline (3.26 g, 15.37 mmol, 67.2%) as a colorless oil. 1H NMR (300 MHz, CDCl3):delta 1.63(1H,s), 2.77(2H,t,J=6.0 Hz), 3.11(2H,t,J=5.9 Hz), 3.95(2H,s), 6.85-6.90(1H,m), 7.21-7.26(2H,m).
With hydrogen; In pentan-1-ol; water; at 130℃; under 22502.3 Torr; for 3h;Autoclave;Catalytic behavior;
General procedure: In a typical experiment, the above-prepared thermoregulated phasetransferPt nanocatalyst, n-decane (100 mg) and a certain amount ofsubstrates were added in the autoclave. Then the reactor was replacedthree times with 2 MPa H2 and stirred under hydrogen pressure at adesignated temperature for an appointed time. After reaction, the reactorwas cooled to room temperature and depressurized. The upperproduct phase was easily separated from the lower catalyst phase anddirectly analysed by GC and GC-MS.
With sodium hydroxide; sodium tetrahydroborate;
Step 1 25 L of melted glacial acetic acid and 2.5 L of water were added to a 50 L reactor, and 6-bromoisoquinoline (2.5 kg, 12.02 mol, 1.00 equivalent) was added to the reactor. The reaction temperature was adjusted to 10 C. At 10-15 C., 1.43 kg of sodium borohydride was added in portions, and after feeding was finished over 7 hours, it was further stirred for 2 hours. After the reaction was completed, the reaction solution was slowly added dropwise to a solution of sodium hydroxide (17.5 kg) in water (87.5 L) at 5-15 C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 10 hours, and filtered to give 6-bromo-1,2,3,4tetrahydroisoquinoline (8 kg, watercontaining crude product, purity of 95%) as a white solid, which was directly used in the next step. m/z 212, 214 (1:1) [M+H]+.
Step A: Preparation of l-(6-Bromo-3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxyethanone. A magnetically stirred flask equipped with a drying tube was charged with a solution of6-bromo-l,2,3,4-tetrahydroisoquinoline (3.43 g, 16.2 mmol) in anhydrous toluene (40 mL), to which was added 2,2-dimethyl-l,3-dioxolan-4-one (1.9 g, 16.2 mmol). The resulting solution was refluxed for 20 h. The reaction mixture was cooled, extracted with 1 N HCl (30 mL), followed by brine (20 mL), and the organic extract was dried over MgSO4. The resulting solution was reduced in volume to about 25 mL, and heptane (25 mL) was gradually added over 20 min as precipitate formed. The resulting white solid was collected by filtration and rinsed with 1 : 1 toluene/heptane to provide the title compound. LCMS m/z = 270.1 [M+H]+; 1H NMR (400 MHz, CDCl3) delta 2.48 (bs, IH), 2.87-2.94 (m, 2H), 3.55 (t, J= 5.9 Hz, 1.2H), 3.89 (t, J= 6.1 Hz, 0.8H), 4.26 (s, 2H), 4.40 (s, 0.8H), 4.75 (s, 1.2H), 7.00 (d, J= 8.3 Hz, 0.4H), 7.07 (d, J= 8.3 Hz, 0.6H), 7.32-7.39 (m, 2H).
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃; for 16h;
To a solution of Boc-L-proline (Int-5a, 406 mg, 1.88 mmol) in 10 mL of DMF was added amine Int-6a (400 mg, 1.88 mmol), EDCI (450 mg, 2.35 mmol), HOBT (317 mg, 2.35 mmol), and Hunig's base (0.65 mL, 3.76 mmol). The resulting reaction was heated at 85 0C and allowed to stir at this temperature for 16 hours. The reaction mixture was cooled to room temperature and was then partitioned between EtOAc and water. The organic phase was separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo to provide a crude residue which was purified using (ISCO) flash column chromatography (EtO Ac/Hex, 0 to 50% EtOAc eluent ) to provide compound Int-6b (680 mg, 88%).
88%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃; for 16h;
To a solution of Boc-L-proline (Int-15a, 406 mg, 1.88 mmol) in 10 mL of DMF was added amine Int-16a (400 mg, 1.88 mmol), EDCI (450 mg, 2.35 mmol), HOBT (317 mg, 2.35 mmol), and diisopropylethylamine (0.65 mL, 3.76 mmol). The resulting reaction was heated at 85 0C and allowed to stir at this temperature for 16 hours. The reaction mixture was cooled to room temperature and was then partitioned between EtOAc and water. The organic phase was separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to provide a crude residue which was purified using (ISCO) flash column chromatography (EtO Ac/Hex, 0 to 50% EtOAc eluent ) to provide Compound Int-16b (680 mg, 88%).
