* 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] Journal of the American Chemical Society, 1939, vol. 61, p. 183
4
[ 3132-99-8 ]
[ 22483-09-6 ]
[ 58794-09-5 ]
[ 63927-22-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6378 - 6382
5
[ 6630-33-7 ]
[ 22483-09-6 ]
[ 63927-22-0 ]
Yield
Reaction Conditions
Operation in experiment
49.8%
Stage #1: for 3 h; Inert atmosphere; Reflux; Dean-Stark Stage #2: With aluminum (III) chloride In dichloromethane at 0 - 45℃; for 2 h; Inert atmosphere
A mixture of 2-bromobenzaldehyde (50 g, 270 mmol) , aminoacetaldehyde dimethyl acetal (28.4 g, 270 mmol) and toluene (400 mL) was refluxed under argon. Dehydration was carried out using dean stark for 2.0 hours. After removal of calculated amount of water, the reflux was continued for 1.0 hour. The toluene was evaporated under reduced pressure, the residue was dissolved in dichloromethane (600 mL) , and the solution was cooled to 0°C. To the cooled solution was slowly added aluminium chloride (118.9 g, 891.7 mmol) under argon. The reaction mixture was stirred at 45°C for 2.0 hours. After the completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature and slowly poured into an ice water. The mixture was basified with 10percent sodium hydroxide solution, and the dichloromethane layer was separated. The aqueous layer was re-extracted with dichloromethane (2 x 100 mL) . The combined dichloromethane layers were washed with brine, and dried over sodium sulfate. The dichloromethane was evaporated, and the residue was purified by silica gel (100-200 mesh) column chromatography 5 with 8-12percent. ethyl acetate in hexane as a mobile phase to give the title compound as an off-white solid (28 g, 49.8percent). MS(ESI)m/z: 208 [M (79Br)+l] ,210 [M (81Br)+l]; XH NMR (400 MHz, DMSO-d5) : δ 7.17 (t, J= 7.8 Hz, 1H) ; 7.91 (d, J= 6.0 Hz, 1H) ; 8.02 (d, J = 8.4 Hz, 1H) ; 8.05 (d, J = 8.8 Hz, 1H) ; 8.65 10 (d, J = 5.2 Hz, 1H) 9.48 (s, IH) .
Stage #1: at 0℃; for 0.166667 h; Stage #2: at 0℃; for 5 h;
NaBH3CN (30.20 g, 480.64 mmol) was added to a mixture of 8-bromoisoquinoline(20.00 g, 96.13 mmol) in MeOH (300 mL) at 0 °C. The resulting mixture was stirredfor 10 minutes and Boron trifluoride diethyl etherate (68.22 g, 480.64 mmol) was added dropwise at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C and then refluxed for 4 hours. Sat. Na2CO3 (5 mL) was added and solvent was concentrated under reduced pressure. The remaining liquid was poured into water and extracted withCH2C12. The organic layer was washed with brine, dried over Mg504, filtered and evaporated in vacuo to give 20 g of intermediate 21(98percent yield) which was used in the next step without further purification.
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at 0℃; for 1 h;
To a solution of 8-bromoisoquinoline (2.0 g, 9.6 mmol) in THE (40 mL) was added dropwise n-BuLi (2.5 M, 4.2 mL, 10.6 mmol) at -78 °C under nitrogen. After 1 hour, B(OMe)3 (2.0 g, 19.2 mmol) was added to the reaction and the mixture was warmed to 0 °C for 1 hour. The reaction was quenched by aqueous NaHCO3 andextracted with EtOAc 3 times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 75 (680 mg, 41percent) as a slightly yellow solid. LCMS (m/z: m+1):174.1.
