* 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.
With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tert-butyl XPhos In 1,4-dioxane; water at 100℃; for 1.5 h;
AB21-1 (lg, 4.83 mmol) was dissolved in dioxane (5 mL) Adding tris (dibenzylideneacetone) dipalladium (lllmg, 0.19 mmol) and 2-di-tert-butylphosphine 2 ', 4', 6'-triisopropylbiphenyl (82 mg, 0.19 mmol) Then, potassium hydroxide (812 mg, 14.49 mmol) dissolved in 5 mL of water was added and heated to 100 ° C for 1.5 hours. After cooling to room temperature, 2N HCl (20 mL) was added, stirred for 1 hour, concentrated under reduced pressure, extracted with dichloromethane (30 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid (526 mg, 75percent).
With ammonium hydroxide; copper(ll) sulfate pentahydrate In water at 190℃; for 6 h;
Reference Example 1 Synthesis of 6-aminoisoquinoline (Reference Compound 1) 6-bromoisoquinoline that weighed 17.2 g (see WO 2008/077553), 200 mL of 28percent ammonia water and 10.8 g of copper (II) sulfate pentahydrate were put into the autoclave and tightly sealed, and the mixture was then stirred at 190° C. for 6 hours. After cooling to room temperature, the reaction solution was poured into 250 mL of a 10percent aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (100 mL*5). The extract was dried over anhydrous sodium sulfate, filtered, and then concentrated. The obtained crude product was suspended in dichloromethane and then filtered to obtain 10.2 g of the compound of interest as a light brown crystal (85percent). 1H-NMR spectrum (CDCl3, δ ppm): 5.54 (br s, 2H), 6.58 (s, 1H), 7.00 (d, J=9.0 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 8.32 (d, J=5.5 Hz, 1H), 8.98 (s, 1H)
Preparation Example G-1. Isoquinoline-6-carboxylic acid A solution prepared by adding (4-bromobenzylydene)-(2,2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160°C for 2 hours. The reaction solution was gradually cooled to 0°C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2percent) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N,N-dimethylformamide (3.8mL) were added zinc cyanide (431 mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100°C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100°C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83percent) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160°C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 percent) as a yellow solid.
78%
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 90℃; for 24 h; Inert atmosphere
To a suspension of 6-bromoisoquinoline (624 mg, 3.0 mmol) and Pd(PPh3)4 (173 mg, 0.15 mmol) in DMF (6 mL) was added Zn(CN)2 (210 mg, 1.8 mmol), and the reaction mixture was stirred at 90 °C under N2 for 24 h. After cooling to room temperature, H2O (40 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and dried over Na2SO4. After concentration and purification by column chromatography (petroleum ether/ethylacetate = 3:1), 55 was obtained as a white solid (360 mg, 78percent). 1H NMR (400 MHz, CDCl3) d 9.37 (s, 1H), 8.70 (d, J = 5.6 Hz, 1H),8.25 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.73(d, J = 5.6 Hz, 1H).
Reference：
[1] Patent: EP1782811, 2007, A1, . Location in patent: Page/Page column 58
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5861 - 5872
5
[ 34784-05-9 ]
[ 557-21-1 ]
[ 106778-42-1 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 100℃; for 3.5 h;
A solution prepared by adding (4-bromobenzylydene)-(2,2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160°C for 2 hours. The reaction solution was gradually cooled to 0°C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2percent) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N,N-dimethylformamide (3.8mL) were added zinc cyanide (431mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100°C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100°C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83percent) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160°C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 percent) as a yellow solid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2583 - 2586
[2] Journal of the American Chemical Society, 1939, vol. 61, p. 183
[3] Patent: CN106831575, 2017, A,
9
[ 1122-91-4 ]
[ 22483-09-6 ]
[ 34784-05-9 ]
Yield
Reaction Conditions
Operation in experiment
35%
Stage #1: for 12 h; Reflux; Dean-Stark Stage #2: With chloroformic acid ethyl ester In tetrahydrofuran at -10℃; for 0.166667 h;
A mixture of 4-bromobenzaldehyde (300.0 g, 1620.0 mmol) and amino acetaldehyde dimethyl acetal (170.4 g, 1620 mmol) in anhydrous toluene (1.5 L) was refluxed under a Dean-Stark condenser for 12 h. The solution was concentrated under vacuum. The residue was dissolved in anhydrous THF and cooled to -10 °C. Ethyl chloroformate (193.3 ml_, 1782 mmol) was added and stirred for 10 min at -10 °C, and then allowed to warm to room temperature. Subsequently trimethyl phosphite (249.6 ml_, 1782.0 mmol) was added dropwise to the reaction mixture and stirred for 10 h at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in anhydrous DCM (1.5 L) and stirred for 30 minutes. The reaction mixture was cooled to 0 °C, and titanium tetrachloride (1.2 L, 6480 mmol) was added dropwise. The reaction mixture was stirred at 40 °C for 6 days. The reaction mixture was poured into ice and pH was adjusted to 8 - 9 with aqueous 6N NaOH solution. The suspension was extracted three times with EtOAc. The organic layer was extracted with 3 M HCI. The acidic aqueous solution was adjusted to pH to 7 - 8 with 3N NaOH solutions and extracted two times with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the product. Crude compound was dissolved in minimum amount of DCM and mixed with pentane to get compound A1 as light brown solid. Yield: 90 g (35percent). Rf: 0.6 (30percent EtOAc in petroleum ether). LCMS m/z = 209 (M + 1 ). 1H NMR (400 MHz, cf6-DMSO): δ 7.82 (m, 2H), 8.1 1 (d, J = 8.8 Hz, 2H), 8.30 (br s, 1 H), 8.56 (d, J = 6.0 Hz, 1 H), 9.35 (s, 1 H).