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 130℃; for 1h;Irradiation with microwave;Product distribution / selectivity;
A mixture of 6-bromo-1 ,2,3,4-tetrahydroisoquinoline (2.86g, 12 mmol, Allichem LLC), zinc cyanide (1.76g, 15 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.33g, 1.2 mmol) in DMF (20ml) was split between two microwave vials and heated (microwave) for 60min at 1300C. The mixture was concentrated in vacuo and the residue dissolved in DCM and loaded onto a silica cartridge. The cartridge was eluted with a gradient of 2M ammonia in methanol / DCM (5-10%). The appropriate fractions were combined and evaporated in vacuo to give 1 ,2,3,4-tetrahydro-6- isoquinolinecarbonitrile (1.41 g) as a colourless solid. LCMS (Method formate): Retention time 0.36min, MH+ = 158
Boc2O (3.52 g, 16.14 mmol) was added to a solution of <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> (3.26 g, 15.37 mmol) in THF (45 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0?8% ethyl acetate/hexane) to give tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (5.05 g, 16.18 mmol, quant.) as a colorless oil. 1H NMR (300 MHz, CDCl3):delta 1.49(9H,s), 2.80(2H,t,J=5.9 Hz), 3.62(2H,t,J=5.9 Hz), 4.51(2H,s), 6.97(1H,d,J=8.7 Hz), 7.28-7.32(2H,m).
97%
In dichloromethane; at 20℃; for 0.5h;
Add <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> (1.4 g, to a reaction flask containing dichloromethane (20 mL).6.60 mmol) and di-tert-butyldicarbonate (2.16 g, 9.90 mmol). After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc: EtOAc: EtOAc: EtOAc) 2.0 g, colorless oil, yield: 97%).
87%
With triethylamine; In dichloromethane; at 0 - 35℃; for 16h;
To a stirred solution of 122a (700 mg, 3.31 mmol) in anhydrous DCM (10 ml) was added triethylamine (0.92 ml, 6.63 mmol) and di-tert-butyl dicarbonate (1.44 g, 6.63 mmol) at 0C. The reaction mixture was stirred at 20-35C for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the reaction mixture was diluted with water (30 ml) and extracted with dichloromethane (2 x 30 ml). The combined organic layers were washed with brine (30 ml), followedby drying over anhydrous Na2S04 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 10% ethyl acetate/pet ether as an eluentto get the desired compound as an oily liquid (900 mg, 87%). NMR (400 MHz, DMSO-d6) delta 7.39 (s, 1H), 7.36 (dd, J = 7.8, 1.9 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 1H), 4.45 (s, 2H), 3.52 (t, J = 5.9 Hz, 2H), 2.77 (t, J = 5.9 Hz, 2H), 1.47 (s, 9H).
74.7%
With triethylamine; In dichloromethane; at 20℃; for 12h;
To a solution of <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> (1.00 g, 4.72 mmol) in DCM (20 mL) was added TEA (1.314 mL, 9.43 mmol) followed by di-tertbutyldicarbonate (1.31 mL, 5.66 mmol) and the reaction mixture was stirred at ambient temperature for 12 h. The reaction was quenched with water and extracted with DCM (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by CombiFlash (Redi sep-12 g, 15 % EtOAc/n-hexanes) to obtain Intermediate 1-22 (1.10 g, 74.7 %), as alight brown liquid. ?HNIVIR (300 MHz, DMSO-d6) oe ppm 1.42 (s, 9 H), 2.77 (t, J 5.85 Hz, 2 H), 3.52 (t, J= 5.85 Hz, 2 H), 4.45 (s, 2 H), 7.14 (d, J= 7.93 Hz, 1 H), 7.33-7.40 (m, 2 H). LCMS (MethodE): retention time 3.41 mi [M+H] 316.0.