(R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid [(R)-2-[4-(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide[ No CAS ]
(R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {(R)-1-(4-chloro-benzyl)-2-[4-(2-methanesulfonyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide[ No CAS ]
(R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid ((R)-1-(4-chloro-benzyl)-2-oxo-2-{4-[2-(propane-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-piperazin-1-yl}-ethyl)-amide[ No CAS ]
(R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid [(R)-2-[4-(2-benzenesulfonyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide[ No CAS ]
3-[2-[4-(2-acetyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-1-(4-chloro-benzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
3-{1-(4-chloro-benzyl)-2-[4-(2-methanesulfonyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-2-oxo-ethylcarbamoyl}-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
3-(1-(4-chloro-benzyl)-2-oxo-2-{4-[2-(propane-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinolin-8-yl]-piperazin-1-yl}-ethylcarbamoyl)-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
3-[2-[4-(2-benzenesulfonyl-1,2,3,4-tetrahydro-isoquinolin-8-yl)-piperazin-1-yl]-1-(4-chloro-benzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 2.46 g (11.8 mmol) <strong>[63927-22-0]8-bromoisoquinoline</strong>, 1.68 mL (14.1 mmol) benzyl bromide, and 10 mL ethanol. The solution was heated at reflux for 6 hr, cooled, and evaporated. The oil was dissolved in 50 mL methanol, and 1.73 g (27.6 mmol) sodium cyanoborohydride was added. The solution was stirred at room temperature for 5 days, then diluted with water and extracted with three portions of ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate to afford 1.98 g (59percent) of an oil. 1H-NMR (delta, CDCl3): 2.68 (m, 2H), 2.88 (m, 2H), 3.68 (m, 2H), 3.75 (m, 2H), 7.0-7.1 (m, 2H), 7.2-7.4 (m, 6H).
8-bromoisoquinoline (24). To 7.0 mL (60.0 mmol) 2-bromobenzaldehyde (23) was added 10.0 mL (69.0 mmol) aminoacetaldehyde diethyl acetal. After 3 h at 100° C., the reaction mixture was cooled to room temperature and the layers separated. The organic layer was purified by vaccum distillation to give 15.89 g bromobenzalaminoacetal (b.p. 141-148° C. at approximately 1 mm Hg). To 143 g concentrated sulfuric acid at 0° C. was added 15.89 g bromobenzalaminoacetal. With mechanical stirring, the resulting mixture was added in portions over 5 min to 20 g phosphoric anhydride in 10 g concentrated sulfuric acid maintained at 160° C. After 25 min at 160° C., the reaction mixture was cooled, poured onto ice and washed with 300 mL ethyl ether. The aqueous layer was basified with solid NaOH to pH=10 and extracted with EtOAc repeatedly. The combined EtOAc layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (75*110 mm silica gel, linear gradient 0.5-3percent (10percent NH4H:MeOH):CH2CI2) produced 24. 1H NMR (CDCl3, 400 MHz) 89.627 (s, 1H, ArH); 8.622 (d, 1H, J=5.67 Hz, ArH); 7.858 (dd, 1H, J=0.87, 7.45 Hz, ArH); 7.799 (d, 1H, J=8.32 Hz, ArH); 7.631 (d, 1H, J=5.76 Hz, ArH); 7.538 (dd, 1H, J=7.50, 8.23 Hz, ArH); MS (Electrospray): m/z 207.9, 209.0 (M+H, 79Br, 81Br).
With copper(I) iodide; triethylamine;bis(triphenylphosphine)palladium(II) dichloride; In dichloromethane;
EXAMPLE 72 Preparation of 3-(8-isoquinolinyl)-2-propyn-1-ol In an inert atmosphere, 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of <strong>[63927-22-0]8-bromoisoquinoline</strong>, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of 3-(8-isoquinolinyl)-2-propyn-1-ol, mp 138°-139° C.
With copper(I) iodide; triethylamine;bis(triphenylphosphine)palladium(II) dichloride; In dichloromethane;
EXAMPLE 72 Preparation of 3-(8-isoquinolinyl)-2-propyn-1-ol In an inert atmosphere, 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.13 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of <strong>[63927-22-0]8-bromoisoquinoline</strong>, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of 3-(8-isoquinolinyl)-2-propyne-1-ol, mp 138°-139° C.
With copper(I) iodide; triethylamine;bis(triphenylphosphine)palladium(II) dichloride; In dichloromethane;
EXAMPLE 72 Preparation of 3-(8-isoquinolinyl)-2-propyn-1-ol In an inert atmosphere, 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of <strong>[63927-22-0]8-bromoisoquinoline</strong>, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of 3-(8-isoquinolinyl)-2-propyne-1-ol, mp 138°-139° C.