14%
Stage #1: at 120℃; Dean-Stark Stage #2: at 160℃; for 0.5 h;
General procedure: Aminoacetaldehyde dimethylacetal (3.0 eq.) was added to a solution of bromobenzaldehyde13b or 13c (1.0 eq.) in toluene (30 mL). Each reaction mixture was refluxed (Dean–Stark apparatus)at 120 °C. After consumption of the starting material, each reaction mixture was concentrated todryness, then dissolved in conc. H2SO4 (2 mL) and added to a cold solution of P2O5 in conc. H2SO4(0.5 mL). Each reaction mixture was heated at 160 °C for 30 min, allowed to cool to RT, neutralizedwith NaOH (10 M), extracted with EtOAc, and concentrated to dryness. Each residue was subjected toFCC to afford 6-bromoisoquinoline (14b, 30 mg, 0.14 mmol, 14percent) and 7-bromoisoquinoline (14c, 99 mg,0.47 mmol, 22percent) [20,21]. Ethylchloroformate (1.0 eq.) was added to a solution of isoquinoline 14b or14c (1.0 eq.) in DCM at 0 °C and stirred at the same temperature for 30 min, followed by additionof 2-trimethylsilylthiazole (1.0 eq.). Each reaction mixture was stirred at RT for 3 h, concentratedto dryness, and each residue was subjected to FCC. Each product was dissolved in benzene (5 mL),o-chloranil (1.0 eq.) was added, and each reaction mixture was refluxed for 5 h. Each reaction mixturewas diluted with 5percent NaOH (10 mL), extracted with DCM, and concentrated to dryness. Each reactionmixture residue was subjected to FCC to afford the products 9b and 9c.6-Bromo-1-(2-thiazolyl)isoquinoline (9b): 6-Bromoisoquinoline (14b, 30 mg, 0.14 mmol) was synthesizedstarting from 4-bromobenzaldehyde (13c, 200 mg, 1.08 mmol) in 14percent yield. Compound 9b wassynthesized starting from 6-bromoisoquinoline (14b, 100 mg, 0.48 mmol) in 15percent yield over two steps(21 mg, 0.07 mmol), obtained as an orange powder, m.p. 103–105 °C.
Reference：
[1] Patent: WO2015/181676, 2015, A1, . Location in patent: Page/Page column 132-133
[2] Dalton Transactions, 2015, vol. 44, # 18, p. 8552 - 8563
[3] Molecules, 2017, vol. 22, # 8,
[4] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 2, p. 437 - 447
10
[ 63927-21-9 ]
[ 34784-05-9 ]
Yield
Reaction Conditions
Operation in experiment
1.2%
With phosphorus pentoxide In sulfuric acid at 160℃; for 2 h;
Preparation Example G-1. Isoquinoline-6-carboxylic acid A solution prepared by adding (4-bromobenzylydene)-(2,2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160°C for 2 hours. The reaction solution was gradually cooled to 0°C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2percent) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N,N-dimethylformamide (3.8mL) were added zinc cyanide (431 mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100°C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100°C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83percent) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160°C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 percent) as a yellow solid.
1.2%
With phosphorus pentoxide In sulfuric acid at 0 - 160℃; for 2 h;
A solution prepared by adding (4-bromobenzylydene)-(2,2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160°C for 2 hours. The reaction solution was gradually cooled to 0°C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2percent) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N,N-dimethylformamide (3.8mL) were added zinc cyanide (431mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100°C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100°C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83percent) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160°C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 percent) as a yellow solid.
Stage #1: With chlorosulfonic acid In dichloromethane at -20 - 45℃; for 10 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; waterCooling with ice
Step 2To a stirred solution of N-(4-bromobenzyl)-2,2-dimethoxyethanamine (10 g, 0.037 mol) in CH2C12 (100 mL) was added C1S03H (21.3 g, 0.18 mol) at -20 °C dropwise. The resulting reaction mixture was allowed to stir at 45 °C for 10 h. The resulting reaction mixture was diluted with CH2C12 and ice cold H20, then neutralized with aqueous NaHC03. The organic layer was separated and aqueous layer extracted with CH2C12. The combined organic layers were dried over Na2S04 and concentrated at reduced pressure to get crude 6- bromoisoquinoline, which was purified by silica gel chromatography eluting with 5-15 percent EtOAc-hexanes to afford 6-bromoisoquinoline (0.9 g, 12 percent) as yellow liquid
Reference：
[1] Patent: EP3192791, 2017, A1,
[2] European Journal of Medicinal Chemistry, 2019, p. 317 - 333
24
[ 34784-05-9 ]
[ 226942-29-6 ]
Yield
Reaction Conditions
Operation in experiment
67.2%
at 10 - 35℃; for 1.5 h;
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
Commercially available 5-bromoindanone (5.1 g, 24.3 mmol) was diluted into methanol (150 mL), cooled to 0 0C, and treated with sodium borohyd?de (1.8 g, 48.6 mmol). The reaction mixture was warmed to room temperature, aged overnight, and then partitioned between water and methylene chloride, the organic phase separated, dried and concentrated in vacuo. The clean crude alcohol (5.0 g, 97%) was isolated and used in the next step without purification. This hydroxybromoindane (5.04 g, 23.6 mmol) was diluted into toluene (100 mL), treated with catalytic p-toluenesulfomc acid (400 mg), and the reaction mixture refluxed under Dean-Stark trap conditions for 6 h. The mixture was cooled to room temperature, extracted with saturated aqueous sodium bicarbonate, and the organic phase separated, d?ed and concentrated in vacuo. The clean crude <strong>[33065-61-1]bromoindene</strong> (4.6 g, 100%) was isolated as an oil and used in the next step without purification. This <strong>[33065-61-1]bromoindene</strong> (4.5 g) was diluted into (1 : 1) methanol-methylene chloride (150 mL), chilled to -78 0C, and treated with ozone for 30 minutes, removed from the ozonator, warmed to room temperature, and treated with solid sodium bicarbonate (2.5 g) and dimethylsulfide (3 mL). The reaction mixture was aged for 14 h, treated with 78% ammonium hydroxide in water (30 mL), and the mixture maintained at room temperature overnight. The reaction mixture was then concentrated in vacuo, re-dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, and the organic phase separated, dried and concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage, SiO2, 20% EtOAc-heptane) to provide the solid bromoisoqumolme. EXAMPLE 59 was prepared from this bromoisoqumohne by first Heck coupling in a similar manner as described in EXAMPLE 53 above and illustrated in Scheme 8. The resultant lsoquinohne acrylamide methyl ester intermediate was saponified with LiOH, and the acid reduced with p-toluenesulfonyl hydrazide, both in a similar manner as described in the examples above to provide the desired product. LCMS m/z 321 (M++ 1)
With anhydrous potassium acetate In 1,4-dioxane at 90℃; for 2h; Inert atmosphere;
3 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline
To a solution of 6-bromoisoquinoline (1.04 g, 5.0 mmol), bis(pinacolato)diboron (2.54 g, 10.0 mmol) and potassium acetate (1.96 g, 20.0 mmol) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (365 mg, 0.5 mmol) in 1,4-dioxane (15.0 mL). The mixture was stirred at 90 °C under nitrogen for 2.0 h and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2/1) to afford 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (0.79 g, 3.1 mmol, 62% yield) as white solid. LC-MS: m/z= 256.0 [M+H]+, retention time 1.41 min (Method B).