25.5%
With dmap; In tetrahydrofuran; at 25℃; for 3h;
To a solution of 6-bromo-l, 2, 3, 4-tetrahydroisoquinoline (400 mg, 1.89 mmol, 1.00 equiv) in tetrahydrofuran (2.00 mL) was added Boc20 (617 mg, 2.83 mmol, 1.50 equiv) and dimethylaminopyridine (46.1 mg, 377 pmol, 0.20 equiv). The mixture was stirred at 25 C for 3 h and was subsequently filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 20/1 to 3/1) to afford tert- butyl 6-bromo-3, 4-dihydro- l //-isoquinoline-2-carboxylate (150 mg, 480 pmol, 25.5% yield) as a white solid. 1H NMR (400MHz, CD3OD) d = 7.38 - 7.32 (m, 2H), 7.07 (d, =8.0 Hz, 1H), 4.52 (br s, 2H), 3.64 (br t, J=6.0 Hz, 2H), 2.84 (t, =6.0 Hz, 2H), 1.51 (s, 9H).
In dichloromethane; at 20℃; for 3h;
tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1 H)-carboxylate (1913) A solution of di-terf-butyldicarbonate (1.1 1 mL, 4.76 mmol) in DCM (4 mL) was added dropwise to a suspension of 6-bromo-1 ,2,3,4-tetrahydroisoquinoline (0.990 g, 4.67 mmol) in DCM (6 mL) and the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo to give ferf-butyl 6-bromo-3,4-dihydroisoquinoline-2(1 H)-carboxylate (1.564 g, 4.66 mmol, 100%) as an orange oil. The product was used without further purification in the next step. 1H NMR (DMSO-d6) delta: 7.39 (1 H, d), 7.36 (1 H, dd), 7.14 (1 H, d), 4.45 (2H, s), 3.53 (2H, dd), 2.77 (2H, dd), 1.43 (9H, s).
With triethylamine; In dichloromethane; at 0 - 25℃; for 15h;
To a solution of6-bromo-1,2,3,4-tetrahydroisoquinoiine (19.17 g, 90.39 mmol) in DCM (200 rnL) was addedTEA (18.29 g, 180.77mmoi) and Boc2O (23.67 g, 108.46 mmol) at 0C. After the completionof the addition, the mixture was stirred at 25C for 15 h. Water (300 mL) was added, and themixture was extracted with EtOAc (3xi00 mL). The organic layer was dried over Na2SO4 andconcentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PR EtOAc ::: 50: Ito 10:1) to give the title compound,
2.9 g
With triethylamine; In tetrahydrofuran; at 20℃; for 3h;
A mixture of 6-bromo-l,2,3,4-tetrahydroisoquinoline (2 g, 9.43 mmol), Boc20 (2.26 g, 2.41 mL, 10.4 mmol) and Et3N (1.91 g, 2.63 mL, 18.9 mmol) in THF (30 mL) was stirred at rt. For 3 hrs. The resulting mixture was diluted with aqueous Na2C03 solution and extracted with EA (30 mL) twice. The combined organic layer was washed with brine, dried over aqueous Na2S04, filtered, and concentrated in vacuo to afford tert-butyl 6-bromo-3,4-dihydro-lH- isoquinoline-2-carboxylate (2.9 g) as white solid which was directly used in the next step without any further purification
With sodium cyanoborohydride; In methanol; at 20℃;
To a solution of 6-bromo-l ,2,3,4-tetrahydroisoquinoline (5.0 g, 23.6 mmol) and formaldehyde (1.4 g, 47.2 mmol) in methanol (100 mL) was added sodium cyanoborohydride (5.9 g, 94.4 mmol). The mixture was stirred at room temperature overnight. On completion, the reaction mixture was poured into water (20 mL). Organics were then extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica chromatography [petroleum ether/ethyl acetate = 1 : 1.5] to give compound B-124 (6.3 g, crude) as a yellow oil: LCMS: (ES+) m/z (M+H)+ = 226.0, tR=1.408.
3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoic acid[ No CAS ]
ethyl 3-(3-(((R)-4-ethyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)methyl)-4-methylphenyl)-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)propanoate[ No CAS ]
A mixture of paraformaldehyde (350 mg, 3.63 mmol, 2.20 equiv) in methanol (1.00 mL) was stirred at 60 C for 1 h and then cooled to 40 C. To the mixture was added AcOH (1 drop) and 6-bromo-l, 2, 3, 4-tetrahydroisoquinoline (350 mg, 1.65 mmol, 1.00 equiv) followed by NaCNBH3 (114 mg, 1.82 mmol, 1.1 equiv). The mixture was stirred at 40C for 1 h and was subsequently filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (petroleum ether/ethyl acetate = 2/1) to afford 6-bromo-2-methyl-3, 4-dihydro -1 H- isoquinoline (360 mg, 1.59 mmol, 96.5% yield) as a yellow oil. 1H NMR (400MHz, CD3OD) d = 7.32 (s, 1H), 7.28 (dd, =2.0, 8.4 Hz, 1H), 7.00 (d, =8.0 Hz, 1H), 3.57 (s, 2H), 2.94 (t, =6.0 Hz, 2H), 2.75 - 2.72 (m, 2H), 2.46 (s, 3H).