With copper(I) iodide; triethylamine;bis(triphenylphosphine)palladium(II) dichloride; In dichloromethane;
EXAMPLE 168 Preparation of 3-(8-isoquinolinyl)-2-propyn-1-ol In an inert atmosphere. 0.068 g of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide was added with stirring to a deoxygenated solution of 1 g of <strong>[63927-22-0]8-bromoisoquinoline</strong>, 0.56 mL of propargyl alcohol and 2 mL of triethylamine in 25 mL of dichloromethane. The mixture was stirred at room temperature for 2 hours and then at reflux for 20 hours. The cooled reaction was filtered and the filtrate was concentrated in vacuo. The residual oil was purified by HPLC (ethyl acetate-toluene; 2:3) to yield 0.4 g of -(8-isoquinolinyl)-2-propyne-1-ol, mp 138°-139° C.
1-(8-naphthyl)-isoquinoline (8-NAIQ). 1-(8-naphthyl)-isoquinoline was obtained from thereaction of <strong>[63927-22-0]8-bromoisoquinoline</strong> and naphthalene-1-boronic acid by Suzuki coupling [8].
monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In tetrahydrofuran; at 80℃;Inert atmosphere;
To a suspension of <strong>[63927-22-0]8-bromoisoquinoline</strong> (2.Og, 9.7mmol), Q-phos (68mg, 0.096mmol) and Pd(dba)2 (132mg, 0.14mmol) in dry THF (3OmL) was added 4OmL of (2-tert- butoxy-2-oxoethyl)zinc(II) bromide solution under N2 protection. The resulting mixture was heated at 80 0C overnight. The solvent was evaporated under vacuum and the crude residue was diluted with ethyl acetate (10OmL) and washed with water (3 x 5OmL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under vacuum to give a residue which was purified with silica gel chromatography to give tert-butyl 2- (isoquinolin-8-yl)acetate (1.85g, 78percent).
75%
With monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; bis(dibenzylideneacetone)-palladium(0); In tetrahydrofuran; at 80℃;Inert atmosphere;
Preparation of Compound 31-12[004881 To a suspension of <strong>[63927-22-0]8-bromoisoquinoline</strong> (1.5 g, 7.3mmol), Q-phos (52 mg, 0.O73mmol) and Pd(dba)2 (63 mg,0.1 lmmol) in dry THF (30 mL) was added 40 mL of (2-tert-butoxy-2-oxoethyl)zinc(II) bromide solution (20 ml, 0.5 M) under N2. The resulting mixture was heated at 80°C overnight. The solvent was evaporated under vacuum and the crude residue was diluted with ethyl acetate and washed with water. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under vacuum to give a residue which was purified by silica gel chromatography to give tert-butyl 2-(isoquinolin-8-yl)acetate (Compound 31-12, 1.33g, yield 75percent) as a white solid. MS m/z 244[M+1]. ?H NMR (400 MHz, CDC13) 59.46 (s, 1H), 8.56-8.54(d, J= 5.6 Hz 1H), 7.76-7.74 (d, J= 8.0 Hz 1H), 7.66-7.6 1 (m, 2H),7.48-7.47(d, J= 6.8 Hz 1H ),4.07(s,2H), 1.42(s,9H).
The oil was dropped into 5OmL of concentrated H2SO4 and the mixture was heated to 130-140 0C for 30mins, then the reaction mixture was poured into 50OmL if ice-water and adjust to pH~8 with 5N sodium hydroxide solution. The aqueous solution was extracted with DCM (250mLX5) and washed with water (3 x 5OmL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under vacuum. The crude solid was purified with silica gel to give 8- bromoisoquinoline (2.2g, two steps 10.6%).