62%
With anhydrous potassium acetate In 1,4-dioxane at 90℃; for 2h; Inert atmosphere;
3 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline
To a solution of 6-bromoisoquinoline (1.04 g, 5.0 mmol), bis(pinacolato)diboron (2.54 g, 10.0 mmol) and potassium acetate (1.96 g, 20.0 mmol) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (365 mg, 0.5 mmol) in 1,4-dioxane (15.0 mL). The mixture was stirred at 90 °C under nitrogen for 2.0 h and cooled to room temperature. Ethyl acetate and water were added to the solution, and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2/1) to afford 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (0.79 g, 3.1 mmol, 62% yield) as white solid. LC-MS: m/z= 256.0 [M+H]+, retention time 1.41 min (Method B).
54%
With anhydrous potassium acetate In N,N-dimethyl-formamide at 80℃; for 17h;
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In dimethyl sulfoxide at 160℃; for 0.166667h; Microwave irradiation;
5.6.52.A Part A. 6-(4.4.5.5-Tetramethyi-[1.3.2Jdioxaborolan-2-yll-isoquinoline
A mixture of 6-bromoisoquinoline (208 mg, 1 mmol), bis(pinacolato)diboron (279 mg, 1.1mmol), KOAc (323 mg, 3.3 mmol) and Pd(dppf)2Ci2 (73 mg, 0.1 mmol) in DMSO (3 ml) was heated ina microwave for 10 min at 160°C. The mixture was diluted with water (20 ml) and extracted with10 EtOAc (4 x 20 ml). The combined EtOAc was washed with water (15 ml) and brine (15 ml) then dried(Na2S04). The solvent was removed to give the titled compound which was used directly for nextstep.
270 mg
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In tetrahydrofuran Inert atmosphere; Reflux;
1.6.1 1) Synthesis of Intermediate A6-2:
The A6-1 (210mg, 1.01mmol) was dissolved in tetrahydrofuran (10mL), was added bis (pinacolato) borate (305mg, 1.20mmol), KOAc(294mg, 3.00mmol), Pd (dppf) 2Cl2 (80mg, 0.10mmol), purged with nitrogen, refluxed overnight, cooled to room temperature, suction filtered through Celite,The filtrate was spin-dried, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to give a yellow gummy solid (270mg, 106%).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In 1,4-dioxane at 25 - 90℃; for 17h; Inert atmosphere;
29.A
Step A: Bis(pinacolato)diboron (366 mg, 1.4 mmol) and KOAc (354 mg, 3.6 mmol) were added to a solution of 6-bromoisoquinoline (250 mg, 1.2 mmol) in dioxane (150 mL) at 25°C under the protection of nitrogen gas, followedby adding a catalyst Pd(dppf)Cl2·CH2Cl2 (294 mg, 360 mmol). The mixture was stirred at 25°C for 10 min and thenheated to 90°C with stirring for 17 hours. The mixture was cooled down to 25°C and concentrated under reducedpressure to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (300 mg, a crude product) as a blacksolid, which was used directly in the next step. MS (ESI) M/Z: 274 (M + 1).
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 90℃; for 10h; Inert atmosphere;
Synthesis of Intermediate 18N:
Raw materials 18N-1 (500 mg, 2.40 mmol, 1 eq), bis(pinacolato)diboron (610.27 mg, 2.40 mmol, 1 eq), Pd(dppf)2Cl2 (175.85 mg, 240.32 µmol, 0.1 eq), potassium acetate (471.70 mg, 4.81 mmol, 2 eq) were dissolved in 1,4-dioxane (22 mL), the mixture was heated to 90°C under nitrogen protection and stirred at 90°C for 10 hours. LCMS showed that the raw materials disappeared and detected the MS value of the boric acid corresponding to 18N. The product was judged to be borate according to TLC experience. The reaction was filtered and concentrated to give a crude product of compound 18N. (0124) Relevant characterization data: LCMS m/z: 174.2 [M+H].
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; for 20h;
Synthesis of 6-bromo-2H-isoquinolin-1-one (Intermediate 113) A solution of Intermediate 112 (1.04 g) in methylene chloride (3 ml) was added with a solution of 3-chloroperbenzoic acid (2.16 g) in methylene chloride (10 ml) and stirred for 20 hours.The reaction mixture was added with methylene chloride (200 ml) and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine.The organic layer was dried, and then the solvent was evaporated under reduced pressure.A solution of the residue in acetic anhydride (10 ml) was refluxed by heating for 5 hours.The reaction mixture was concentrated under reduced pressure, and the residue was added with 2.5 N aqueous sodium hydroxide (20 ml) and stirred at 100 C. for 1 hour.The reaction mixture was cooled to room temperature and neutralized with 5 N aqueous hydrochloric acid under ice cooling to obtain the deposited title compound (Intermediate 113, 623 mg).Mass (LCMS): 224 (M+), retention time: 3.16 minutes (elution condition: B). The other abbreviations used in the tables have the same meanings as defined above. The 1H-NMR data of the compounds of Examples 430 to 509 are shown in Table 25.
With copper(l) iodide; potassium iodide In DMF (N,N-dimethyl-formamide) at 130℃; for 3h; Microwave irradiation;
67.A A. Preparation of 6-iodoisoquinoline
Heat a mixture of 6-bromoisoquinoline (Aldrich; 0.320 g, 1.54 mmol), copper (I) iodide (0.155 g, 0.815 mmol), and potassium iodide (1.27 g, 7.96 mmol) inN, N- dimethylformamide (5.0 mL) to 130 C at 3 h under microwave irradiation. Pour the cooled reaction mixture into 4: 1 DICHLOROMETHANE/DIETHYL ether (100 mL) and filter. Wash the filtrate with 5% aqueous sodium bisulfite solution (2 x 50 mL). Dry the organic layer over sodium chloride, decant the organic layer, and remove the solvents under reduced pressure. Dry the residue under vacuum for 18 h to give 0.4 g (100%) of the title compound as a dark red-brown solid. This material is carried on directly to the next step without further purification. MS (electrospray, M/Z) 256.1 (M+1).
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 3.5h;
A solution prepared by adding (4-bromobenzylydene)-(2,2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160C for 2 hours. The reaction solution was gradually cooled to 0C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2%) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N,N-dimethylformamide (3.8mL) were added zinc cyanide (431mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83%) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 %) as a yellow solid.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃; for 10h;Inert atmosphere;
6-bromoisoquinoline (5.0g, 24.0mmol) was dissolved in N, N-dimethylformamide (25mL) and zinc cyanide (1.69g, 14.4mmol) was added. The suspension was degassed under argon bubbling for 10min before Pd(PPh3)4 (1.39g, 1.2mmol) was added. The reaction mixture was heated to 90C for 10h and then diluted with ethyl acetate. The solution was washed brine for three times, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate, v/v, 75:25) to give the title product as white solid (2.79g, 84%). 1H NMR (300MHz, CDCl3) delta 9.36 (s, 1H), 8.69 (d, J=5.7Hz, 1H), 8.24 (s, 1H), 8.10 (d, J=8.6Hz, 1H), 7.74 (dd, J=12.6, 7.1Hz, 2H).