78.2%
Into a 250-mL round-bottom flask, was placed 6-bromo-l,2,3,4-tetrahydroisoquinoline (6.0 g, 28.3 mmol) in MeOH (100 mL) under N2. To the stirred solution was added HCHO (1.02 g, 34 mmol) in portions at RT. The resulting solution was stirred for 4 h, then NaBLbCN (3.56 g, 56.6 mmol) was added in portions at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of water (100 mL) and extracted with 3x150 mL ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was eluted from a silica gel column with acetate/petroleum ether (1 : 1). This resulted in 5 g (78.2%) of the title compound as a white solid. MS-ESI: 226/228 (M+l).
With formic acid; at 150℃; for 0.25h;Microwave irradiation;
6-Bromo-2-methyl-1,2,3,4-tetrahydroisoquinolineTo a solution of 6-bromo-1 ,2,3,4-tetrahydroisoquinoline (1 g, 4.72 mmol) in formic acid (10 mL, 261 mmol) was added formaldehyde (37%) (2 mL, 72.6 mmol). The reaction was stirred at 150 C for 15 min in a microwave reactor. T he reaction mixture was concentrated under vaccum, cooled to 0 C, quenched with saturated NaHC03solution, extracted with EtOAc (2X), The organic layer washed with brine, dried under anhydrous Na2S04and filtered. The filtrate was reduced under pressure to afford 6-bromo-2-methyl- 1 ,2,3,4-tetrahydroisoquinoline (900 mg, 3.85 mmol, 82 % yield). LC-MS m/z 226 (M+H)+, 1.29 min (ret. time). The crude compound was used for next step without further purification.
(S)-2-(6-Amino-5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetic acid[ No CAS ]
(S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-6-(hydroxymethyl)-2-methylpyridin-3-yl)acetate[ No CAS ]
(S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-6-(hydroxymethyl)-2-methylpyridin-3-yl)acetic acid[ No CAS ]
(S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-6-cyano-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)acetate[ No CAS ]
(S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-6-cyano-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)acetic acid[ No CAS ]
(S)-2-(6-amino-5-(2-(benzofuro[3,2-d]pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetic acid[ No CAS ]
(S)-2-(5-(2-(benzofuro[3,2-d]pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-6-(hydroxymethyl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetic acid[ No CAS ]
(S)-isopropyl 2-(6-(bromomethyl)-5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate[ No CAS ]
(S)-2-(6-(azetidin-1-ylmethyl)-5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetic acid[ No CAS ]
(S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methyl-6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)acetic acid[ No CAS ]
(S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methyl-6-(piperidin-1-ylmethyl)pyridin-3-yl)acetic acid[ No CAS ]
(S)-2-(6-(6-azaspiro[2.5]octan-6-ylmethyl)-5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetic acid[ No CAS ]
(S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-6-((4,4-dimethylpiperidin-1-yl)methyl)-2-methylpyridin-3-yl)acetic acid[ No CAS ]
(S)-2-(6-(7-azaspiro[3.5]nonan-7-ylmethyl)-5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetic acid[ No CAS ]
6-bromo-2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.8%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 16h;
To a solution of <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> (1.25 g, 5.88 mmol) in DCM (25 mL) was added 2-chloro-6-methylbenzaldehyde (1.0 g, 6.5 mmol) and acetic acid (0.337 mL, 5.88 mmol) inDCM (25 mL). Then sodium triacetoxyborohydride (1.62 g, 7.64 mmol) was added. Themixture was stirred at r.t for 16 hrs. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by recrystallization with EtOAc to give 6-bromo- 2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline (1.44 g, 4.11 mmol, 69.8%yield). LCMS (M+H): 350.00, 352.00.