With potassium phosphate; copper(l) iodide; L-proline; In N,N-dimethyl-formamide; at 150℃; for 16h;
Example No. 58; Preparation of Compound No. 58 [0355] A solution of 2,8-dimethyl-2,3 ,4,5-tetrahydro- lH-pyrido[4,3-b]indole (0.1 g, 0.499 mmol), <strong>[63927-22-0]8-bromoisoquinoline</strong> (0.155 g, 0.748 mmol), potassium phosphate (0.317 g, 1.495 mmol), Cul (9 mg, 0.047 mmol) and L-Proline (11 mg, 0.095 mmol) in dry DMF (3 mL) was heated at 150 °C for 16h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5- (isoquinolin-8-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.8 (d, 1H), 8.62 (d, 1H), 8.42 (bs, 1H), 8.4 (d, 1H), 8.3 (t, 1H), 8.0 (d, 1H), 7.42 (s, 1H), 7.0 (d, 1H), 6.87 (bs, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.16 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).
With potassium phosphate; copper(l) iodide; L-proline; In N,N-dimethyl-formamide; at 150℃; for 16h;
Example No. 58: Preparation of Compound No. 58[0346] A solution of 2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole (0.1 g, 0.499 mmol), <strong>[63927-22-0]8-bromoisoquinoline</strong> (0.155 g, 0.748 mmol), potassium phosphate (0.317 g, 1.495 mmol), Cul (9 mg, 0.047 mmol) and L-Proline (11 mg, 0.095 mmol) in dry DMF (3 mL) was heated at 150 °C for 16h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5- (isoquinolin-8-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indole. 1H NMR (TFA salt, D o ( pm . , H , . , H , . s, H , . , H , eta nu alpha, ), 7.42 (s, 1H), 7.0 (d, 1H), 6.87 (bs, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.16 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 100℃; for 18h;Inert atmosphere;
General procedure: In an argon gas atmosphere, tetrakis(triphenylphosphine)palladium (83 mg) and a 2 M aqueous sodium carbonate solution (2.2 mL) were added to a mixture of <strong>[63927-22-0]8-bromoisoquinoline</strong> (300 mg), 2,4-difluorophenylboronic acid (342 mg), 1,2-dimethoxyethane (10 mL), and ethanol (1 mL), followed by stirring for 18 hours at an oil temperature of 100° C. The reaction liquid was cooled to room temperature, and then water and ethyl acetate were added thereto to perform liquid separation. The organic layer was washed with saturated brine and then dried, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining 8-(2,4-difluorophenyl)isoquinoline (312 mg).
2-(isoquinolin-8-ylamino)acetic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 50 - 110℃;
To a round bottomed flask containing <strong>[63927-22-0]8-bromoisoquinoline</strong> (3g, 14.4 mmol) are addedC52CO3 (13.2 g, 40.4 mmol), glycine ethyl ester hydrochloride (2.21g, 15.9 mmol), BINAP(449 mg, 0.72 mmol) and Pd2(dba)3 (0.397 g, 0.433 mmol) followed by 50 mL toluene. Theresulting brown suspension is allowed to stir at 80C for 2 h, at 50C overnight then at 110Cfor 9 h.After cooling the suspension is filtered over Celite. The celite cake is rinsed three times withEtOAc. The combined organic phase is washed with brine, dried over Na2SO4 and filtered.Evaporation of the solvents in vacuo yields 4.64 g of a brown oil. Flash-chromatography onsilica-gel (Eluent: gradient of heptane I EtOAc 90:10 to 0:100) yields 2.33 g (70%) of the subtitle compound as yellow solid.LC-B: tR = 0.47 mm; [M+H] = 231.2; 1H-NMR (CDCI3) oe: 9.41 (5, 1 H), 8.52 (d, J = 5.7 Hz, 1H), 7.58 (d, J = 5.7 Hz, 1 H), 7.53 (t, J = 7.9 Hz, 1 H), 7.20 (d, J = 8.2 Hz, 1 H), 6.54 (d, J =7.7 Hz, 1 H), 5.49 (5, 1 H), 4.34 (q, J = 7.1 Hz, 2 H), 4.09 (d, J = 4.9 Hz, 2 H), 1.36 (t, J = 7.1Hz, 3H)