83%
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 3.5h;
Preparation Example G-1. Isoquinoline-6-carboxylic acid A solution prepared by adding (4-bromobenzylydene)-(2,2-diethoxyethyl) amine (synthesized from 4-bromobenzaldehyde, according to the method described in J. Org. Chem., vol. 48, 3344-3346 (1983)) (51.4g, 0.189mmol) to an ice-cold concentrated sulfuric acid (20g) was added to a solution prepared by adding diphosphorus pentoxide (40g) to an ice-cold concentrated sulfuric acid (360g), and the solution was stirred at 160C for 2 hours. The reaction solution was gradually cooled to 0C, the solution was filtered through Celite pad, the filtrate was neutralized with sodium carbonate. This solution was further filtrated through Celite pad, this filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and 6-bromoisoquinoline (482mg, 1.2%) was obtained as an orange oil. Next, to a solution of 6-bromoisoquinoline (382mg, 1.84mmol) in N,N-dimethylformamide (3.8mL) were added zinc cyanide (431 mg, 3.67mmol) and tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) under nitrogen atmosphere, and the mixture was stirred at 100C for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (42mg, 0.0367mmol) was further added, and the mixture was stirred for 2.5 hours at 100C. The reaction mixture was allowed to room temperature, ethyl acetate and water were added for extraction, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane : ethyl acetate), and isoquinoline-6-carbonitrile (234mg, 83%) was obtained as a yellow solid. Lastly, isoquinoline-6-carbonitrile (51mg, 0.331 mmol) was dissolved in diethyleneglycol (1.0mL), potassium hydroxide (9mg, 0.166mmol) was added thereto, followed by stirring at 160C for 3 hours. The reaction mixture was allowed to room temperature, neutralized using hydrochloric acid, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated. Water was added to the residue, the precipitated solid was collected, washed with water, dried in vacuo, so as to obtain the title compound (12mg, 21 %) as a yellow solid.
78%
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere;
To a suspension of 6-bromoisoquinoline (624 mg, 3.0 mmol) and Pd(PPh3)4 (173 mg, 0.15 mmol) in DMF (6 mL) was added Zn(CN)2 (210 mg, 1.8 mmol), and the reaction mixture was stirred at 90 C under N2 for 24 h. After cooling to room temperature, H2O (40 mL) was added and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and dried over Na2SO4. After concentration and purification by column chromatography (petroleum ether/ethylacetate = 3:1), 55 was obtained as a white solid (360 mg, 78%). 1H NMR (400 MHz, CDCl3) d 9.37 (s, 1H), 8.70 (d, J = 5.6 Hz, 1H),8.25 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.73(d, J = 5.6 Hz, 1H).
67.1%
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; Sealed tube;
Add 6-bromoisoquinoline (2 g, 9.61 mmol), zinc cyanide (2.25 g, 19.22 mmol), Pd(PPh3)4 (1.2 g, 1.44 mmol) and DMF (30 mL) to a 100 mL reaction flask at room temperature in. Sealed, replaced with nitrogen three times, heated to 100 C and stirred for 1 hour.After the reaction solution was cooled to room temperature, it was diluted with 100 (mL) ethyl acetate.The organic phase is washed with saturated brine.Dry over anhydrous sodium sulfate, filter, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (eluent: PE:EA/5: 1) Isoquinoline-6-carbonitrile (1.0 g, yellow solid, yield: 67.1%).
With lithium chloride;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃;Microwave irradiation;
To a mixture of lithium chloride (0.295 g, 6.94 mmol) (flame-dried), 6-bromoisoquinoline (0.1805 g, 0.868 mmol), and Pd(PPh3)4 (0.0501 g, 0.0434 mmol) in a microwave reaction vessel, was added a solution of N-(5-(tributylstannyl)thiazol-2-yl)acetamide (0.561 g, 1.30 mmol) in DMF (2.00 mL, 0.868 mmol). The mixture was sealed and heated at 100 C. (oil bath) overnight. After cooling, the mixture (solidified) was diluted with EtOAc and water (2 mL each) and sonicated for 10 minutes. The resulting mixture was filtered, and the solid was washed with water and more EtOAc to provide N-(5-(isoquinolin-6-yl)thiazol-2-yl)acetamide (0.2177 g, 0.808 mmol) as a yellow solid. LCMS (M+H+) 270.3 calc. for C14H12N3OS 270.3; 1H NMR (400 MHz, DMSO-d6) delta ppm 12.32 (br s, 1H), 9.27 (s, 1H), 8.48 (d, J=5.67 Hz, 1H), 8.13-8.15 (m, 3H), 8.06 (d, J=7.20 Hz, 1H), 7.85 (d, J=5.67 Hz, 1H), 2.20 (s, 3H).
With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃;
General Procedure A for the Hartwig-Buchwald amination reaction:1.0 eq of the arylbromide, 1.5 eq Cs2CO3 and 1.2 eq of the amine were dissolved in toluene. If the amine was taken as a salt another equivalent of CS2CO3 was used; if additionally the arylbromide was used as a salt (HCI- or TFA-salt of the isoquinolines), again, 1 additional equivalent of CS2CO3 was used. The solution was degassed and flushed with argon. Then, 0.03 eq Pd(OAc)2 and 0.045 eq BINAP were added and the solution was heated at 100 0C until the reaction was complete or no further improvement could be achieved. For product isolation, the solution was cooled to room temperature, filtered and the filtrate was evaporated. The residue was taken up in H2O and extracted ethyl acetate. The organic layer was separated, dried with MgSO4 and the solvent was removed i. vac. The crude product was purified by preparative HPLC. The following compounds were synthesized following General Procedure A (Table 1):
In 1-methyl-pyrrolidin-2-one; at 150 - 170℃; for 2h;Microwave irradiation;
[00204] Isoquinoline-6-carbonitrile: 6-Bromoisoquinoline (0.876 g, 4.18 mmol) purchased from Gateway Chemical Technology, Inc. was mixed with CuCN (1.12 g, 12.54 mmol) in 5 mL NMP in a microwave heating tube. The tube was heated under microwave to 15O0C for 1 hour and 17O0C for one hour. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. After removing the solvent, the remaining residue was passed through a silica gel plug using 5% 2M ammonia in MeOH in DCM as the eluant. The crude product (100 mg) was used directly in the next step.
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]+.