69.8%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 16h;
To a solution of 6- bromo-l,2,3,4-tetrahydroisoquinoline (1.25 g, 5.88 mmol) in DCM (25 mL) was added 2- chloro-6-methylbenzaldehyde (1.0 g, 6.5 mmol) and acetic acid (0.337 mL, 5.88 mmol) in DCM (25 mL). Then sodium triacetoxyborohydride (1.62 g, 7.64 mmol) was added. The mixture was stirred at r.t for 16 hrs. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04and concentrated. The residue was purified by recrystallization with EtOAc to give 6-bromo- 2-(2-chloro-6-methylbenzyl)-l,2,3,4-tetrahydroisoquinoline (1.44 g, 4.11 mmol, 69.8 % yield). LCMS (M+H): 350.00, 352.00. 1H NMR (400MHz, DMSO-d6) delta 7.32 - 7.14 (m, 5H), 6.99 (d, 7=8.1 Hz, 1H), 3.77 (s, 2H), 3.56 (s, 2H), 2.78 - 2.72 (m, 2H), 2.71 - 2.66 (m, 2H), 2.41 (s, 3H).
69.8%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 16h;
To a solution of 6- bromo-l,2,3,4-tetrahydroisoquinoline (1.25 g, 5.88 mmol) in DCM (25 mL) was added 2- chloro-6-methylbenzaldehyde (1.0 g, 6.5 mmol) and acetic acid (0.337 mL, 5.88 mmol) in DCM (25 mL). Then sodium triacetoxyborohydride (1.62 g, 7.64 mmol) was added. The mixture was stirred at r.t for 16 hrs. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by recrystallization with EtOAc to give 6-bromo- 2-(2-chloro-6-methylbenzyl)-l,2,3,4-tetrahydroisoquinoline (1.44 g, 4.11 mmol, 69.8 % yield). LCMS (M+H): 350.00, 352.00. NMR (400MHz, DMSO-de) delta 7.32 - 7.14 (m, 5H), 6.99 (d, J=8.1 Hz, 1H), 3.77 (s, 2H), 3.56 (s, 2H), 2.78 - 2.72 (m, 2H), 2.71 - 2.66 (m, 2H), 2.41 (s, 3H).
5-cyclopropyl-2,6-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]quinolin-4-one[ No CAS ]
5-cyclopropyl-2,6-dimethyl-7-(1,2,3,4-tetrahydroisoquinolin-6-yl)oxazolo[4,5-c]-quinolin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,2-dimethoxyethane; water; at 60℃; for 0.5h;Microwave irradiation;
5-Cyclopropyl-2,6-dimethyl-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)oxazolo[4,5-c]- quinolin-4-one (Intermediate B) (69 mg, 0.18 mmol), [1 , T- bis(diphenylphosphino)ferrocene]palladium(ll) chloride dichloromethane complex (14 mg, 0.02 mmol), CS2CO3 (178 mg, 0.55 mmol), and 6-bromo-1 ,2,3,4-tetrahydroisoquinoline (38 mg, 0.18 mmol) were dissolved in a mixture of monoglyme (1 mL) and H2O (0.3 mL). The reaction solution was then irradiated with microwaves at 60C for 30 min. The solution was diluted with MeOH, filtered, dry-loaded onto silica and purified by flash chromatography using a gradient of 0-10% MeOH in DCM. The fractions containing the required product were then concentrated in vacuo to give 5-cyclopropyl-2,6-dimethyl-7-(1 , 2,3,4- tetrahydroisoquinolin-6-yl)oxazolo[4,5-c]-quinolin-4-one (2 mg, 3 %) as a pale yellow solid. 1 H NMR (Method A) (CDC ): delta 7.70 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.19 - 7.10 (m, 3H), 4.15 (s, 2H), 3.62 (m, 1 H), 3.25 (t, 2H), 2.93 (t, 2H), 2.68 (s, 3H), 2.53 (s, 3H), 1.31 - 1.26 (m, 2H), 0.71 - 0.65 (m, 2H); LC-MS (Method D) 386.4 [M+H]+; RT 1.68 min
Step 2 Sodium bicarbonate (1.21 kg) and Boc2O (2.62 kg) were added to a solution of <strong>[226942-29-6]6-bromo-1,2,3,4tetrahydroisoquinoline</strong> (2.55 kg, 12.02 mol, 1.00 equivalent) in ethyl acetate (12.5 L) and water (12.5 L) at 20 C., and the reaction solution was stirred at 20 C. for 12 hours. After the reaction was completed, the reaction mixture was allowed to stand for layering, and the aqueous phase was extracted again with ethyl acetate (10 L*2). The organic phases were combined and washed once with water (10 L), dried over anhydrous sodium sulfate, filtered and concentrated to give N-tert-butoxycarbonyl-6bromo-1,2,3,4-tetrahydroisoquinoline (3.5 kg, 11.21 mol, yield of 91.4%, purity of 98%) as a yellow oil. m/z 256, 258 (1:1) [M+H-56]+; 1H NMR (400 MHz, CDCl3) delta=7.29 (m, 2H), 6.98 (d, 1H), 4.51 (s, 2H), 3.63 (t, 2H), 2.81 (t, 2H), 1.49 (s, 9H).