8-(N-(2-((2-(dimethylamino)ethyl)(2-(trifluoromethyl)benzyl)amino)-2-oxoethyl)-2,2,2-trifluoroacetamido)-N-meth yl-3,4-dihydroisoquinoline-2(1H)-carboxamide[ No CAS ]
(7R,8aS)-2-(5-((8-(1-(4-fluorophenethyl)-1H-imidazol-5-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)thiazol-2-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol[ No CAS ]
1-[2-(4-fluorophenyl)ethyl]-1H-imidazole[ No CAS ]
[ 63927-22-0 ]
C20H16FN3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100 mg
With palladium diacetate; potassium carbonate; tricyclohexylphosphine; In N,N-dimethyl-formamide; at 130℃; for 14h;
Step A - Preparation of Int Int 65-1 To a solution of Int 3-1 (219 mg, 1.15 mmol) and 3-bromoisoquinoline (200 mg, 0.96 mmol) in DMF (5 mL) was added potassium carbonate (391 mg, 2.88 mmol), TCP (53 mg, 0.19 mmol) and Pd(OAc)2 (21 mg, 0.10 mmol). The mixture was stirred at 130°C for 14 hours. The mixture was cooled and poured into Iota0 (10 mL) and extracted with EtOAc (10 mL x 3), the combined organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated. The crude mixture was and purified by TLC to give Int 65-1 (100 mg). H NMR (CDC13): delta 9.05 (s, 1H), 8.57 (d, J=6.4Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 7.66-7.70 (m, 2H), 7.53 (s, 1H), 7.31 (d, J=6.8Hz, 1H), 6.93-6.95 (m, 1H), 6.77-6.81 (m, 2H), 6.66-6.69 (m, 2H), 4.00 (t, J=7.2Hz, 2H), 2.68 (t, J=7.2Hz, 2H). MS (ESI): m/z (M+H)+ 318.
100 mg
With palladium diacetate; potassium carbonate; tricyclohexylphosphine; In N,N-dimethyl-formamide; at 130℃; for 14h;
Step A - Preparation of Int 65-1 Int 65-1 To a solution of Int 3-1 (219 mg, 1.15 mmol) and 3-bromoisoquinoline (200 mg, 0.96 mmol) in DMF (5 mL) was added potassium carbonate (391 mg, 2.88 mmol), TCP (53 mg, 0.19 mmol) and Pd(OAc)2 (21 mg, 0.10 mmol). The mixture was stirred at 130°C for 14 hours. The mixture was cooled and poured into H20 (10 mL) and extracted with EtOAc (10 mL x 3), the combined organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated. The crude mixture was and purified by TLC to give Int 65-1 (100 mg). 1H NMR (CDC13): delta 9.05 (s, 1H), 8.57 (d, J=6.4Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 7.66-7.70 (m, 2H), 7.53 (s, 1H), 7.31 (d, J=6.8Hz, 1H), 6.93-6.95 (m, 1H), 6.77-6.81 (m, 2H), 6.66-6.69 (m, 2H), 4.00 (t, J=7.2Hz, 2H), 2.68 (t, J=7.2Hz, 2H). MS (ESI): m/z (M+H)+ 318.
8-[(R)-4-(2-imidazo[4,5-b]pyridin-3-yl-acetyl)-3-methyl-piperazin-1-yl]-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester[ No CAS ]
(R)-4-isoquinolin-8-yl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8.15 g
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 90℃; for 3h;Inert atmosphere;
60.1. (R)-4-Isoquinolin-8-yI-2-methyl-piperazine- 1-carboxylic acid tert-butyl ester:To a solution of <strong>[63927-22-0]8-bromoisoquinoline</strong> (5.3g) in toluene (1 20mL) was added successively (R)5 1-N-Boc-2-methylpiperazine (4.84g), tris(dibenzylideneacetone)dipalladium (0) (1.17g), rac2,2-bis(diphenylphosphino)-1 ,1 -binaphthalene (2.38g) and sodium tert-butoxide (3.42g). The reaction mixture was stirred at 90°C under argon for 3h, cooled down and filtered through celite. The plug was washed with EA and the resulting solution was evaporated to dryness. The crude was purified by CC (Biotage, SNAP bOg cartridge, solvent A: Hept;solvent B: EA; gradient in percentB: 15 for 3CV, 15 to 50 over 4CV, 50 for 4CV) to afford 8.1 5g of brown foam. LC-MS (B): tR = 0.70 mm; [M+H]: 328.26.
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