With copper(l) iodide; In N,N-dimethyl-formamide; at 140℃; for 3h;Inert atmosphere;
500 g of 6-bromoisoquinoline was added 2L of N, N-dimethylformamide, Followed by addition of cuprous cyanide 420 g, Cuprous iodide 80g, Under nitrogen protection, Heated to 140 degrees Celsius, reaction 3h, TLC was monitored until the reaction was complete, after cooling, poured into 1 L of water, filtered, and the filter cake was added in portions to 400 mL of aqueous ammonia and 400 mL of water, But then add too high; then add 0.8L ethyl acetate stirring, the filter, filter cake with EA to the product less, the water phase separation extraction, and then add the filter cake to 400mL ammonia and 400mL water, then add Ethyl acetate after stirring, filter, filter cake products, water phase separation extraction, after the combined ethyl acetate phase, saturated brine washing 2 times, dry suction filter, The solvent was concentrated to give the product of step S1 6-cyanoisoquinoline
Stage #1: 6-bromo-isoquinoline; Triisopropyl borate With n-butyllithium In tetrahydrofuran; hexane at -70 - 20℃; for 1h;
Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃; for 1h;
1.1 (1) Synthesis of XX-1
In a 100mL reaction vessel, 3.75g (18.0mmol) of 6-bromo-isoquinoline and 4.06g (21.6mmol) of triisopropyl borate were mixed in anhydrous tetrahydrofuran (50ml), and the mixture was cooled to- 70 degrees Celsius. Next, n-butyllithium solution: 12.4 ml (about 1.6 M hexane solution, 19.8 mmol) was dropped into the reaction vessel, and the mixture was stirred for 1 hour, and then raised to room temperature. In addition, after adding 15 ml of 5N hydrochloric acid and reacting the mixture at room temperature for 1 hour, the precipitated solid was filtered to obtain XX-1 (1.86 g, yield 49%).
Stage #1: 6-bromo-isoquinoline; Triisopropyl borate With n-butyllithium In tetrahydrofuran at -78℃; for 1.5h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at -20℃;
18'
Isoquinolin-6-ylboronic acid hydrochloride. A flame-dried 100 mL round bottom flask was charged with 10 mL THF, triisopropyl borate (1 g, 5.8 mmol, Aldrich) and 6-bromoisoquinoline (1 g, 4.8 mmol, Astatech). The mixture was cooled to -78°C, and n-butyllithium (3.6 mL, 5.8 mmol, Aldrich) was added dropwise to the reaction over about 1 hour. The mixture was stirred for 0.5 hours at -78°C and then warmed to -200C. After 5.0 mL 2.0 N HCl was added to the reaction mixture, it was concentrated under reduced pressure in a rotary evaporator until a precipitate formed. The white solid (0.6 g) HCl salt of isoquinolin-6-ylboronic acid was recovered by filtration. The product was used directly without further purification. LCMS (API-ES) m/z (%): 174 (100%, M++H).
With sodium t-butanolate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃; for 12h;Inert atmosphere;
Step 1: tert-Butyl 8-(isoquinolin-6-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate Sodium t-butylate (6.24 mmol, 3.0 eq.) was added to a solution of <strong>[336191-17-4]ter<strong>[336191-17-4]t-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate</strong></strong> (2.08 mmol, 1.0 eq.) and 6-bromoisoquinoline (2.08 mmol, 1.0 eq.) in toluene (10 ml) and the reaction mixture was degassed with N2. BINAP (0.124 mmol, 0.06 eq.) and Pd acetate (0.04 mmol, 0.02 eq.) were added and the mixture was heated at 120 C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated on a rotary evaporator. The crude product was purified by means of column chromatography (silica gel, 5% methanol in methylene chloride) in order to obtain the desired product. Yield: 52%
Stage #1: 6-bromo-isoquinoline With N-chloro-succinimide; sulfuric acid at 0 - 50℃; for 12h;
Stage #2: With sodium hydroxide In water Cooling with ice;
43
Example 43: 6-Bromo-5-chloroisoquinoline:6-Bromoisoquinoline (200 mg) was dissolved in concentrated sulfuric acid (2.0 mL), NCS (257 mg) was added to the resultant solution at 0°C and the resultant mixture was stirred at 0°C for one hour. NCS (128 mg) was added to the mixture, the resultant mixture was stirred at 50°C for 5 hours, further NCS (128 mg) was added thereto and the mixture was stirred for 6 hours. The reaction mixture was poured into ice, the pH value of the mixture was adjusted to 14 by the addition of a 10% aqueous sodium hydroxide solution and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resultant residue was purified by the silica gel column chromatography (hexane: ethyl acetate = 2:1) to obtain a desired compound (208 mg) as colorless powder. 1H NMR (CDCl3, 400 MHz): δ 7.78 (1H, d, J = 8.6 Hz), 7.82 (1H, d, J = 8.6 Hz), 8.05 (1H, d, J = 6.1 Hz), 8.68 (1H, d, J = 6.1 Hz), 9.25 (1H, s). EIMS(+):241 [M]+.
With ammonium hydroxide; copper(ll) sulfate pentahydrate; In water; at 190℃; for 6h;
Reference Example 1Synthesis of 6-aminoisoquinoline (Reference Compound 1)6-bromoisoquinoline that weighed 17.2 g (see WO 2008/077553), 200 mL of 28percent ammonia water and 10.8 g of copper (II) sulfate pentahydrate were put into the autoclave and tightly sealed, and the mixture was then stirred at 190° C. for 6 hours.After cooling to room temperature, the reaction solution was poured into 250 mL of a 10percent aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (100 mL*5).The extract was dried over anhydrous sodium sulfate, filtered, and then concentrated.The obtained crude product was suspended in dichloromethane and then filtered to obtain 10.2 g of the compound of interest as a light brown crystal (85percent).1H-NMR spectrum (CDCl3, delta ppm): 5.54 (br s, 2H), 6.58 (s, 1H), 7.00 (d, J=9.0 Hz, 1H), 7.35 (d, J=5.5 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 8.32 (d, J=5.5 Hz, 1H), 8.98 (s, 1H)
isoquinolin-6-yl(2,6,6-trimethylcyclohex-1-enyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: 6-bromo-isoquinoline With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.666667h;
Stage #2: 2,6,6-trimethylcyclohex-1-enecarbaldehyde In tetrahydrofuran; hexane at -78 - 20℃;
1a Example 1a: isoquinolin-6-yl(2,6,6-trimethylcyclohex-1 -enyl)methanol
A solution of 6-bromoisoquinoline (274 mg, 1 .3 mmol) in dry tetrahydrofuran (2 mL) was added dropwise to a solution of n-butyl lithium (1 .6 M in hexane, 0.8 mL, 1 .3 mmol) at -78 °C and stirred at this temperature for 30 minutes. Then 2,6,6-trimethylcyclohex-1 -enecarbaldehyde (100 mg, 0.66 mmol) in dry tetrahydrofuran (1 .5 mL) was added and stirring at -78 °C was continued for 1 hour after which the reaction was allowed to warm slowly to room temperature. The mixture was quenched with saturated aqueous ammonium chloride and the organics extracted extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (131 mg, Yield: 71 %). Rf 0.5 (2: 1 petroleum ether/ethyl acetate); 1 H NMR (400 MHz, CDCI3) δ 9.22 (s, 1 H), 8.50 (d, J = 5.6 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 2 H), 7.65 (d , J - 6.4 Hz, 2 H), 5.55 (s, 1 H), 2.00 (t, J = 6.0 Hz, 2 H), 1 .74-1 .56 (m, 5 H), 1 .33 (s, 3 H), 1 .24 (s, 3 H), 1 .17 (s, 3 H) ppm; Mass spectrum (ESI +ve) m/z 282 (M + H+>.