tert-butyl 6-(((3R)-1-((3-(cyclopropylmethyl)-7-fluoro-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)carbamoyl)piperidin-3-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[ No CAS ]
5-(2-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)isobenzofuran-1(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.5%
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 14h;
To a solution of <strong>[226942-29-6]6-bromo-1,2,3,4-tetrahydroisoquinoline</strong> (0.700 g, 3.30 mmol) in DCM (30 mL) was added Intermediate 1-13 (0.640 g, 3.63 mmol) followed by sodium triacetoxyborohydride (1.40 g, 6.60 mmol). The resulting reaction mixture was stirred at ambient temperature for 14 h. The reaction mixture was diluted by water (50 mL) and extracted with DCM (2 x 50 mL). The combined extracts were washed with brine (50mL), dried over anhydrous sodium sulfate and concentrated. The crude was washed withdiethyl ether (2 x 50 mL) to afford Intermediate 6A (1.05 g, 73.5 %) as a brown solid. ?HNIVIR (400 MHz, DMSO-d6) ppm 2.70-2.80 (m, 6 H), 2.99 (t, J= 10 Hz, 2 H), 3.59 (s, 2H), 5.37 (s, 2 H), 7.03 (d, J= 10.8 Hz, 1 H), 7.27 (d, J= 2.4 Hz, 1 H), 7.31 (s, 1 H), 7.50(d, J= 10.4 Hz, 1 H), 7.56 (s, 1 H), 7.76 (d, J= 10.4 Hz, 1 H). LCMS (MethodR):retention time 1.03 mi (M+H) 374.2.
benzyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h;
A solution of 6-bromo-dihydroisoquinoline (300 mg, 1.42 mmol) in CH2Ch (8 mL) was cooled to 0 C and iPr2NEt (243 mg, 1.88 mmol) and CbzCl (322 mg, 1.88 mmol) were added. The reaction was stirred at room temperature forl6 h. The reaction was diluted with CH2CI2 (10 mL) and poured into water (20 mL). The layers were separated and the aqueous layer was extracted with CH2CI2 (3 x 20 mL). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure. The crude mixture was purified via flash column chromatography eluting with EtOAc:hexanes (5:95) to give 400 mg (81%) of compound KTL- 01-202 as a clear oil: NMR (400 MHz) delta 7.41 - 7.27 (comp, 7 H), 6.97 (d, / = 10.3 Hz, 1 H), 5.18 (s, 2 H), 4.59 (s, 2 H), 3.70 (br s, 2 H), 2.82 (br s, 2 H); HRMS (ESI) m/z CivHieBrNCh (M+Na)+ calcd for 368.0257 and 370.0238; found 368.0257 and 370.0238.
81%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h;
A solution of 6-bromo tetrahydroisoquinoline (300 mg, 1.42 mmol) in CH2Cl2 (8 mL) was cooled to 0 C, and i-Pr2NEt (243 mg, 1.88 mmol) and CbzCl (322 mg, 1.88 mmol) were added. The reaction was stirred at room temperature for 16 h. The reaction was diluted with CH2Cl2 (10 mL) and poured into water (20 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude mixture was purified via flash column chromatography eluting with EtOAc:hexanes (5:95) to give 400 mg (81%) of 9 as a colorless oil: 1H NMR (400 MHz) delta 7.41 - 7.27 (comp, 7 H), 6.97 (d, J = 10.3 Hz, 1 H), 5.18 (s, 2 H), 4.59 (s, 2 H), 3.70 (br s, 2 H), 2.82 (br s, 2 H); HRMS (ESI) m/z C17H16BrNO2 (M+Na)+ calcd for 368.0257 and 370.0238; found 368.0257 and 370.0238.
(S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)acetic acid[ No CAS ]
(S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate[ No CAS ]
(S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid[ No CAS ]
With manganese(IV) oxide; In dichloromethane; at 20℃; for 18h;
To a solution of 6-broino- I ,2,3,4-tetrahydro- iso-quinoline (1500 g, 71.1 mrnol) in DCM (160 mL) was added activated Mn0 (77.84 g, 859.7mmol). The mixture was stirred for 18 h at 11 and filtered. The filtrate was concentrated n vacuo, and the residue was purified by silica gel chroniatographv (PE:EtOAc =20:1 to 5:1) to afford the title compound.
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