71%
Stage #1: 6-bromo-isoquinoline With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h;
Stage #2: 2,6,6-trimethylcyclohex-1-enecarbaldehyde In tetrahydrofuran; hexane at -78℃; for 1h;
1.1a Example 1a: isoquinolin-6-yl(2,6,6-trimethylcyclohex-1-enyl)methanol
A solution of 6-bromoisoquinoline (274 mg, 1.3 mmol) in dry tetrahydrofuran (2 mL) was added dropwise to a solution of n-butyl lithium (1.6 M in hexane, 0.8 mL, 1.3 mmol) at -78 °C and stirred at this temperature for 30 minutes. Then 2,6,6-trimethylcyclohex-1-enecarbaldehyde (100 mg, 0.66 mmol) in dry tetrahydrofuran (1.5 mL) was added and stirring at -78 °C was continued for 1 hour after which the reaction was allowed to warm slowly to room temperature. The mixture was quenched with saturated aqueous ammonium chloride and the organics extracted extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (131 mg, Yield: 71%). Rf 0.5 (2:1 petroleum ether/ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1 H), 8.50 (d, J = 5.6 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 6.4 Hz, 2 H), 5.55 (s, 1 H), 2.00 (t, J = 6.0 Hz, 2 H), 1.74-1.56 (m, 5 H), 1.33 (s, 3 H), 1.24 (s, 3 H), 1.17 (s, 3 H) ppm; Mass spectrum (ESI +ve) m/z 282 (M + H+).
6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 95℃; for 12h;Inert atmosphere;
General procedure: Procedure A: To a solution of 5-bromo-2-(4-methoxybenzyl)isoindolin-1-one (1, 0.5 g, 1.5 mmol) in dioxane (10 mL) was added <strong>[271-70-5]7H-<strong>[271-70-5]pyrrolo[2,3-d]pyrimidine</strong></strong> (2, 0.27 g, 2.25 mmol) and potassium tert-butoxide (0.51 g, 4.52 mmol) followed by the addition of XantPhos (0.087 g, 0.15 mmol). The reaction mixture was degassed with argon for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (0.14 g, 0.15 mmol) was then added and the reaction mixture was heated at 90 C. and maintained at that temperature for 12 h. (0193) Following heating, the reaction mixture was cooled and concentrated under reduced pressure. The concentrated reaction mixture was extracted in ethyl acetate. The organic layer was separated, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel (100-200 mesh) column chromatography using 5% methanol in dichloromethane as eluent so as to afford 2-(4-methoxybenzyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)isoindolin-1-one (3). Yield: 0.21 g, 38%;
With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tert-butyl XPhos; In 1,4-dioxane; water; at 100℃; for 1.5h;
AB21-1 (lg, 4.83 mmol) was dissolved in dioxane (5 mL) Adding tris (dibenzylideneacetone) dipalladium (lllmg, 0.19 mmol) and 2-di-tert-butylphosphine 2 ', 4', 6'-triisopropylbiphenyl (82 mg, 0.19 mmol) Then, potassium hydroxide (812 mg, 14.49 mmol) dissolved in 5 mL of water was added and heated to 100 ° C for 1.5 hours. After cooling to room temperature, 2N HCl (20 mL) was added, stirred for 1 hour, concentrated under reduced pressure, extracted with dichloromethane (30 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a pale yellow solid (526 mg, 75percent).
General procedure: Aminoacetaldehyde dimethylacetal (3.0 eq.) was added to a solution of bromobenzaldehyde13b or 13c (1.0 eq.) in toluene (30 mL). Each reaction mixture was refluxed (Dean-Stark apparatus)at 120 C. After consumption of the starting material, each reaction mixture was concentrated todryness, then dissolved in conc. H2SO4 (2 mL) and added to a cold solution of P2O5 in conc. H2SO4(0.5 mL). Each reaction mixture was heated at 160 C for 30 min, allowed to cool to RT, neutralizedwith NaOH (10 M), extracted with EtOAc, and concentrated to dryness. Each residue was subjected toFCC to afford 6-bromoisoquinoline (14b, 30 mg, 0.14 mmol, 14%) and 7-bromoisoquinoline (14c, 99 mg,0.47 mmol, 22%) [20,21]. Ethylchloroformate (1.0 eq.) was added to a solution of isoquinoline 14b or14c (1.0 eq.) in DCM at 0 C and stirred at the same temperature for 30 min, followed by additionof 2-<strong>[79265-30-8]trimethylsilylthiazole</strong> (1.0 eq.). Each reaction mixture was stirred at RT for 3 h, concentratedto dryness, and each residue was subjected to FCC. Each product was dissolved in benzene (5 mL),o-chloranil (1.0 eq.) was added, and each reaction mixture was refluxed for 5 h. Each reaction mixturewas diluted with 5% NaOH (10 mL), extracted with DCM, and concentrated to dryness. Each reactionmixture residue was subjected to FCC to afford the products 9b and 9c.6-Bromo-1-(2-thiazolyl)isoquinoline (9b): 6-Bromoisoquinoline (14b, 30 mg, 0.14 mmol) was synthesizedstarting from 4-bromobenzaldehyde (13c, 200 mg, 1.08 mmol) in 14% yield. Compound 9b wassynthesized starting from 6-bromoisoquinoline (14b, 100 mg, 0.48 mmol) in 15% yield over two steps(21 mg, 0.07 mmol), obtained as an orange powder, m.p. 103-105 C.
6-bromo-2-(4-methoxybutyl)isoquinolin-2-ium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33.3%
In acetonitrile; for 12h;Reflux; Inert atmosphere;
6-Bromoisoquinoline (500mg, 2.4mmol) and 1-bromo-4-methoxybutane (601mg, 3.6mmol) were dissolved in acetonitrile (50mL). The resulting mixture was heated to reflux for 12h under argon atmosphere. After cooling to room temperature, the solvent was evaporated under reduced pressure and the crude residue was chromatographed over silica gel using a mixture of CH2Cl2/ methanol (20/1) to give a yellow solid 6-Bromo-2-(4-methoxybutyl)isoquinolin-2-ium bromide 3 (300mg, 33.3percent yield). 1H NMR (400MHz, DMSO-d6) delta 10.11 (s, 1H), 8.85 (dd, J=6.8, 1.4Hz, 1H), 8.71 (d, J=1.8Hz, 1H), 8.52 (d, J=6.8Hz, 1H), 8.42 (d, J=8.9Hz, 1H), 8.23 (dd, J=8.8, 2.2Hz, 1H), 4.71 (t, J=7.5Hz, 2H), 3.36 (t, overlapped with solvent residual signals, 2H), 3.21 (s, 3H), 2.12?2.01 (m, 2H), 1.62?1.51 (m, 2H). 13C NMR (101MHz, DMSO-d6) delta 150.30, 137.82, 136.05, 134.40, 132.21, 131.46, 129.58, 126.00, 124.85, 71.09, 60.74, 57.89, 27.62, 25.64. HRMS (ESI) (m/z): [M-Br-]+ calcd for [C14H17BrNO]+, 294.0488; found, 294.0484. Compound 3 (200mg, 0.53mmol) was dissolved in water (5mL) and an aqueous solution of ammonium hexafluorophosphate was added until no more precipitate formed. The solid was filtrated and dried in vacuo. Dissolving the solid in dichloromethane (10mL) under anhydrous and Ar conditions at 0°C and a dichloromethane solution (5mL) of BBr3 (1.1mmol) was added dropwise. The reaction mixture was gradually restored to room temperature and stirred for 8h, then water (15mL) was added to hydrolyze the reactant. After that an aqueous solution of ammonium hexafluorophosphate was added and the organic phase was extracted using dichloromethane and evaporated under reduced pressure. The crude residue was dissolved in acetone (5mL) and tetrabutylammonium chloride was added until no more precipitate formed. Finally, the precipitate was chromatographed over silica gel using a mixture of CH2Cl2/methanol (15/1) to give a light yellow solid (80mg, 47.7percent yield). 1H NMR (400MHz, D2O) delta 9.71 (s, 1H), 8.54 (d, J=6.9Hz, 1H), 8.47 (s, 1H), 8.32 (d, J=6.9Hz, 1H), 8.27 (d, J=8.9Hz, 1H), 8.12 (d, J=9.0Hz, 1H), 4.74 (t, J=7.4Hz, 2H), 3.63 (t, J=6.3Hz, 2H), 2.29?2.19 (m, 2H), 1.91?1.81 (m, 2H). 13C NMR (101MHz, D2O) delta 146.49, 135.39, 132.34, 132.17, 129.75, 128.61, 126.89, 123.58, 122.69, 58.70, 57.97, 25.15, 24.47. HRMS (ESI) (m/z): [M-Cl-]+ calcd for [C13H15BrNO]+, 280.0332; found, 280.0329.
With ammonium peroxydisulfate; caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere; Irradiation; Green chemistry; regioselective reaction;
Procedure A for compounds (3a-3p) in Schemes 2
General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
With N-ethyl-N,N-diisopropylamine; In toluene; at 50.0℃; for 3.0h;Inert atmosphere;
General procedure: Dimethylsulfamoyl chloride (34; 0.144 mL, 1.34 mmol) was added to a solution of isoquinoline (5; 157 mg, 1.22 mmol) and <strong>[5526-13-6]1H-indol-7-yl acetate</strong> (33; 213 mg, 1.22 mmol) in toluene (4 mL) at r.t. The mixture was concentrated to a thick but stirrable paste (1.5 mL), which was stirred at 50 C for 3 h. TLC and LCMS showed reaction was largely complete by this time. The mixture was diluted with EtOAc (40 mL), washed with H2O (40 mL) and sat. brine (20 mL), dried (Na2SO4), filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (loading in CH2Cl2) (eluent: gradient 20 to 50% EtOAc in heptane). Fractions containing the desired product were evaporated to afford the title compound 37a (208 mg, 42%) as a white solid
Stage #1: isopropylmagnesium chloride With zinc(II) chloride In tetrahydrofuran at 0℃; for 1.5h; Inert atmosphere;
Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In tetrahydrofuran for 0.25h;
Stage #3: 6-bromo-isoquinoline In tetrahydrofuran for 12h;
1 1. Synthesis of 6-isopropylisoquinoline
Under nitrogen protection, 78.6 g (0.58 mol) of anhydrous zinc chloride was added to the three-necked flask, tetrahydrofuran.800mL,Lower the temperature of the reaction system to 0 ° C,480 mL (0.96 mol) of isopropylmagnesium chloride was added dropwise, and the mixture was stirred for one and a half hours.Then, 3.5 g (1 mol%) of bisphenylphosphinoferrocene palladium dichloride was added and stirred for 15 minutes.Add 6-bromoisoquinoline 100g dropwise(0.48 mmol). The reaction was stopped after 12 hours.The reaction solution was extracted with ethyl acetate and water and dried and evaporated. The crystal obtained by concentration was purified by recrystallization to obtain 61.6 g (yield: 75%).6-isopropylisoquinoline.
(S)-2-chloro-4-(1-(2-(isoquinolin-6-ylamino)propyl)-1H-pyrazol-3-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.9%
With copper(l) iodide; metformin hydrochloride; caesium carbonate In ethanol for 48h; Inert atmosphere; Reflux;
(S)-2-chloro-4-(1-(2-(pyridin-3-ylamino)propyl)-1H-pyrazol-3-yl)benzonitrile (3b)
General procedure: A suspension of the amine 15 (100 mg,0.38 mmol), 3-bromopyridine (91.0 mg, 0.58 mmol), CuI (7.2 mg,0.038 mmol), metformin hydrochloride (12.6 mg, 0.076 mmol),Cs2CO3 (248.0 mg, 0.76 mmol) in EtOH (2.0 mL) was heated toreflux under N2. The reaction mixture was stirred for 48 h. Themixture was cooled to room temperature and diluted with ethylacetate. The solid was removed by filter and then the filtrate wasconcentrated under reduced pressure. The crude product was purifiedby column chromatography using a solvent gradient of 5-10%MeOH in DCM to afford the compound 3b as a yellow solid. Yield:65.0 mg, 50.8%.
80 mg
With metformin hydrochloride; caesium carbonate In ethanol at 80℃;
17 Example 5. Synthesis of Compound SKLB-C 4651 in the Present Invention
General procedure: Intermediate (S)-4-(1-(2-aminopropyl) -1 H-pyrazol-3-yl)-2-chlorobenzonitrile was synthesized using the procedure described in Example 1 (C).Iodobenzene (100 mg, 0.48 mmol), (S)-4-(1-(2-aminopropyl) -1 H-pyrazol-3-yl)-2-chlorobenzonitrile (104.4 mg, 0.4 mmol), cesium carbonate (260.6 mg, 0.8 mmol), metformin hydrochloride (13.2 mg, 0.08 mmol) and ethanol (2 mL) were added to the reaction tube, nitrogen was pumped 3 times, heated to 80°C overnightCold to room temperature, brown. Ethyl acetate was diluted, washed with water, washed with saturated sodium chloride, and purified by column 25% ethyl acetate/petroleum ether via column to give 90 mg of an yellow viscous, ie, SKLB-C 4651
methyl 2-(isoquinolin-6-yl)-2-phenylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
Stage #1: 6-bromo-isoquinoline; 2-phenylpropionic acid methyl ester With bis(dibenzylideneacetone)-palladium(0) In toluene at -78℃; for 0.166667h;
Stage #2: With tri-tert-butyl phosphine In toluene at 20℃; for 16h;
3
To a solution of compound 0038-1 (590 mg, 3.6 mmol) in toluene (10 mL) was added LDA (2.0 M, 2.1 mL, 4.3 mmol) at -78 °C and stirred at this temperature for 10 min. Pd2(dba)3(50 mg) and 0038-2 (500 mg, 2.4 mmol) was added and stirred at this temperature for 10 min, then t-BmP (242 mg, 1.2 mmol) in toluene (10 mL) was added and the resulting reaction mixture was stirred for 16 h at rt. Water was added the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated, the crude was purified by C.C. to give the desired product 0038-3 (130 mg, yield: 18%) as colorless oil.
Stage #1: (vinyl)trimethoxylsilane; 6-bromo-isoquinoline With (1,2-dimethoxyethane)dichloronickel(II); tetrabutylammonium triphenyldifluorosilicate In N,N-dimethyl acetamide Inert atmosphere;
Stage #2: (vinyl)trimethoxylsilane
General procedure (GP3)
General procedure: General procedure (GP3)In a nitrogen-filled glove box, aromatic halide (0.2 mmol, 1.0 eq.), TBAT (270 mg, 0.5 mmol,2.5 eq.), NiCl2(glyme) (4.4 mg, 0.02 mmol, 10 mol%) and DMA (1.0 mL) were charged to an8 mL vial equipped with a magnetic stirrer bar. The vinyltrimethoxysilane (59.1 mg, 0.4 mmol,2.0 eq.) was added. The vial was removed from the glove box, and the reaction mixture wasstirred at 50 for 12 h. The reaction mixture was then diluted with EtOAc and washed withwater. The organic phase was dried over Na2SO4, filtered, and concentrated, and the residuewas purified by column chromatography on silica gel to give the product.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 100℃; for 120h; Inert atmosphere;
Synthesis of 6-(2,6-Diisopropylphenyl)isoquinoline
A suspension of 6-bromoisoquinoline (28.0 g, 135 mmol), (2,6-diisopropylphenyl)boronic acid (29.1 g, 141 mmol), and K2CO3 (55.8 g, 404 mmol) in a mixture of 1,4-dioxane (300 mL) and water (200 mL) was sparged with nitrogen for 20 min. Pd(PPh3)4 (7.78 g, 6.73 mmol) was added and the reaction mixture was stirred at 100° C. for 48 hours. The reaction mixture was cooled to RT, sparged with nitrogen for 10 min, additional Pd(PPh3)4 (7.78 g, 6.73 mmol) was added and the reaction mixture was stirred at 100° C. for 24 h. The reaction mixture was cooled to RT and filtered, sparged with nitrogen for 15 min, additional Pd(PPh3)4 (4.0 g, 4.6 mmol) was added and the reaction mixture was stirred at 100° C. for 48 h. The reaction mixture was cooled to RT and diluted with ice-water (1.0 L) and extracted with EtOAc (3*500 mL). The combined organics were washed with water (500 mL) and brine (500 mL), concentrated onto silica gel and purified by column chromatography in two equal batches (silica gel, 0-20% EtOAc/isohexane) to obtain the desired product as a colourless oil, which solidified on standing (84% yield).
84%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 100℃; for 120h; Inert atmosphere;
Synthesis of 91 6-(2,6-Diisopropylphenyl)isoquinoline
A suspension of 92 6-bromoisoquinoline (28.0 g, 135 mmol), 93 (2,6-diisopropylphenyl)boronic acid (29.1 g, 141 mmol), and K2CO3 (55.8 g, 404 mmol) in a mixture of 94 1,4-dioxane (300 mL) and 95 water (200 mL) was sparged with nitrogen for 20 min. 96 Pd(PPh3)4 (7.78 g, 6.73 mmol) was added and the reaction mixture was stirred at 100° C. for 48 hours. The reaction mixture was cooled to RT, sparged with 97 nitrogen for 10 min, additional Pd(PPh3)4 (7.78 g, 6.73 mmol) was added and the reaction mixture was stirred at 100° C. for 24 hours. The reaction mixture was cooled to RT and filtered, sparged with nitrogen for 15 min, additional Pd(PPh3)4 (4.0 g, 4.6 mmol) was added and the reaction mixture was stirred at 100° C. for 48 hours. The reaction mixture was cooled to room temperature (RT) and diluted with ice-water (1.0 L) and extracted with EtOAc (3×500 mL). The combined organics were washed with water (500 mL) and brine (500 mL), concentrated onto silica gel and purified by column chromatography in two equal batches (silica gel, 0-20% EtOAc/isohexane) to desired product as a colourless oil, which solidified on standing ( 84% yield).
6-(1-(phenylsulfonyl)-1H-indol-3-yl)isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In 1,4-dioxane; water at 60℃; Inert atmosphere;
Stage #1: 6-bromo-isoquinoline; Triisopropyl borate With n-butyllithium In tetrahydrofuran at -78 - -20℃; for 2h;
Stage #2: hydrogenchloride In tetrahydrofuran; water
6-bromo-1-(4,4,4-trifluorobutyl)isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: 6-bromo-isoquinoline With 4-hydroxy-10,13-dimethoxydinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine 4-sulfide; trifluoroacetic acid In dichloromethane at 20℃; for 0.25h; Inert atmosphere; Darkness;
Stage #2: 4,4,4-Trifluorobutan-1-ol In dichloromethane at 27 - 29℃; for 20h; Irradiation;
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